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Encyclopedia of Genetics PDF
Encyclopedia of Genetics PDF
Encyclopedia of Genetics PDF
Genetics
Revised Edition
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Encyclopedia of
Genetics
Revised Edition
Volume 1
Aggression
Hybridization and Introgression
First Printing
v
Encyclopedia of Genetics, Revised Edition
vi
Publishers Note
The award-winning Encyclopedia of Genetics of recent discoveries and developments. Basics
was originally created in 1999 to provide the of biologyfrom the molecular and cellular
general reader with a thorough yet accessible levels through the organismal level, from Men-
overview of one of modern sciences most vital delian principles to the latest on DNA sequenc-
and intriguing fields. This 2004 Revised Edition ing technologyconstitute the core coverage.
adds 64 new overview essays on current topics Medical topics comprise a significant number
to the original entries, reflecting the rapid de- of essays, as the genetic predisposition for
velopments in an exciting and often contro- many illnesses and syndromes has increasingly
versial branch of science that is increasingly come to light. Genetic technologies that prom-
shaping our world. ise a world without hunger, disease, and disabil-
Of the 172 original entries (168 overviews ityand promise to rewrite human values
plus 4 appendices), 7 overviews (Biotechnol- are addressed as well. The encyclopedias scope
ogy, Genetic Medicine, Immune Deficiency embraces the key social and ethical questions
Disorders, Lethal Alleles, Meiosis, Meth- raised by these new genetic frontiers: from
ane-Producing Bacteria, and Sheep Clon- cloning to stem cells to genetically modified
ing) have been dropped because they have foods and organisms.
been superseded by other, updated or new, es- Each essay follows a standard format, includ-
says; 26 have been replaced because they were ing ready-reference top matter and the follow-
so out of date as to demand completely new ing standard features:
coverage (two of these, Aging and Mitosis
and Meiosis, are from other Salem publica- Fields of study lists one or more of a dozen
tions, deemed more up to date than the origi- subdisciplines of genetics or biology under
nal entries); and 131 were moderately to which the topic falls.
heavily revised and updated by the editor as Significance provides a definition and sum-
deemed appropriate. mary of the topics importance.
All essays bibliographies are new or are fully
updated. The four appendices have been up- Key terms, concepts central to the topic, are
dated and two new ones, Web Sites and No- next identified and defined.
bel Prizes for Discoveries in Genetics, have Subheads break the main body of each essay
been added. Featured in this new edition are into clearly marked subtopics.
25 new sidebars, or mini-essays (500 words
each). These sidebars, appearing in shaded The contributors byline lists the biologist or
boxes, offer coverage of particularly significant other area expert who wrote the essay.
and current subtopics appended to the over- The See also section lists cross-references to
view essays. A list displaying the status of the es- other essays of interest.
says, designed to assist librarians in comparing
the two editions, appears at the end of this Further Reading lists sources for further
study with annotations; all of these biograph-
note.
ical sections have been fully updated and
The result, in two volumes, is 223 overviews,
reformatted to include the latest relevant
25 sidebars, and 6 appendices: a 30 percent in-
works and full citation data for easy library
crease based on number of overview essays,
access.
and an increase of more than 40 percent in
overall word length. The set surveys this con- Web Sites of Interest, finally, includes anno-
tinually evolving discipline from a variety of tated entries for the most authoritative free
perspectives, offering historical and technical sites on the Internet, including the sponsor-
background along with a balanced discussion ing organization and URL. This section,
vii
Encyclopedia of Genetics, Revised Edition
which appears in more than half the essays, tance of the Internet to bioinformatics and to
was included for topics (such as diseases and general education in genetics is reflected in the
syndromes) for which authoritative govern- new Web Sites appendix.
ment agencies, professional or academic so- The articles in the Encyclopedia of Genetics, Re-
cieties, or support organizations were avail- vised Edition are arranged alphabetically by ti-
able, with only the occasional nod to a tle; an alphabetical list of contents appears at
particularly useful personal URL. All sites the beginning of each volume. To help readers
were accessed by the editors in August, 2003. locate topics of interest by area of study, a Cate-
gory Index, a Personages Index, and a com-
A series of appendices supplements the prehensive Subject Index are included at the
overview essays: An updated Time Line of Ma- end of volume 2. Nearly 100 diagrams, charts,
jor Developments in Genetics offers a chrono- graphs, drawings, and tables elucidate com-
logical overview of the fields development. plex concepts, and more than one hundred
Nobel Prizes for Discoveries in Genetics lists photographs illustrate the text.
Nobel Prize winners (all prizes) whose contri- We wish to thank the many biologists and
butions altered the history of genetics. An up- other scholars who contributed both to the
dated Biographical Dictionary of Important original edition and this revised edition; their
Geneticists has more than doubled in size, now names and academic affiliations appear in the
including all Nobel laureates whose discoveries Contributor List that follows. Special credit is
in genetics garnered them the award, as well as due the editor of the Revised Edition, Dr. Bryan
numerous others. The updated Glossary pro- D. Ness of the Department of Biology, Pacific
vides definitions of more than 500 commonly Union College. Professor Ness paid close at-
used terms and important concepts. The up- tention to the contents of every essay, carefully
dated general Bibliography references impor- updating all of the original text, elucidating
tant works in each field of study, joining with in- complex concepts for the general reader, and
dividual articles Further Reading sections to making valuable contributions to the project
offer plentiful citations to recently published on all levels.
sources for additional reasearch. The impor-
viii
Preface to the Revised Edition
In the five years since publication of the first late and are analyzed, medicine will certainly
edition of Encyclopedia of Genetics, the field of become a more exact science, enabling therapy
genetics has continued to expand, if possible, to be tailored to a persons genotype.
exponentially. The volume of data flowing from As spinoffs of the Human Genome Project,
genetics research is so great that new methods the genomes of many model organisms have
of organizing and analyzing it are still being also been sequenced, a process that has been
devised. As with any expanding field, practical accelerated by the development of technolo-
applications have lagged behind predictions. gies such as the polymerase chain reaction and
The Human Genome Project, now completed, automated sequencers. Only a handful of small
which was predicted to usher in a new era in genomes had been sequenced at the time the
medical genetics, has so far had only minor ef- first edition of Encyclopedia of Genetics was pub-
fects, and the many genetically modified (GM) lished five years ago; today, hundreds of ge-
crops that were supposed to revolutionize agri- nomes have been sequenced, including some
culture have caused more controversy than suc- larger genomes such as those of Arabidopsis thal-
cess. Yet, like most technologies of the past that iana (the model mustard plant), Drosophila me-
took time to gain acceptance, the knowledge lanogaster (the fruit fly), and Caenorhabditis ele-
and technologies flowing from the Human Ge- gans (the model round worm). Many other
nome Project will almost certainly gain influ- genome sequencing projects are under way,
ence and acceptance over the next decades. and as more genomes are sequenced, geneti-
The slow and steady application of these tech- cists will obtain ever clearer insights into how
nologies will eventually have a world-changing our genes make us who we arenot to mention
impact on all aspects of life. how our genomes relate to those of other or-
The current revised edition is an attempt to ganisms (the focus of comparative genomics)
increase the coverage begun in the first edition and hence how such organisms can be manipu-
and to cover as many of the new developments lated genetically to our benefit.
in genetics as possible, a daunting task consid- Since the cloning of Dolly the sheep in 1996,
ering that new discoveries seem to happen a variety of other mammals have been cloned,
weekly. By way of perspective, consider what including mice and, most recently, a horse.
has occurred in the field of genetics in the past This brave new world of cloning has spawned
five years. The Human Genome Project, proba- the imaginations of filmmakers and writers as
bly the most widely publicized genetic project surely as space exploration did in earlier gener-
of the past century, saw the completion of the ationsfueling wild speculations about the pos-
human genome sequence two years ahead of its sibility of reviving ancient life-forms, such as the
original scheduleappropriately, fifty years af- dinosaurs of Michael Crichton and Stephen
ter the discovery by James Watson and Francis Spielbergs Jurassic Park (1993), and, more re-
Crick of the double-helical structure of DNA. cently, claims of human cloning that are plausi-
The field of genomicsthe study of the se- ble if not probable, though fraught with both
quence and structure of the genomes of vari- technical and ethical obstacles. Shortly after
ous organismshas now solidly entered the Dolly was cloned, for example, it was discov-
public consciousness and has spawned the re- ered that her telomeres (the ends of her chro-
lated specialty proteomics, the study of the pro- mosomes) were shorter than normal for a juve-
teins expressed by genomes, which focuses on nile sheep. Telomeres are known to shorten
differences among cell types as well as differ- throughout the life spans of many organisms
ences between gene expression in health and and have been implicated as part of the cause,
disease. Although these studies have not yet or at least one of the effects, of aging. With her
transformed medicine, as more data accumu- shortened telomeres, the big question was, how
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Encyclopedia of Genetics, Revised Edition
would it affect her longevity? In February of cell lines and on alternatives such as the less
2003 the answer came when Dolly had to be controversial adult source of stem cells.
euthanized because she was suffering signifi- Regardless of the eventual decisions regard-
cantly from a form of arthritis usually seen only ing human cloning and research using fetal
in older sheep, as well as advanced lung disease. stem cells, the ethical questions raised by both
Her early decline, at six years of age, cast doubt endeavors clearly run parallel. With the end-
on the hoped-for success of cloning mammals. less potential uses of such technologies, where
Of course, the cloning of Dolly fueled in- might they lead? Where does the necessity to
creased speculation about the feasibility of hu- solve human suffering end and the brave new
man cloning. Considering Dollys premature world of self-proliferation, designer traits,
death and other health issues, most geneticists worker and military subclasses, perfect prog-
do not consider the technology ready for hu- eny, and potential ecological disaster begin?
man cloning. Ethically, human cloning, indeed What obligations do we have to fulfill the new
organismal cloning of all types, is extremely promise of genetic science to alleviate human
controversialwith myriad implications eco- suffering, and what obligations do we have to
nomically, socially, politically, and ecologically limit that promise out of concern for greater
(as human manipulation supplants traditional detriment?
methods of natural selection as a force in evolu- This last consideration is now a very real con-
tion)but it is even more so when the high cern. GM crop plants were once considered the
probability of producing a debilitated human Holy Grail of agricultural genetics, seen as a so-
clone is considered. lution to everything from more effectively bat-
Along with the budding debate over cloning tling pests and weeds to correcting Third
is another, related issue that arose simulta- World nutritional deficiencies and utilizing
neously at the beginning of the new millen- marginal habitats such as saline soil. Much of
nium: the use of fetal stem cells in research. the early headiness surrounding the potential
Some geneticists believe that stem cells of high-yield and transgenic crops has dissi-
totipotent cells, capable of differentiating pated and opposition has increased against the
into essentially any other kind of cellmay use of such plants. Objections range from fears
have potential for treating a variety of neuro- over human health and safety to ecological and
logical diseases such as Alzheimers and Parkin- economic concerns. Most Europeans have re-
sons, as well as conditions requiring new or- jected GM foods completely, and even consum-
gans that might be generated by implanting ers in the United States are uncomfortable us-
stem cells with the genetic instructions to de- ing themor at least feel that it is their right to
velop into ears or kidneys that could be grown be informed, through labeling, before making
on animals especially designated for this pur- purchase decisions. If the many concerns ex-
pose. Unfortunately, the best stem cells come pressed by consumers cannot be addressed,
from developing fetuses, and the ethics of har- GM crops may not be embraced widely for
vesting fetal stem cells from aborted fetuses is some time, if ever.
hotly debated. The much-touted potential of With these advances, and many others not
using adult stem cells instead is clouded by mentioned, the general public has become
both political and social agendas and the fact overwhelmed with the implications. Although
that they have not yet proven to be nearly as ver- the terms are casually thrown around in the me-
satile or easy to culture as fetal stem cells. In the dia and strident statements are made, the gen-
United States, research on fetal stem cells has eral public has become increasingly uncomfort-
been limited to a small number of cell lines ex- able with a technology they barely understand.
isting at the time that the federal government As a result, opposition from many directions
addressed the issue in 2001; it was determined continues to build, epitomized by both the fed-
to withhold funding from any research group eral ban on stem cell research mentioned above
that harvests fetal stem cells as a part of their and the Human Cloning Prohibition Act that is
work. Research continues on the limited stem now making its way through Congress.
x
Preface to the Revised Edition
Especially with regard to GM foods, many ge- general Bibliography; and a select list of genet-
neticists consider the root problem to be lack ics Web sites aimed at students and nonspecial-
of knowledge about genetics on the part of ists. In addition, every essay carries a Further
nonscientists. Although terms such as DNA, Reading section that has been thoroughly re-
cloning, GM food, and gene therapy have viewed, updated, and annotatedto which we
entered the public vocabulary, many people have added more than 400 new books and arti-
gain their understanding of these technologies cles published since the first edition. In recog-
from the science fiction of books, film, and tele- nition of the influence of the Internet on stu-
vision rather than from the science on which dent research, we for the first time include, in
they are founded. Those who are opposed to more than half the essays, a section headed
genetic technology have taken advantage of Web Sites of Interest targeted at the essays
this safety-first attitude and have spread fear topic. Finally, every effort has been made to
about genetic technology, coining inflamma- make the essays user-friendly, easy to read, and
tory terms like Franken foods and citing the clear, with the goal of improving the presenta-
law of unintended consequences. Conse- tion and understandability of all the old, as well
quently, many nonscientists misunderstand the as the new, essays.
issues and mistrust the scientists doing the Even as this edition goes to press, it is already
work, picturing them as ambitious and amoral beginning to go out of date. Genetics is a dy-
rather than as responsible researchers. Part of namic field that deserves close attention as we
the problem lies with geneticists themselves, begin the new millennium. Nevertheless, the
many of whom find it difficult to communicate basic scientific principles presented here will
with nonscientists. Geneticists need to learn to provide science students with insight into the
communicate in a way that the general public topics on which they can build, and that funda-
will understand. Without a broad understand- mental understanding will repay students and
ing by the general public, genetics will con- general readers regardless of their ultimate oc-
tinue to be viewed by many in a negative light. cupations or career interests. Such an under-
It is in this spirit that the current volumes standing behooves all of us: The potential of ge-
were updated and expanded. The articles con- netic principles to completely alter the way we
tained herein are written specifically with the live and interact with the environment is pro-
nonscientist in mindand specifically to ex- found. We will see changes in the way doctors
plain, as simply as possible, some of the science diagnose and treat disease, new GM crops and
behind the technologies and issues described animals, powerful new forensics techniques,
above. All original topics were considered for and unique ways to solve environmental and so-
updating, many were heavily revised, 26 were cietal problems. There are potential dangers as
entirely replaced, and 64 are entirely new. In well, and these must be carefully analyzed and
other cases, recent advances put a spotlight on vetted in the public forum. As we attempt to
topicssuch as Bioinformatics, Biological navigate our genetic future, knowledge will be
Weapons, Smallpox, and Xenotransplants essential if we are to take full advantage of the
that were too minor or obscure to have been in- positive benefits, and prevent the negative con-
cluded in the previous edition. sequences, of genetic technology. It is hoped
Other improvements in this edition include that the information contained here will open
the addition of 25 sidebars, elucidating par- a new world of understanding to the nonspe-
ticularly important and timely subtopics; a new cialist and encourage further exploration of
time line of Nobel laureates whose work in ge- the amazing world of genetics, which offers
netics garnered them the award; a Biographi- frontiers for exploration just as real as those of
cal Dictionary of Important Geneticists that is space or oceanic explorationand in many
twice its original size; more than 100 new defi- ways more personal and tangible.
nitions added to the Glossary; an updated Bryan D. Ness
Time Line of Major Developments in Genet- August, 2003
ics; a heavily expanded and re-categorized
xi
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Preface to the First Edition
The science of genetics, once the purview of transmission genetics, including single and
only of serious students and professionals, has multifactorial inheritance, chromosome map-
in recent decades come of age and entered the ping, linkage and recombination, sex linkage,
mainstream of modern life. An unparalleled ex- mutagenesis, and chromosomal aberrations,
plosion of new discoveries, powerful new mo- were first investigated by Morgan and his stu-
lecular techniques, and practical applications dents.
of theories and research findings has brought The subdisciplines of bacterial and molecu-
genetics and its related disciplines to the fore- lar genetics had their beginnings in the 1940s,
front of public consciousness. The successful when bacteria and their viruses became fa-
cloning of Dolly the sheep has sparked wide- vored genetic systems for research because of
spread public interest and debate and raised their relative simplicity and the ease with which
new questions about the ethics of this and they could be grown and manipulated in the
other genetic technologies. Gene therapy has laboratory. In particular, the common intesti-
made the transition from science fiction to re- nal bacterium Escherichia coli was studied in-
ality and is used to treat serious diseases, and tensely, and today far more is known about
there is increasing demand for the newest the biology of this single-celled organism than
health professionals, genetic counselors, at hos- about any other living system. In 1952, James
pitals and medical centers around the world. As Watson and Francis Crick provided the molec-
we celebrate the new millennium, it is perhaps ular model for the chemical structure of DNA,
worth noting that the young science of genetics the genetic material, and the next twenty years
celebrates its one hundredth birthday. saw great progress in the understanding of the
Among many other events of historical im- molecular nature of essential cellular processes
portance, the year 1900 marked the rediscov- such as DNA replication, protein synthesis, and
ery of the Austrian monk Gregor Mendels ex- the control of bacterial gene expression.
perimental work on the inheritance of traits in The 1970s witnessed the discovery of a
the garden pea. Mendel had published his re- unique class of enzymes known as restriction
sults thirty-four years earlier, but his work at- endonucleases, which set the stage for the de-
tracted little attention and soon faded into ob- velopment of the exciting new technology
scurity. By the close of the nineteenth century, known by various names as cloning, genetic en-
however, much had happened on the scientific gineering, or recombinant DNA technology.
front. Chromosomes had been discovered, and Since that time, research has progressed rap-
the cellular processes of mitosis and meiosis idly on several fronts, with the development of
had been observed under the microscope. The genetic solutions to many practical problems in
physical bases for understanding Mendels prin- the fields of medicine, agriculture, plant and
ciples of inheritance had been established, and animal breeding, and environmental biology.
the great significance of his pioneering work With the help of the new technology, many of
could finally be appreciated. The so-called chro- the essential questions in cell and molecular bi-
mosome theory of heredity was born, and the ology that were first addressed in bacteria and vi-
age of transmission genetics had arrived. ruses in the 1950s and 1960s can now be effec-
The first great geneticist to emerge (and tively studied in practically any organism.
some would still call him the greatest of the And what are the major problems remaining
twentieth century) was Thomas Hunt Morgan, to be solved? No doubt there are many, some of
who established his fly laboratory at Colum- which cannot even be articulated given the
bia University and began studying the princi- present state of scientific understanding. Two
ples of transmission genetics, using the fruit fly important questions, however, are drawing dis-
as a model organism. All the major principles proportionate shares of attention in the cur-
xiii
Encyclopedia of Genetics, Revised Edition
rent sphere of basic research. One of these is individual cell cycle or during the developmen-
the problem variously referred to as the sec- tal cycle of an organism? How is gene expres-
ond genetic code or protein folding. Scien- sion controlled differentiallythat is, how are
tists know how a particular molecule of DNA, different sets of genes turned on or off in dif-
with a known sequence of nucleotide subunits, ferent tissues in the same organism at the same
can cause the production of a particular unique time? Many human genetic diseases are now
protein composed of a known sequence of known or suspected to be caused by errors in
amino acid subunits. What is not understood, gene expressionthat is, too much or too little
however, is the process by which that protein of a particular protein is made in the critical tis-
will spontaneously fold into a characteristic sues at the critical developmental timesso
three-dimensional shape in which each amino the answers to these and related questions are
acid interacts with other amino acids to pro- sure to suggest new possibilities for gene ther-
duce a functional protein that has the proper apy or other treatments.
pockets, ridges, holes, protuberances, and other The purpose of these reference volumes is
features that it needs in order to be biologically twofold. First, the editors seek to highlight some
active. If all the rules for protein folding were of the most exciting new advances and applica-
known, it would be possible to program a com- tions of genetic research, particularly in the
puter to create an instant three-dimensional fields of human medical genetics and agricul-
picture of the protein resulting from any given ture. Second, we hope to provide a solid basis
sequence of amino acids. Such knowledge for understanding the fundamental principles
would have great applications, both for under- of genetics as they have been developed over
standing the mechanisms of action of known this first one hundred years, along with an ap-
proteins and for designing new drugs for thera- preciation of the historical context in which
peutic or industrial use. the most important discoveries were made. It is
The second big question at the forefront our hope that such an understanding and ap-
of experimental genetic inquiry relates to the preciation might help to inspire a new genera-
control of gene expression in humans and tion of geneticists who will continue to expand
other higher organisms. In other words, what the boundaries of scientific knowledge well
factors come into play in turning on or turning into the next millennium.
off genes at the proper times, either during an Jeffrey A. Knight
xiv
Contributor List
Barbara J. Abraham Fred Buchstein Daniel J. Fairbanks
Hampton University John Carroll University Brigham Young University
xv
Encyclopedia of Genetics, Revised Edition
xvi
Contributor List
xvii
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Alphabetical List of Contents
Volume 1
Aggression . . . . . . . . . . . . . . . . . . 1 Central Dogma of Molecular
Aging . . . . . . . . . . . . . . . . . . . . . 3 Biology . . . . . . . . . . . . . . . . . 128
Albinism . . . . . . . . . . . . . . . . . . . 9 Chemical Mutagens . . . . . . . . . . . . 131
Alcoholism. . . . . . . . . . . . . . . . . . 11 Chloroplast Genes . . . . . . . . . . . . . 133
Allergies . . . . . . . . . . . . . . . . . . . 13 Cholera . . . . . . . . . . . . . . . . . . . 137
Altruism . . . . . . . . . . . . . . . . . . . 16 Chromatin Packaging . . . . . . . . . . . 140
Alzheimers Disease . . . . . . . . . . . . . 19 Chromosome Mutation . . . . . . . . . . 144
Amniocentesis and Chorionic Chromosome Structure . . . . . . . . . . 147
Villus Sampling. . . . . . . . . . . . . . 23 Chromosome Theory of Heredity . . . . 152
Ancient DNA . . . . . . . . . . . . . . . . 27 Chromosome Walking and
Animal Cloning . . . . . . . . . . . . . . . 31 Jumping . . . . . . . . . . . . . . . . . 158
Anthrax . . . . . . . . . . . . . . . . . . . 35 Classical Transmission Genetics. . . . . . 160
Antibodies . . . . . . . . . . . . . . . . . . 38 Cloning. . . . . . . . . . . . . . . . . . . 166
Antisense RNA . . . . . . . . . . . . . . . 42 Cloning: Ethical Issues . . . . . . . . . . 170
Archaea . . . . . . . . . . . . . . . . . . . 45 Cloning Vectors . . . . . . . . . . . . . . 174
Artificial Selection . . . . . . . . . . . . . 48 Color Blindness . . . . . . . . . . . . . . 179
Autoimmune Disorders . . . . . . . . . . . 51 Complementation Testing. . . . . . . . . 181
Complete Dominance . . . . . . . . . . . 184
Bacterial Genetics and Cell Congenital Defects. . . . . . . . . . . . . 187
Structure . . . . . . . . . . . . . . . . . 54 Consanguinity and Genetic Disease . . . 191
Bacterial Resistance and Super Criminality . . . . . . . . . . . . . . . . . 193
Bacteria . . . . . . . . . . . . . . . . . . 61 Cystic Fibrosis . . . . . . . . . . . . . . . 195
Behavior . . . . . . . . . . . . . . . . . . . 65 Cytokinesis . . . . . . . . . . . . . . . . . 198
Biochemical Mutations . . . . . . . . . . . 70
Bioethics . . . . . . . . . . . . . . . . . . . 73 Developmental Genetics . . . . . . . . . 201
Biofertilizers . . . . . . . . . . . . . . . . . 77 Diabetes . . . . . . . . . . . . . . . . . . 207
Bioinformatics. . . . . . . . . . . . . . . . 79 Dihybrid Inheritance . . . . . . . . . . . 210
Biological Clocks . . . . . . . . . . . . . . 83 Diphtheria . . . . . . . . . . . . . . . . . 214
Biological Determinism. . . . . . . . . . . 86 DNA Fingerprinting . . . . . . . . . . . . 216
Biological Weapons . . . . . . . . . . . . . 88 DNA Isolation . . . . . . . . . . . . . . . 220
Biopesticides . . . . . . . . . . . . . . . . 92 DNA Repair . . . . . . . . . . . . . . . . 223
Biopharmaceuticals . . . . . . . . . . . . . 96 DNA Replication. . . . . . . . . . . . . . 227
Blotting: Southern, Northern, DNA Sequencing Technology. . . . . . . 233
and Western . . . . . . . . . . . . . . . 98 DNA Structure and Function . . . . . . . 237
Breast Cancer . . . . . . . . . . . . . . . 101 Down Syndrome . . . . . . . . . . . . . . 244
Burkitts Lymphoma . . . . . . . . . . . . 106 Dwarfism . . . . . . . . . . . . . . . . . . 248
xix
Encyclopedia of Genetics, Revised Edition
Volume 2
Hybridomas and Monoclonal Lactose Intolerance . . . . . . . . . . . . 484
Antibodies . . . . . . . . . . . . . . . . 441 Lamarckianism. . . . . . . . . . . . . . . 485
Hypercholesterolemia . . . . . . . . . . . 445 Lateral Gene Transfer . . . . . . . . . . . 489
Linkage Maps . . . . . . . . . . . . . . . 491
Icelandic Genetic Database . . . . . . . . 447
Immunogenetics . . . . . . . . . . . . . . 449 Mendelian Genetics . . . . . . . . . . . . 494
In Vitro Fertilization and Embryo Metafemales . . . . . . . . . . . . . . . . 499
Transfer . . . . . . . . . . . . . . . . . 454 Miscegenation and
Inborn Errors of Metabolism . . . . . . . 458 Antimiscegenation Laws . . . . . . . . 501
Inbreeding and Assortative Mating . . . . 461 Mitochondrial Diseases . . . . . . . . . . 503
Incomplete Dominance . . . . . . . . . . 465 Mitochondrial Genes . . . . . . . . . . . 505
Infertility . . . . . . . . . . . . . . . . . . 468 Mitosis and Meiosis . . . . . . . . . . . . 509
Insurance. . . . . . . . . . . . . . . . . . 471 Model Organism:
Intelligence . . . . . . . . . . . . . . . . 474 Arabidopsis thaliana . . . . . . . . . . . 513
Model Organism:
Klinefelter Syndrome . . . . . . . . . . . 479 Caenorhabditis elegans . . . . . . . . . . 516
Knockout Genetics and Knockout Model Organism:
Mice . . . . . . . . . . . . . . . . . . . 481 Chlamydomonas reinhardtii . . . . . . . . 520
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Alphabetical List of Contents
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Encyclopedia of Genetics, Revised Edition
Appendices
Biographical Dictionary of Bibliography . . . . . . . . . . . . . . . . 832
Important Geneticists. . . . . . . . . . 767 Web Sites . . . . . . . . . . . . . . . . . . 859
Nobel Prizes for Discoveries in
Genetics . . . . . . . . . . . . . . . . . 780 Indexes
Time Line of Major Developments Category Index . . . . . . . . . . . . . . . III
in Genetics . . . . . . . . . . . . . . . 784 Personages Index. . . . . . . . . . . . . . VII
Glossary . . . . . . . . . . . . . . . . . . 804 Subject Index . . . . . . . . . . . . . . . . XI
xxii
Encyclopedia of
Genetics
Revised Edition
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Aggression The earliest evidence for a genetic contribu-
Field of study: Human genetics and social tion to these complex behaviors comes from
issues twin and adoptee studies. Genes also increase
Significance: Aggression refers to behavior directed the liability for many clinical conditions that in-
toward causing harm to others. Aggressive anti- clude aggressive behaviors, such as conduct dis-
social behavior is highly heritable, and antisocial order (physically aggressive acts such as bully-
behavior (ASB) during childhood is a good pre- ing or forced sexual activity) and antisocial
dictor of ASB in adulthood and crime. Physical acts personality disorder (persistent violation of so-
of aggression are sometimes distinguished from the cial norms, including criminal behavior) and
more context-sensitive covert ASBs, including for personality traits that often accompany ag-
theft, truancy, and negative peer interactions. gression, such as impulsivity and irritability.
Differences in measuring ASBs partly account
Key terms for the variability in heritability estimates, which
antisocial behavior (ASB): behavior that vi- range from 7 to 81 percent, but many studies
olates rules or conventions of society and/or indicate a heritability for genetic influences of
personal rights 0.40-0.50, a minor influence of shared environ-
impulsivity: a tendency to act quickly without ment, and a much more significant influence of
planning or a clear goal in mind nonshared environment (environment unique
irritability: a tendency to overreact to minor to the individual).
stimuli; short-temperedness or volatility
liability: the risk of exhibiting a behavior; the Aggression and Human Development
higher ones score for a measure of liability, Aggressive behavior develops in children
the greater is ones the risk of exhibiting the through a complex interaction of many envi-
behavior ronmental and biological factors. Also increas-
serotonin: a neurotransmitter, 5-hydroxytryp- ing liability for aggression and perhaps crimi-
tamine (5-HT), present in blood platelets, nality are such factors as low socioeconomic
the gastrointestinal tract, and certain re- status and parental psychopathology. A consis-
gions of the brain, which plays role in initiat- tent finding is that the measure of the activity of
ing sleep, blood clotting, and stimulating the central nervous systems serotonin corre-
the heartbeat, and levels of which have been lates inversely with levels of lifetime aggression,
correlated with aggressive behavior as well as tendency to physically assault, irritability, and
depression and panic disorder impulsivity. Some of the implicated genes regu-
late serotonin synthesis, release, and reuptake
Aggression and Related Behaviors as well as metabolism and receptor activation,
Aggression or agonistic behavior in animals and vary from individual to individual. Seroto-
is usually an adaptive response to specific envi- nergic dysfunction is also noted in alcoholism
ronmental situations during competition for with aggression and in suicide attempters and
resources, as in establishing dominance and a completers. Brain injuries can also exacerbate
territory or in sexual competition. Rat and mice tendencies to exhibit ASBs.
studies indicate it is partly genetic, because se- Some aggression, however, is a normal part
lective breeding produces strains that differ in of development. Thus, Terrie Moffitt and col-
levels of aggression. Human aggression can leagues distinguish between adolescent-limited
also represent a variety of natural responses to aggressiontimes when most adolescents are
challenging situations. Measures of aggression rebelling against adult authorityand life-
vary, but of greatest concern are antisocial be- course persistent ASB, which likely reflects
haviors (ASBs) such as crime and delinquency neuropsychological deficits and specific tem-
and whether some individuals are more likely peraments that are often exacerbated in un-
to engage in these behaviors than others. supportive family settings. Genetic factors play
2 Aggression
vision the telomeres get shorter. When the Alzheimers disease is located on chromosome
telomeres get to a certain critical length, DNA 21, possibly accounting for the common symp-
replication seems to no longer be possible, and toms.
the cell enters senescence. Although the pro- Werners syndrome is a very rare autosomal
cess discussed above is fairly consistent with recessive disease. The primary symptoms are
most studies, the mechanism whereby a cell severe atherosclerosis and a high incidence of
knows it has reached the limit is unknown. cancer, including some unusual sarcomas and
A result of these genetic changes in aging hu- connective tissue cancers. Other degenerative
mans is that illnesses of all kinds are more com- changes include premature graying, muscle at-
mon, partly because the immune system seems rophy, osteoporosis, cataracts, and calcification
to function more slowly and less efficiently with of heart valves and soft tissues. Death, usually by
age. Other diseases, like cancer, are a direct re- atherosclerosis, often occurs by fifty or sixty
sult of the relentless accumulation of mutations. years of age. The gene responsible for Werners
Cancers generally develop after a series of mu- syndrome has been isolated and encodes a
tations or chromosomal rearrangements have DNA helicase (called WRN DNA helicase), an
occurred that cause the mutation of or inappro- enzyme that is involved in helping DNA strands
priate expression of proto-oncogenes. Proto- to separate during the process of replication.
oncogenes are normal genes that are involved The faulty enzyme is believed to cause the pro-
in regulating the cell cycle and often are respon- cess of replication to stall at the replication
sible for moving the cell forward toward mitosis fork, the place where DNA replication is ac-
(cell division). Mutations in proto-oncogenes tively taking place, which leads to a higher-
transform them into oncogenes (cancer genes), than-normal mutation rate in the DNA, al-
which results in uncontrolled cell division, though more work is needed to be sure of its
along with the other traits displayed by cancer mechanism.
cells. Hutchinson-Gilford progeria shows even
more rapid and pronounced premature aging.
Progeroid Syndromes as Models of Aging Effects begin even in early childhood with bald-
Several progeroid syndromes have been ing, loss of subcutaneous fat, and skin wrin-
studied closely in hopes of finding clues to the kling, especially noticeable in the facial features.
underlying genetic mechanisms of aging. Al- Later, bone loss and atherosclerosis appear,
though such studies are useful, they are limited and most affected individuals die before the
in the sense that they display only some of the age of twenty-five. The genetic inheritance pat-
characteristics of aging. Also, because they are tern for Hutchinson-Gilford progeria is still de-
typically due to a single mutant gene, they rep- bated, but evidence suggests it may be due to a
resent a gross simplification of the aging pro- very rare autosomal dominant gene, which may
cess. Recent genetic analyses have identified represent a defect in a DNA repair system.
the specific genetic defects for some of the Cockayne syndrome, another very rare auto-
progeroid syndromes, but often this has only somal recessive defect, displays loss of subcuta-
led to more questions. neous fat, skin photosensitivity (especially to ul-
Down syndrome is the most common traviolet, or UV, light), and neurodegeneration.
progeroid syndrome and is usually caused by Age of death can vary but seems to center
possession of an extra copy of chromosome 21 around forty years of age. The specific genetic
(also called trisomy 21). Affected individuals defect is known and involves the action of a few
display rapid aging for a number of traits such different proteins. At the molecular level, the
as atherosclerosis and cataracts, although the major problems all relate to some aspect of
severity of the effects varies greatly. The most transcription, the making of messenger RNA
notable progeroid symptom is the development (mRNA) from the DNA template, which can
of Alzheimers disease-like changes in the brain also affect some aspects of DNA repair.
such as senile plaques and neurofibrillary tan- Another, somewhat less rare, autosomal re-
gles. One of the genes sometimes involved in cessive defect is ataxia telangiectasia. It displays
Aging 5
In April, 2003, fifteen-year-old John Tacket announced the discovery of a gene that causes the disease he suffers from, progeria, a
syndrome that accelerates aging. (AP/Wide World Photos)
a whole suite of premature aging symptoms, discovered, they will likely also be involved with
including neurodegeneration, immunodefi- DNA or the cell cycle in some way. Based on
ciency, graying, skin wrinkling, and cancers, es- many of the common symptoms of aging, these
pecially leukemias and lymphomas. Death usu- findings are not too surprising.
ally occurs between forty and fifty years of age.
The specific defect is known to be loss of a pro- Genetic Models of Aging
tein kinase, an enzyme that normally adds phos- The increasing understanding of molecular
phate groups to other proteins. In this case, the genetics has prompted biologists to propose a
kinase appears to be involved in regulating the number of models of aging. Each of the models
cell cycle, and its loss causes shortening of is consistent with some aspect of cellular genet-
telomeres and defects in the repair of double- ics, but none of the models, as yet, is consistent
stranded breaks in DNA. One of the proteins with all evidence. Some biologists have sug-
it appears to normally phosphorylate is p53, a gested that a combination of several models
tumor-suppressor gene whose loss is often asso- may be required to adequately explain the pro-
ciated with various forms of cancer. cess of aging. In many ways, understanding of
Although the genes involved in the various the genetic causes of aging is in its infancy, and
progeroid syndromes are varied, they do seem geneticists are still unable to agree on even the
to fall into some common functional types. probable number of genes involved in aging.
Most have something to do with DNA replica- Even the extent to which genes control aging at
tion, transcription, or repair. Other genes are all has been debated. Early studies based on
involved in control of some part of the cell cy- correlations between time of death of parents
cle. Although many other genes remain to be and offspring or on the age of death of twins
6 Aging
suggested that genes accounted for 40 to 70 for cell death at old age. The existence of a cel-
percent of the heritability of longevity. More re- lular clock is consistent with the discovery that
cent research on twins has suggested that genes telomeres shorten as cells age.
may only account for 35 percent or less of the In spite of the consistency of the experimen-
observed variability in longevity, and for twins tal evidence, this model fails on theoretical
reared apart the genetic effects appear to be grounds. Programmed senescence, like any
even less. complex biological process, would be required
Genetic theories of aging can be classified to have evolved by natural selection, but natu-
as either genome-based or mutation-based. Ge- ral selection can only act on traits that are ex-
nome-based theories include the classic idea that pressed during the reproductive years. Because
longevity is programmed, as well as some evolu- senescence happens after the reproductive
tion-based theories such as antagonistic pleio- years, it cannot have developed by natural se-
tropy, first proposed by George C. Williams, lection. In addition, even if natural selection
and the disposable soma theory. Mutation- could have been involved, what advantage
based theories are based on the simple concept would programmed senescence have for a spe-
that genetic systems gradually fall apart from cies?
wear and tear. The differences among muta- Because of the hurdles presented by natural
tion-based theories generally involve the causes selection, the preferred alternative genome-
of the mutations and the particular genetic sys- based theory is called antagonistic pleiotropy.
tems involved. Even though genome-based and Genes that increase the chances of survival be-
mutation-based theories seem to be distinct, fore and during the reproductive years are det-
there is actually some overlap. For example, rimental in the postreproductive years. Because
the antagonistic pleiotropy theory (a genome- natural selection has no effect on genes after
based theory) predicts that selection will weed reproduction, these detrimental effects are not
out lethal mutations whose effects are felt dur- weeded out of the population. There is some
ing the reproductive years, but that later in life physiological support for this in that sex hor-
lethal mutations will accumulate (a mutation- mones, which are required for reproduction
based theory) because selection has no effect earlier in life, cause negative effects later in life,
after the reproductive years. such as osteoporosis in women and increased
cancer risks in both sexes.
Genome-Based Theories of Aging The disposable soma theory is similar but is
The oldest genome-based theory of aging, based on a broader physiological base. It has
sometimes called programmed senescence, sug- been noted that there is a strong negative corre-
gested that life span is genetically determined. lation among a broad range of species between
In other words, cells (and by extrapolation, the metabolic rate and longevity. In general, the
entire organism) live for a genetically predeter- higher the average metabolic rate, the shorter
mined length of time. The passing of time is lived the species. In addition, the need to re-
measured by some kind of cellular clock and produce usually results in a higher metabolic
when the predetermined time is reached, cells rate during the reproductive years than in later
go into a self-destruct sequence that eventually years. The price for this high early metabolic
causes the death of the organism. Evidence for rate is that systems burn out sooner. This the-
this model comes from the discovery that ani- ory is not entirely genome-based, but also has a
mal cells, when grown in culture, are only able mutation-based component. Data on mutation
to divide a limited number of times, the so- rates seem to show a high correlation between
called Hayflick limit discussed above, and then high metabolic rate and high mutation rates.
they senesce and eventually die. Further evi- One of the by-products of metabolism is the
dence comes from developmental studies where production of free oxygen radicals, single oxy-
it has been discovered that some cells die spon- gen atoms with an unpaired electron. These
taneously in a process called apoptosis. A pro- free radicals are highly reactive and not only
cess similar to apoptosis could be responsible cause destruction of proteins and other mole-
Aging 7
cules, but also cause mutations in DNA. So the velop skin cancer very easily, which typically
high metabolic rate during the reproductive leads to death.
years causes a high incidence of damaging DNA The major flaw in this theory is that it pre-
mutations which lead to many of the diseases of dicts that senescence should be a random pro-
old age. After reproduction, natural selection cess, which it is not. A related theory called er-
no longer has use for the body, so it gradually ror catastrophe also predicts that mutations
falls apart as the mutations build up. Unfortu- will build up over time, eventually leading to
nately, all attempts so far to assay the extent of death, but it suffers from the same flaw. Elderly
the mutations produced have led to the conclu- individuals do seem to possess greater amounts
sion that not enough mutations exist to be the of abnormal proteins, but that does not mean
sole cause of the changes observed in aging. that these must be the ultimate cause of death.
The free radical theory of aging is more
Mutation-Based Theories of Aging promising and is probably one of the most fa-
The basic premise of all the mutation-based miliar theories to the general public. This the-
theories of aging is that the buildup of muta- ory has also received much more attention
tions eventually leads to senescence and death, from researchers. The primary culprit in this
the ultimate cause being cancer or the break- theory is free oxygen radicals, which are highly
down of a critical system. The major support for reactive and cause damage to proteins, DNA,
these kinds of theories comes from a number of and RNA. Free radicals are a natural by-product
recent studies that have found a larger number of many cellular reactions and most specifically
of genetic mutations in elderly individuals than of the reactions involved in respiration. In fact,
in younger individuals, the same pattern being the higher the metabolic rate, the more free
observed even when the same individual is as- radicals will likely be produced. Although this
sayed at different ages. The differences among theory also involves a random process, it is a
the various mutation-based theories have to do more consistent and predictable process, and
with what causes the mutations and what kinds through time it can potentially build on itself,
of DNA are primarily affected. As mentioned causing accelerated DNA damage with greater
above, the disposable soma theory also relies, age.
in part, on mutation-based theories. Significant attention has focused on mito-
The most general mutation-based theory is chondrial DNA (mtDNA). Because free radi-
the somatic mutation/DNA damage theory, cals are produced in greater abundance in res-
which relies on background radiation and other piration, which takes place primarily in the
mutagens in the environment as the cause of mitochondria, mtDNA should show more mu-
mutations. Over time, the buildup of these mu- tations than nuclear DNA. In addition, as DNA
tations begins to cause failure of critical bio- damage occurs, the biochemical pathways in-
chemical pathways and eventually causes death. volved in respiration should become less effi-
This theory is consistent with experimental evi- cient, which would theoretically lead to even
dence from the irradiation of laboratory ani- greater numbers of free radicals being pro-
mals. Irradiation causes DNA damage, which, if duced, which would, in turn, cause more dam-
not repaired, leads to mutations. The higher age. This kind of positive feedback cycle would
the dose of radiation, the more mutations re- eventually reach a point where the cells could
sult. It has also been noted that there is some not produce enough energy to meet their needs
correlation between the efficiency of DNA re- and they would senesce. Assays of mtDNA have
pair and life span. Further support comes from shown a greater number of mutations in the el-
observations of individuals with more serious derly, and it is a well-known phenomenon that
DNA repair deficiencies, such as those affected mitochondria are less efficient in the elderly.
by xeroderma pigmentosum. Individuals with Muscle weakness is one of the symptoms of
xeroderma pigmentosum have almost no abil- these changes.
ity to repair the type of DNA damage caused by The free radical theory has some appeal, in
exposure to UV light, and as a result they de- the sense that ingestion of increased amounts
8 Aging
of antioxidants in the diet would be expected Insurance; Mitochondrial Genes; Mutation and
to reduce the number of free radicals and thus Mutagenesis; Oncogenes; Stem Cells; Telo-
potentially delay aging. Although antioxidants meres; Tumor-Suppressor Genes.
have been used in this way for some time, no
significant increase in life span has been ob- Further Reading
served, although it does appear that cancer in- Arking, Robert, ed. Biology of Aging: Observations
cidence may be reduced. and Principles. 2d ed. Sunderland, Mass.:
Sinauer, 2001. A revised edition of a 1990
From Theory to Practice text that examines such topics as defining
Many of the genetic theories of aging are in- and measuring aging, changes in popula-
triguing and even seem to be consistent with tions, genetic determinants of longevity, and
experimental evidence from many sources, but aging as an intracellular process.
none of them adequately addresses longevity Austad, Steven N. Why We Age: What Science Is
at the organismal level. Although telomeres Discovering About the Bodys Journey Throughout
shorten with age in individual cells, cells con- Life. New York: John Wiley & Sons, 1997. A
tinue to divide into old age, and humans do not review of the latest biological research and
seem to die because all, or most, of their cells theories of aging, including an assessment of
are no longer able to divide. Cells from older the oldest attainable age for humans.
individuals do have more mutations than cells Hekimi, Siegfried, ed. The Molecular Genetics of
from younger individuals, but the number of Aging. New York: Springer, 2000. Part of the
mutations observed does not seem adequate to Results and Problems in Cell Differentiation
account for the large suite of problems present series. Illustrated.
in old age. Mitochondria, on average, do func- Macieira-Coelho, Alvaro. Biology of Aging. New
tion more poorly in older individuals and their York: Springer, 2002. A solid text that in-
mtDNA does display a larger number of mu- cludes many figures, tables, charts, and illus-
tations, but many mitochondria remain high trations.
functioning and appear to be adequate to sus- Manuck, Stephen B., et al., eds. Behavior, Health,
tain life. and Aging. Mahwah, N.J.: Lawrence Erlbaum,
Essentially, geneticists have opened a crack 2000. Examines a host of health care dilem-
in the door to a better understanding of the mas associated with the elderly. One section
causes of aging, and the theories presented considers the basic tenets of genetic and mo-
here are probably correct in part, but much lecular biology, including some of the meth-
more research is needed to sharpen the under- ods of looking at heritable differences in
standing of this process. The hope of geneti- health and well-being. Illustrated.
cists, and of society in general, is to learn how Medina, John J. The Clock of Ages: Why We Age,
to increase longevity. Presently, it seems all that How We AgeWinding Back the Clock. New
is possible is to help a larger number of peo- York: Cambridge University Press, 1996. A
ple approach the practical limit of 120 years book written especially for the general
through lifestyle modification and medical in- reader. Covers aging on a system-by-system
tervention. Going significantly beyond 120 basis and includes a large section on the ge-
years is probably a genetic problem that will not netics of aging.
be solved for some time. Ricklefs, Robert E., and Caleb E. Finch. Aging:
Bryan Ness A Natural History. New York: W. H. Freeman,
See also: Alzheimers Disease; Autoimmune 1995. A good general introduction to the bi-
Disorders; Biochemical Mutations; Biological ology of aging by two biologists who special-
Clocks; Biological Determinism; Cancer; Chem- ize in aging research.
ical Mutagens; Developmental Genetics; Diabe- Rusting, Ricki L. Why Do We Age? Scientific
tes; DNA Repair; Genetic Engineering: Medical American 267 (December, 1992). Summa-
Applications; Heart Disease; Human Genetics; rizes the changes that occur with aging and
Human Growth Hormone; Immunogenetics; the roles of oxidants and free radicals.
Albinism 9
Timiras, Paola S. Physiological Basis of Aging and humans are susceptible to sunburns and skin can-
Geriatrics. 3d ed. Boca Raton, Fla.: CRC Press, cer, while albino animals lack the ability to adjust
2003. Divided into three main sections, this to environments in which nonalbino animals
text addresses the basic processes of bioger- thrive.
ontology, surveys the aging of body systems,
and provides a synopsis of pharmacologic, Key terms
nutritional, and physical exercise guidelines melanism: the opposite of albinism, a condi-
for preserving physical and mental health tion that leads to the overproduction of mel-
into senescence. Illustrated with numerous anin
tables and graphs. photophobia: a condition, often observed in
Toussaint, Olivier, et al., eds. Molecular and Cel- albinos, in which sunlight is painful to the
lular Gerontology. New York: New York Acad- eyes
emy of Sciences, 2000. Elucidates the molec- piebaldism: a condition involving the patchy
ular mechanisms of aging. absence of skin pigment seen in partial albi-
Yu, Byung Pal, ed. Free Radicals in Aging. Boca nos
Raton, Fla.: CRC Press, 1993. An in-depth
discussion of the importance of free radicals Occurrence and Symptoms
in aging. Tyrosine, an amino acid, is normally con-
verted by the body to a variety of pigments
Web Sites of Interest called melanins, which give an organism its
Alliance for Aging Research. http://www.aging characteristic colors in areas such as the skin,
research.org. Provides information on ge- hair, and eyes. Albinism results when the body
netics and the aging process, including how is unable to produce melanin because of de-
the Human Genome Project will affect the fects in the metabolism of tyrosine. Those with
future of health and health care. albinism can be divided into two subgroups:
American Geriatrics Society. http://www tyrosinase-negative (those who lack the enzyme
.americangeriatrics.org. The national soci- tyrosinase) and tyrosinase-positive (those in
ety for health care providers for older per- whom tyrosinase is present but inactive). The
sons, posting information on genetic screen- most serious case is that of complete albinism
ing for such disorders as Alzheimers disease. or tyrosinase-negative oculocutaneous albinism,
Centagenetix. http://www.centagenetix.com. in which there is a total absence of pigment.
This groups mission is to support better un- People with this condition have white hair, col-
derstanding of the aging process and asso- orless skin, red irises, and serious vision defects.
ciated diseases; the site offers a scientific The red irises are caused by the lack of pig-
overview, media center, and information on mentation in the retina and subsequent light
related careers. reflection from the blood present in the retina.
National Institue on Aging. http://www.nia.nih These people also display rapid eye movements
.gov. Supports research programs on the bi- (nystagmus) and suffer from photophobia, de-
ology and genetics of aging, as well as infor- creased visual acuity, and, in the long run, func-
mation on aging for the public. tional blindness. People with this disorder sun-
burn easily, since their skin does not tan. Partial
albinos have a condition known as piebaldism,
characterized by the patchy absence of skin pig-
Albinism ment in places such as the hair, the forehead,
the elbows, and the knees.
Field of study: Diseases and syndromes Several complex diseases are associated with
Significance: Albinismthe absence of pigment albinism. Waardenberg syndrome is identified
such as melanin in eyes, skin, hair, scales, or feath- by the presence of a white forelock (a lock of
ersis a direct result of decreased or nonexistent hair that grows on the forehead) or the absence
pigmentation of the skin, hair, and eyes. Albino of pigment in one or both irises, Chediak-
10 Albinism
duced by the use of sun protection factor (SPF) mentary disorders in humans and oculocutan-
sunscreens and by covering the skin with cloth- eous albinism (OCA)-1 in Japan. Piebaldism,
ing. Since albinism is basically an inherited Waardenburg syndrome, Hermansky-Pudlak
condition, genetic counseling is of great value syndrome, and tyrosinase gene-related OCA-1
to individuals with a family history of albinism. are closely examined.
Soraya Ghayourmanesh Witkop, C. J., Jr. Clinical Dermatology 7 (1989).
See also: Biochemical Mutations; Complete Includes an overview of albinism.
Dominance; Dihybrid Inheritance; Inborn Er-
rors of Metabolism; Monohybrid Inheritance. Web Sites of Interest
International Albinism Center, University of
Further Reading Minnesota. http://www.cbc.umn.edu/iac.
Gahl, William A., et al. Genetic Defects and Run by a team of research professionals with
Clinical Characteristics of Patients with a a variety of specialities in human albinism
Form of Oculocutaneous Albinism (Herman- clinical genetics, molecular biology, ophthal-
sky-Pudlak Syndrome). New England Jour- mology, dermatology, and biochemistry
nal of Medicine 338, no. 18 (April 30, 1998): who are attempting to understand the cause
125. Discusses several aspects of Hermansky- and effect of albinism and other forms of
Pudlak syndrome. Details the diagnosis of pigment loss. Papers, fact sheets, glossary,
this syndrome in forty-nine patients of Puerto other resources. Links to the Albinism Data-
Rican descent and patients from the main- base, which lists mutations associated with al-
land United States. Two charts. binism.
Gershoni-Baruch, R., et al. Journal of the Ameri- National Organization for Albinism and Hypo-
can Academy of Dermatology 24 (1991). De- pigmentation. http://www.albinism.org. A
scribes the hair bulb tyrosinase test. volunteer organization for albinos and for
King, R. A., V. J. Hearing, D. J. Creel, and W. S. those who care for people with albinism,
Oetting. Albinism. In The Metabolic and Mo- providing resources for self-help and pro-
lecular Basis of Inherited Disease, edited by C. R. moting research and education.
Scriver et al. New York: McGraw-Hill, 1995. A
solid introduction and overview of albinism.
Pollier, Pascale. Journal of Audiovisual Media in
Medicine 24, no. 3 (September, 2001): 127. Alcoholism
Examines the medical, biological, and ge-
netic causes of albinism and provides notes Field of study: Diseases and syndromes
from the authors attendance at a confer- Significance: Alcohol is one of the most widely con-
ence of the Albinism Fellowship. sumed substances of abuse worldwide. Because al-
Scriver, Charles, et al., eds. The Metabolic and cohol dependence can be life-threatening, its poten-
Molecular Bases of Inherited Disease. 8th ed. tial genetic basis is of great interest, and a variety
4 vols. New York: McGraw-Hill, 2001. These of genes have been found linked to its physiologic
authoritative volumes on genetic inheri- markers and to the diagnosis of alcohol depen-
tance, by some of the biggest names in the dence.
field, survey all aspects of genetic disease.
The eighth edition has been thoroughly up- Key terms
dated; more than half of the contents are alcohol dependence: a medical diagnosis
new. given when there is repeated use of alcohol
Tomita, Yasuchi. Molecular Bases of Congeni- over the course of at least a year, despite the
tal Hypopigmentary Disorders in Humans presence of negative consequences, such as
and Oculocutaneous Albinism 1 in Japan. tolerance, withdrawal, uncontrolled use, un-
Pigment Cell Research 13, no. 5 (October, successful efforts to quit, considerable time
2000): 130. Presents a study that identified spent getting or using the drug, and a de-
the molecular bases of congenital hypopig- crease in other important activities
12 Alcoholism
cirrhosis: a disease of the liver, marked by the such as depression, may also be linked to how
development of scar tissue that interferes this disorder may be inherited. It may be that
with organ functioning, that can result from the heritability of depression and alcohol have
chronic alcohol consumption something in common, that there are differ-
fetal alcohol syndrome: a medical condi- ences in heritability by gender, or perhaps that
tion resulting from alcohol use by a mother symptom expression by clients or recognition
while pregnant, usually evidenced by facial by professionals varies by gender as a result of
abnormalities and mental impairments in other factors. Stigma, for instance, may be rele-
the child and sometimes resulting in fetal vant; historically, women with alcohol problems
death have often been misdiagnosed with depression.
Symptom expression of alcohol problems
Defining Alcoholism may also differ by culture and ethnicity, be-
Alcoholism is a word that is used to convey cause people of different cultures vary in terms
that a person is experiencing serious problems of how they express physical and mental ail-
related to the use of alcohol. The technical diag- ments. Different ethnic and racial groups may
nosis of alcohol dependence with physiological have different biological responses to thera-
dependence is the diagnosis that corresponds peutic drugs and drugs such as alcohol. Some
to the notion of alcoholism. That diagnosis, groups may even enjoy greater protection
formally explained in the Diagnostic and Statisti- against alcoholism as a result of their genetics.
cal Manual of Mental Disorders: DSM-IV-TR, or Asians, for example, tend to be unable to toler-
DSM (rev. 4th ed., 2000), issued by the Ameri- ate alcohol because they generally lack an en-
can Psychiatric Association, refers to physical zyme to process it out of the body. In contrast,
and psychological reliance on alcohol, despite there may be differential vulnerability to al-
the presence of problems associated with its use. coholism itself, as well as differential vulnera-
Alcohol-related problems are typically stud- bilities to certain types of organ damage related
ied and tracked by epidemiologists, physicians, to alcoholism. For instance, vulnerability to
psychologists, public health professionals, and cirrhosis, cardiomyopathy, pancreatitis, and
basic scientists. Basic scientists tend to observe Wernicke-Korsakoffs syndrome also might be
the heritability of problem acquisition and ex- heritable and may vary by ethnicity. Latino
pression in lab animals, while the other profes- men, for example, tend to show greater suscep-
sionals tend to track the problem in humans via tibility to alcohol-related liver damage than do
clinical observations and research involving re- white men.
ports of family histories or the review of medi- There is also the issue of early alcohol expo-
cal records. sure and how such early exposure can interact
Due to changes in how the DSM has devel- with genetics to cause problems in develop-
oped its problem definitions over time, re- ment. Fetal alcohol syndrome, for example,
searchers must use care to examine how defini- can result in a childs having mild to severe fa-
tions of alcoholism have changed over time. cial and dental abnormalities, mental impair-
Also, the social stigma associated with alcohol- ments, or problems related to the skeletal and
ism may have caused over- and underrecog- the cardiovascular systems. Problems with vi-
nition of the problem in some groups. For sion, hearing, and attention are also common.
instance, more men are recognized to have alco- Children of alcoholic fathers also can have dif-
holism than women. Alcoholism is also known ficulties in learning, language, and tempera-
to have its strongest genetic findings for men of ment. Causes of such problems are multiple,
alcoholic fathers. However, only about 50 per- including the contributions made by the indi-
cent of male cases are explained by genetics; viduals genes as well as the environmental ef-
thus, there is also a strong environmental com- fects of growing up in a home that may be un-
ponent to this problem. stable as a result of problems in the father. In
Regarding women, however, recent evidence sum, parents who drink may increase the likeli-
suggests that a family history of mood disorders, hood that their children will develop alcohol-
Allergies 13
ism both through genes and through nonge- thor, 2000. This American professional man-
netic environmental circumstances. ual describes all major psychiatric disorders.
There is a chapter devoted to substance use
Alcohol Research disorders.
To date, some important physiological Plomin, Robert, and Gerald E. McClearn, eds.
markers linked to alcoholism have included Nature, Nurture, and Psychology. Washington,
event-related potentials (ERPs) in electroen- D.C.: American Psychological Association,
cephalographic performance (EEGs), frontal 1993. The topic of alcoholism is discussed,
lobe functioning, enzymes responsible for he- among other topics, with an emphasis on
patic alcohol metabolism (such as alcohol comparing the roles of genetics versus social
dehydrogenase and aldehyde dehydrogenase), processes and the environment.
and inhibitor y receptors such as gamma-
aminiobutyric acid (GABA) receptors. There Web Site of Interest
are a variety of genes linked to such physiologic National Institute on Alcohol Abuse and Alco-
markers and to the diagnosis of alcohol depen- holism, ETOH. http://etoh.niaaa.nih.gov.
dence, including ADH2*2, ADH3*1, ALDH2*2, ETOH is the chemical abbreviation for ethyl
CYP 2EI, GABRA6, GABRA1, COMT, DRD4, alcohol. This site includes reports related to
DRD2, and D2. alcohol dependence, including epidemiol-
ogy, etiology, prevention, policy, and treat-
Future Directions ment.
The presence of alcohol in modern life may
have genetic roots. Historically, it helped those
who could tolerate its taste and effects to sur-
vive and be selected for when others who could Allergies
not do so perished as a result of consuming
contaminated water. Alcohol has a complex re- Field of study: Immunogenetics
lationship to human life, and alcoholism will be Significance: In economically developed countries,
studied for some time. Continued study of the allergies are responsible for a large portion of ill-
genes associated with different patterns of alco- nesses and medical expenses. Many allergies have
hol problems, protective genetic effects in pop- genetic components and thus tend to run in
ulations with exceptionally low rates of alcohol- families; the identification of such hereditary fac-
ism, and genetically based interventions (such tors can help in diagnosis and in family plan-
as matching pharmacotherapies to different ning. Moreover, research into the causes of aller-
populations of individuals to forestall the de- gies may lead to a more precise understanding of
velopment of the problem) are assured. The how the immune system functions. This may lead
study of genetics and alcoholism is also likely to ultimately to the development of better drugs to
encourage growth in the field of ethnopharma- treat allergies.
cology, the study of how different therapeutic
drugs differentially affect members of specific Key terms
ethnic groups. antibody: a protein made by the body in re-
Nancy A. Piotrowski sponse to an antigen; antibodies or immu-
See also: Aggression; Behavior; Congenital noglobulins are specific for each antigen
Defects; Criminality; Eugenics; Genetic Testing: antigen: any substance that, when injected
Ethical and Economic Issues; Heriditary Dis- into the body, causes antibody formation
eases; Thalidomide and Other Teratogens. that reacts specifically to that substance; also
known as an allergen or an immunogen
Further Reading hypersensitivity: an exaggerated response
American Psychiatric Association. Diagnostic and of the immune system to an antigen beyond
Statistical Manual of Mental Disorders: DSM- what is considered normal; a synonym for
IV-TR. Rev. 4th ed. Washington, D.C.: Au- allergy
14 Allergies
immune system: the defense mechanism of the cal substances (such as histamines, prostaglan-
body against foreign matter (bacteria, vi- dins, and leukotrienes) that are responsible for
ruses, and parasites); it is composed of dif- many of the common allergic symptoms. The
ferent types of cells and chemical substances third and final stage of an allergic reaction is
the prolonged immune activity caused by the
The Basic Information About Allergies chemical substances released by cells of the im-
Sneezing, sniffling, and wheezing are the mune system. This prolonged or late-phase re-
symptoms most often associated with allergies. action can cause the immune system to con-
Allergies, or hypersensitivities, are the human tinue to react and cause tissue damage.
bodys exaggerated response to a foreign sub- Based on varying responses to antigens, re-
stance such as pollen. Hypersensitivity reac- searchers Peter Gell and Robert Coombs have
tions can be immediate (hay fever) or delayed classified allergies into four types: I (anaphy-
(contact dermatitisfor example, a reaction laxis), II (cytotoxic), III (immune complex),
to latex or poison ivy) depending upon the and IV (cell-mediated). Type I hypersensitiv-
bodys immune reaction to the antigen. ityanaphylaxis, from the Greek ana (against)
Essentially, there are three stages of an aller- and phylaxis (protection), or the opposite of
gic reaction. The first stage causes no symp- protectedcan be further divided into either
toms. It is the immune systems initial contact systemic or local response. Systemic anaphylaxis
with the antigen. The cells of the immune sys- is the whole bodys response to an antigen such
tem react to the antigen by producing IgE anti- as a bee sting. Because of the amount of chemi-
bodies that attach to mast cells and eosinophils cal substances released by the cells of the im-
(two cell types of the immune system) that are mune system, the body reacts immediately by a
circulating in the blood. When the same anti- drop in blood pressure (leading to shock), dif-
gen is encountered a second time and attaches ficulty in breathing, and swelling of the airways.
to two adjacent IgE antibodies on a mast cell, If not treated immediately, anaphylactic shock
the mast cell is said to be activated. During can be fatal. Localized anaphylactic reactions
this second stage, the mast cell releases chemi- (atopy) are the most familiar of the hypersensi-
Magnified view of
Antigens
antibody-antigen
complex
Allergen
(5) T lymphocyte
engulfing antibody-
antigen complex
(4) Antibody-antigen
complex
(1) B lymphocyte (3) Antibodies
(2) Plasma cell
secreting
antibodies
An allergic reaction is caused when foreign materials, or antigens, enter the immune system, which produces B lymphocytes (1) that
cause blood plasma cells to secrete antibodies (2). The antibodies (3) link with antigens to form antibody-antigen complexes (4),
which then are engulfed and destroyed by a T lymphocyte (5). (Hans & Cassidy, Inc.)
Allergies 15
tivities. The symptoms are dependent upon the (drugs that block the release of histamine from
route the antigen uses to enter the body. For mast cells) and anti-inflammatories (steroids),
airborne antigens such as house dust, pollens, and desensitization (allergy shots). Efforts by
and animal dander, symptoms may include hay scientists to learn how the immune system func-
fever (itchy eyes, runny nose, sneezing, and tions and why it overreacts to antigens will lead
coughing) or bronchial asthma (wheezing, to the development of better, less toxic drugs to
coughing, and difficulty breathing). Other combat allergies and their symptoms.
atopic symptoms may include hives, itchy skin, Mary Beth Ridenhour
and diarrhea. Food allergies are also examples See also: Autoimmune Disorders; Genetic
of an atopic reaction. Engineering: Risks; Immunogenetics; Synthetic
Type II (cytotoxic) hypersensitivity reaction Antibodies.
involves the binding of an antigen and anti-
body complex to a cell that destroys the target Further Reading
cell. Examples of this type of hypersensitivity Cutler, Ellen W. Winning the War Against Asthma
are incompatible blood groups (giving type B and Allergies. Albany, N.Y.: Delmar, 1998. This
blood to a person who has type A blood), he- clearly written book provides practical in-
molytic anemia (destruction of red blood formation on all aspects of allergieswhat
cells), and hemolytic disease of a newborn (the they are, their causes, testing, diagnosis, and
mother produces antibodies against the fetus treatment, including nontraditional thera-
based on a protein found in the blood). pies. Preventive measures are covered, as are
Type III (immune complex) hypersensitivity scenarios for various allergy elimination ther-
reaction involves the depositing of immune apies.
complexes (an antigen bound to an antibody) Joneja, Janice M. V., and Leonard Bielory. Un-
on the walls of blood vessels, causing inflamma- derstanding Allergy, Sensitivity, and Immunity.
tion and tissue damage. Glomerulonephritis, New Brunswick, N.J.: Rutgers University
inflammation of the blood vessels in the kid- Press, 1990. The authors provide extensive
neys, is a type III hypersensitivity reaction. This discussion of allergies and the roles played
disease is believed to be a reaction to a particu- by the immune system. They describe the
lar bacterial infection. means by which one can learn to cope with
Contact dermatitis (for example, a reaction allergies and discuss various testing methods
to poison ivy, latex, cosmetics, or jewelry) is a for the identification of allergens.
common example of the last category, type IV Kuby, Janis. Immunology. 4th ed. New York: W. H.
(cell-mediated) hypersensitivity. T cells (a cell Freeman, 2000. The section on hypersensi-
type of the immune system) initially react with tivity in this immunology textbook is well
the antigen; upon a second exposure to the written and includes a mixture of detail and
antigen, clones of the same T cell release chem- overview of the subject. Particularly useful
ical factors that cause a reaction to the antigen. are discussions of the various types of hyper-
This release of chemicals results in a red, itchy sensitivity reactions. Some knowledge of bi-
rash or hives. The reaction to Mycobacterium tu- ology is useful.
berculosis (the bacteria that causes tuberculosis) Lichtenstein, Lawrence. Allergy and the Im-
is a type IV hypersensitivity. The immune sys- mune System. Scientific American 269 (Sep-
tem has also been known to attack itself and tember, 1993). A basic explanation of the
cause disease. These disorders (autoimmune way human allergies work.
disorders), such as multiple sclerosis, juvenile Life, Death, and the Immune System. New York:
diabetes, and systemic lupus erythematosus, W. H. Freeman, 1994. This comprehensive
are only beginning to be understood. collection of articles from Scientific American
provides basic information and research di-
Impact and Applications rections on autoimmune disorders and al-
Treatment of allergies may include avoid- lergies as well as an excellent discussion of
ance of the antigen, use of antihistamines the immune system in general.
16 Altruism
Mak, Tak W., and John J. L. Simard. Handbook of linking to reports and information on immu-
Immune Response Genes. New York: Plenum nology, allergies, gene therapy, HIV/AIDS,
Press, 1998. Contains chapters on such top- and more.
ics as genes of the major histocompatibility
complex and of the antigen-processing path-
ways, autoimmune disorders, cytokines of
the immune system, and leukocyte cluster of
differentiation antigens. Illustrated. Altruism
Steinman, Lawrence. Autoimmune Disease.
Scientific American 269 (September, 1993). Field of study: Population genetics
Describes what happens when the immune Significance: In a strictly Darwinian system, ac-
system develops an autoimmune disorder tions that reduce the success of individual repro-
that causes it to see the body as foreign and duction should be selected against; however, altru-
attack itself. ism, which occurs at a cost to the altruist, is
Theofilopoulos, A. N., ed. Genes and Genetics of observed regularly in natural populations. This
Autoimmunity. New York: Karger, 1999. Ex- paradox may be resolved if the cost of altruism is
amines a broad spectrum of topics related offset by the reproductive success of relatives with
to autoimmunity, including the chapters which altruists share genes. Kin selection results
Immunoglobulin Transgenes in B Lympho- in selection for altruistic behaviors which, if di-
cyte Development, Tolerance, and Autoim- rected at relatives, preserve inclusive reproductive
munity, The Role of Cytokines in Auto- success, and thus Darwinian fitness.
immunity, Genetics of Human Lupus,
and Genetics of Multiple Sclerosis. Illus- Key terms
trated. altruism: behavior that benefits others at the
Tortora, Gerard, et al. Microbiology: An Introduc- evolutionary (reproductive) cost of the al-
tion. San Francisco: Benjamin Cummings, truist
2000. Provides a general overview of the hu- evolution: a change in the frequency of al-
man immune system and allergies via such leles resulting from the differential repro-
topics as microbial metabolism; microbial duction of individuals
genetics; viruses, viroids, and prions; disor- haplodiploidy: a system of sex determination
ders associated with the immune system; and in which males are haploid (developing from
metabolic pathways. unfertilized eggs) and females are diploid
Walsh, William. The Food Allergy Book. New York: inclusive fitness: an individuals total genetic
J. Wiley, 2000. In this excellent guide to contribution to future generations, compris-
one prevalent form of allergy, the author ing both direct fitness, which results from in-
presents useful background information on dividual reproduction, and indirect fitness,
food allergies and a pragmatic guide to iden- which results from the reproduction of close
tifying and eliminating food allergens from relatives
your diet. kin selection: an evolutionary mechanism
manifest in selection for behaviors that in-
Web Sites of Interest crease the inclusive fitness of altruists
Allergic Diseases Resource Center. http:// maternal altruism: altruism on the part of
www.worldallergy.org/allergicdiseasecenter mothers toward offspring as well as between
.shtml. Part of the World Allergy Organiza- and among members of groups comprising
tion, this site provides scientific and medical closely related females
information on allergic diseases, research natural selection: a process whereby envi-
updates, and more. ronmental factors influence the survival and
National Institue of Allergy and Infectious Dis- reproductive success of individuals; natural
eases. http://www.niaid.nih.gov/default.htm. selection leads to genetic changes in popula-
An arm of the National Institutes of Health, tions over time
Altruism 17
reciprocal altruism: mutual exchange of al- atives. Kin selection is the evolutionary mecha-
truistic acts typically associated with highly nism that selects for behaviors that increase the
cohesive social groups inclusive fitness of altruists. Even though there
are potential costs to altruistic behavior, the
Reproductive Success = Survival evolutionary economy of an altruist operates in
If evolutionary outcomes in a Darwinian the black because actors profit (beyond associ-
world are described as natural economies, then ated costs) by helping others who share their
individual reproduction is the currency of these genes. The bottom line is that altruists increase
economies and of natural selection. Given both their inclusive fitness through the reproduc-
naturally occurring genetic variation among tion of others.
individuals and a certain environmental dy-
namic, it follows that some individuals will be Evidence of Kin Selection
better adapted to locally changing environ- One of the best evidences for kin selection is
ments than others. Such differential adapta- the social structure of certain groups of insects,
tion is expressed as a difference in the fre- including the Hymenoptera (ants, bees, and
quency with which individual genes pass into wasps). A unique system of sex determination
future generations. This simple scenario fulfills (haplodiploidy) in which females are diploid
the genetic definition of evolution change in and males are haploid predisposes some group
allele frequencies in natural populationsby members to behave altruistically. In certain
explaining environmental influences on these bees, for example, the queen is diploid and fer-
changes. Note that this argument emphasizes, tile. Worker bees are female, diploid, and ster-
as its central postulate, the importance of indi- ile. Drones are male, developed from unfertil-
vidual reproduction rather than simple sur- ized eggs, and haploid. Such a situation makes
vival. Survival of the fittest is therefore more for unusual patterns of genetic relationship
properly viewed as the differential propagation among hive members. In diploid systems the
of genes. genetic relation between parents and offspring
A challenge to such a scenario is the paradox and among offspring is symmetrical. Offspring
of altruism. Altruism is defined as any behavior receive half of their genetic complement from
that benefits another at a cost to the altruist. their mother and half from the father; sons and
Charles Darwin himself suggested that this daughters are related to each parent by 1 2 and
problem was a special difficulty . . . which at sibs (siblings) are related to each other by 1 2. In
first appeared . . . insuperable, and actually fa- the haplodiploid system such genetic relation-
tal to [the] whole theory of natural selection. ships are asymmetric. Drones are haploid and
The individual who pushes siblings from the receive half of the queens genome. Workers
track as he himself is killed by the rushing loco- are diploid and share 100 percent of their pa-
motive is an altruist; the colony sentinel that is- ternal genes and, on average, half of their ma-
sues an alarm call to her cohort to take cover, ternal genes with their sisters. Sisters are there-
despite the risk of drawing the attention of an fore related to each other by 3 4. Because sisters
approaching predator, is also acting altruisti- and their brothers share no paternal genes,
cally. These behaviors make no sense in Dar- and on average half of their maternal genes,
wins economy, since they appear to decrease they are related to drones by only 1 4. In this
the likelihood of individual reproduction economy it makes sense that workers should
unless, as W. D. Hamilton suggested, Darwin- act altruistically to assist the queen in the pro-
ian success is not limited to the success of indi- duction of sisters. What would appear to be
vidual bodies harboring particular genes but purely altruistic acts, on the part of workers, re-
may be extended to include the reproductive sult in greater inclusive success than if the
success of relatives who share genes with the al- workers had reproduced themselves. In con-
truist. Hamilton defined inclusive fitness as the trast, drones contribute little to community
sum of an individuals own fitness plus the in- welfare and serve only to fertilize the queen.
fluence that individual has on the fitness of rel- Note that in this system there is no conscious
18 Altruism
The altruistic behaviors of honeybees and some other animal species may be a result of selection for behaviors that place the group,
rather than the individual, at a reproductive advantage. (AP/Wide World Photos)
decision on the part of workers not to repro- musculus domesticus, and in some cases individ-
duce; their sterility is an inherent part of this uals can distinguish full sibs from half sibs on
unusual system of sex determination. the basis of their major histocompatibility com-
plexes (glycoproteins important in immune
A Test of Predictions system function). The specific MHC type is
One prediction made by the kind of kin se- fairly unique for each mouse, but related indi-
lection described above is that, assuming the viduals will have similar patterns and share
queen produces male and female offspring in some specific MHC glycoproteins. MHC glyco-
equal proportion, female workers should in- proteins are found in mouse urine, and individ-
vest three times the energy in caring for sisters uals can distinguish these molecules by smell.
that they do for brothers. Because queens are Consistent with the foregoing hypothesis, the
related to both male and female offspring degree of female altruism toward the offspring
equally, one would predict that eggs are equally of close relatives was predicted by the degree of
divided between the sexes. Because workers are relation based on MHC type and type recogni-
related to their sisters by 3 4 and to their broth- tion.
ers by 1 4, one would predict that they should in-
vest three times the energy in care of eggs even- Maternal Altruism
tually yielding sisters that they do in the care of Altruism may be observed in a variety of nat-
eggs eventually yielding brothers. Remarkably, ural systems in which groups comprise individ-
it has been shown that certain worker ants are uals who share a high degree of genetic related-
able to identify and then selectively care for ness. A classic example of this sort occurs with
eggs containing sisters. Kin recognition has Beldings ground squirrels. Males tend to dis-
also been studied in the house mouse, Mus perse from colonies, while females remain to
Alzheimers Disease 19
create highly related maternal groups. Mem- Hill, 2000. Nice analysis of the theoretical
bers of such maternal groups demonstrate al- basis for kin selection including consider-
truistic behaviors such as alarm calling to warn ation of genetic asymmetries associated with
relatives of danger. Although truly altruistic in haplodiploidy.
the sense that alarm callers may incur risk of
personal injury or death, they can be reason-
ably assured of breaking even in this economy
as long as their genes live on in the bodies of Alzheimers Disease
those they have saved by their actions.
Field of study: Diseases and syndromes
Reciprocal Altruism Significance: Alzheimers disease (AD) is the most
It would seem that altruism based on Hamil- common cause of irreversible dementia and ac-
tons argument of inclusive fitness would be counts for approximately two-thirds of all demen-
precluded by human social organization. Sci- tia cases in the United States.
entists have predicted, however, that reciprocal
altruism should exist in systems characterized Key terms
by a high frequency of interaction among mem- amyloid plaques: plaques formed by protein
ber individuals and life spans long enough to fragments from amyloid precursor proteins
allow the recipients of altruistic acts to repay al- beta-amyloid peptide: the main constituent
truists. Note that the theoretical basis for the of the neuritic plaques in the brains of Alz-
existence of reciprocal altruism differs from heimers patients
that for kin selection, and that any system in deterministic mutations: gene mutations
which evidence for reciprocity is found must associated with high risk for developing Alz-
necessarily include the development of a com- heimers
plex web of sophisticated social interaction. familial Alzheimers disease (FAD): inher-
Such systems would be expected to foster traits ited Alzheimers disease
expressing the panoply of human emotion and hippocampus: the area in the brain that en-
the development of certain moral architectures codes memory
and group cohesion. neurofibrillary tangles: abnormally
David A. Smith twisted tau protein threads that lead to the
See also: Behavior; Evolutionary Biology; death of brain cells
Homosexuality; Natural Selection; Population tau protein: threads of protein in the cells of
Genetics; Sociobiology. the brain that stabilize the brains support
structure
Further Reading
Freeman, Scott, and Jon C. Herron. Kin Selec- The Extent of AD
tion and Social Behavior. In Evolutionary Alzheimers disease (AD) is a progressive
Analysis. Upper Saddle River, N.J.: Prentice neurodegenerative disorder that causes a grad-
Hall, 2001. A well-written and logical analysis ual, irreversible, decline in memory, language,
of altruistic behavior. Arguments are sup- visual-spatial perceptions, and judgment which
ported with data and analysis from the pri- are all the result of amyloid plaques, neuro-
mary literature. fibrillary tangles, and neuronal loss. Approxi-
Gould, Stephen Jay. So Cleverly Kind an Ani- mately four million Americans suffer with AD,
mal. In Ever Since Darwin. New York: W. W. a number that is expected to increase to almost
Norton, 1973. An elegantly expressed de- 6 million by 2020. According to the Alzhei-
scription of altruism and haplodiploidy in mers Association, 14 million Americans will be
social insects. diagnosed with AD by 2050 if a cure is not
Volpe, E. Peter, and Peter A. Rosenbaum. Nat- found. Annually, $33 billion is lost by American
ural Selection and Social Behavior. In Under- businesses as a result of AD. At an annual cost of
standing Evolution. 6th ed. Boston: McGraw- $100 billion, AD is the third most costly disease
20 Alzheimers Disease
in the United States. Worldwide, the World Alzheimer, described plaques and neurofibril-
Health Organization (WHO) estimates that by lary tangles in the brain of a mentally disturbed
2050, more than 22 million individuals world- woman and identified them as a component in
wide will have developed AD, and some esti- a type of acceleration in aging. Today, these
mates are larger. AD currently accounts for be- plaques and tangles in the brain are hallmarks
tween 50 and 75 percent of all dementias. Its of AD that are identified on autopsy and are the
prevalence increases from 1 percent at the age only means to definitively diagnose AD. Early-
of sixty-five years to 20-35 percent by the age of onset AD was originally referred to as presenile
eighty-five years. The average life span for AD dementia because it occurred in individuals
sufferers ranges from eight to twenty years fol- younger than sixty or sixty-five years of age.
lowing diagnosis. As AD progresses, individuals Late-onset AD was referred to as senile demen-
become less and less able to perform activities tia because it occurred in individuals older
of daily living because of progressive cognitive than eighty or eight-five years of age. Until re-
and social declines. AD will reach epidemic cently, AD was considered a normal conse-
proportions as the human life span continues quence of aging.
to increase. Understanding the genetic risks
for developing diagnostics to identify AD and Genes Associated with AD
early intervention to treat AD will positively im- AD is not a normal part of aging. Over the
pact the quality of life of individuals who suffer past several years, scientists have discovered ge-
with the disease. netic links to two main types of AD. In the late
1980s scientists discovered amyloid precursor
Historical Perspectives on AD protein (APP). Alpha-, beta-, and gamma-
Greeks and Romans first described symp- secretase enzymes hang onto APP. The beta
toms of AD in their writings about dementias in and gamma enzymes produce a sticky protein
old age. In 1906, a German physician, Dr. Alois called beta-amyloid (A-beta). A-beta builds up
Two images of mouse-brain tissue, one (left) engineered to produce the dark protein deposits that characterize Alzheimers disease, and
the other normal. (AP/Wide World Photos)
Alzheimers Disease 21
in the fluid surrounding the neurons and is the activation of the hippocampus, and de-
responsible for the formation of amyloid creased the interconnection in neurons and
placques in AD. neuron health in humans.
Early-onset AD is caused by mutations in APP
that cause abnormal proteins to form: pre- Risk Factors for AD
senilin 1 and presenilin 2. APP mutations cause Advancing age and heredity are the most im-
amyloid plaque to develop in the hippocam- portant risk factors for the development of AD.
pus. APP mutations on chromosome 21 were While it is known that mutations in APP and
the first gene mutations to be described in as- presenilin 1 and presenilin 2 genes cause early-
sociation with early-onset AD. APP mutations onset AD, causes of late-onset AD are not as
on chromosome 14 also produce presenilin 1. clear-cut. Some scientists hypothesize that late-
APP mutations on chromosome 1 produce pre- onset AD may be initiated by inefficient pro-
senilin 2. Individuals with these deterministic cessing of APP or by enhanced degradation of
mutations will develop early-onset AD. Early- the tau protein. Individuals with ApoE e4 allele
onset AD is rare and usually affects individuals have a two to four times greater risk for devel-
thirty to sixty years of age. Most cases of early- oping AD than those without it. Still, only 30-40
onset AD are inherited and are called familial percent of ApoE e4 allele carriers develop AD.
AD (FAD). Infectious agents, environmental toxins, and
Another type, late-onset AD, is the most metabolic errors that have not yet been identi-
common form of AD, occurring in individuals fied may also be possible causes of late-onset AD.
who are sixty-five years of age and older. Late- Aside from genetic risks involved in the de-
onset AD is caused by mutations in apolipo- velopment of AD, other factors that increase
protein E (ApoE). ApoE is the most common the likelihood for developing AD include trau-
genetic risk factor for developing AD. Scien- matic brain injury and lower socioeconomic
tists believe that these mutations allow longer status, being overweight, lower educational
isoforms of the neurotoxic A-peptide, which level, sedentary lifestyle, depression, elevated
lead to the death of neurons. poE binds to beta- blood cholesterol levels, and vascular diseases
amyloid. The gene that produces ApoE is in the such as hypertension, coronary artery disease,
region of chromosome 19. There are at least atrial fibrillation, and myocardial infarction.
three forms: e2 allele, e3 allele, and e4 allele. Females are also at greater risk for developing
ApoE e2 allele is rare and develops later in life. AD.
It may also protect individuals against AD. ApoE
e3 allelle is the most common allele. According Implications and Interventions
to researchers it appears to be neutral in AD. Early diagnosis of AD is essential to ensure
ApoE e4 allele occurs in approximately 40 per- that proper treatment and early detection of
cent of individuals who develop late-onset AD. other underlying diseases such as depression,
Individuals with ApoE e4 allele may develop AD drug interactions, vitamin deficiencies, or endo-
even if there is no family history of AD. Scien- crinologic problems are ruled out. The Risk
tists believe that protein products from ApoE e4 Evaluation and Education for Alzheimers Dis-
allele bind to APP and form plaques. ease (REVEAL) study investigated the impact
Chromosome 10 has also been identified as of identifying individuals with the ApoE geno-
possibly containing genes that increase the risk type. The ApoE genotype is the most powerful
of developing AD. Though it is still not cer- genetic risk factor for AD and may be instru-
tain whether beta-amyloid plaques cause AD or mental in predicting the chance of developing
are a by-product of AD, the formation of beta- AD. This study offers guidance for using genetic
amyloid from APP is a key process in AD. risk information to screen, evaluate, and edu-
Information has been released by the Na- cate families with relatives suffering from AD.
tional Institutes of Health (NIH) that reported The National Institutes for Health Alzhei-
that an alteration in brain-derived neurotrophic mers Disease Prevention Initiative (NIHADPI)
factor (BDNF) affected memory, influenced was organized to identify factors that will assist
22 Alzheimers Disease
complete results are likely to be reported one fects; Prader-Willi and Angelman Syndromes;
month earlier than for amniocentesis. A termi- Prenatal Diagnosis; RFLP Analysis; Sickle-Cell
nation of pregnancy after chorionic villus sam- Disease; Tay-Sachs Disease; Thalidomide and
pling is expected to have fewer complications Other Teratogens; Turner Syndrome.
than a termination performed at a later stage
in pregnancy. Further Reading
Cummings, Michael R. Human Heredity: Princi-
Impact and Applications ples and Issues. 5th ed. Pacific Grove, Calif.:
Both amniocentesis and chorionic villus sam- Brooks/Cole, 2000. A good introduction to
pling provide significant information to couples human genetics for nonspecialists.
at risk for having a child with a genetic disorder Heyman, Bob, and Mette Henriksen. Risk, Age,
or other type of birth defect. It is estimated that and Pregnancy: Case Study of Prenatal Genetic
approximately one-half of the women over the Screening and Testing. New York: Palgrave,
age of thirty-five who are pregnant utilize amni- 2001. Offers a detailed case study of a prena-
ocentesis or chorionic villus sampling. Thou- tal genetic screening and testing system in
sands of women undergo some form of prena- one hospital, integrating observational, sur-
tal genetic testing each year. Amniocentesis vey, and qualitative interview methods to
increases the risk of spontaneous abortion only provide insight into the risk management di-
about 0.5 percent above the overall general lemmas faced by those who attempt to con-
risk. Chorionic villus sampling probably carries trol genetic futures.
an increased risk of miscarriage of 1 to 2 per- Parry, Vivienne. Antenatal Testing Handbook: The
cent above the overall general risk. It should be Complete Guide to Testing in Pregnancy.
kept in mind, however, that these two tech- Collingdale, Pa.: DIANE, 1998. Provides a
niques are usually not performed unless there readable yet in-depth discussion of each an-
is some additional risk already present in a spe- tenatal test, including amniocentesis, exam-
cific pregnancy. ining what is available, what the tests are for,
The techniques of amniocentesis and chori- and the risks associated with each. Each test
onic villus sampling may assure parents at risk is explained in detail. An index of genetic
of having a child with a genetic disorder that diseases lists the most common handicap-
their child will be born without the disorder. ping conditions, together with their causes
Results may also be such that parents must be (where known) and their detection rates by
told that their child will definitely have a cer- method and stage of pregnancy.
tain disorder. However, even if a couple elects Rapp, Rayna. Testing Women, Testing the Fetus: The
to continue with a pregnancy, the tests provide Social Impact of Amniocentesis in America. New
useful information about the nature of the dis- York: Routledge, 1999. Examines amniocen-
order and about treatments that might be used tesis from an anthropological/sociological
after birth to prepare for raising a child with a perspective, using dozens of anecdotes from
birth defect. It is to be expected that further de- women who have undergone the procedure.
velopments in techniques will dramatically im- Rothman, Barbara Katz. The Tentative Pregnancy:
prove the convenience and safety of prenatal How Amniocentesis Changes the Experience of
testing. Motherhood. New York: Norton, 1993. Dis-
Donald J. Nash cusses how amniocentesis radically alters the
See also: Alcoholism; Bioethics; Congenital way parents think about childbirth and par-
Defects; Cystic Fibrosis; Down Syndrome; enthood, forcing them to confront an array
Dwarfism; Eugenics; Fragile X Syndrome; Ge- of agonizing dilemmas. Surveys technologi-
netic Counseling; Genetic Engineering: Social cal advances in the procedure and includes
and Ethical Issues; Genetic Screening; Genetic two appendices, Using Earlier Tests (on
Testing; Genetic Testing: Ethical and Economic early amniocentesis and chorionic villus
Issues; Hemophilia; Hereditary Diseases; In- sampling) and Maternal Serum Alpha Pro-
born Errors of Metabolism; Neural Tube De- tein Testing.
Ancient DNA 27
rassic Park goes well beyond what is possible, the sterile and the work surfaces are commonly ex-
film brought the idea of resurrecting ancient posed to damaging ultraviolet (UV) rays for
DNA samples before the general public. sixty minutes or more in order to destroy any
foreign DNA. Researchers wear sterile gloves
Problems of Isolation and Analysis and face masks, and all laboratory equipment
The two greatest concerns when attempting and containers that come in contact with the
to isolate ancient DNA are the degree to which samples or solutions must be sterile and are of-
it has degraded and potential contamination ten exposed to UV light as well. A further pre-
with more recent DNA. The amount of DNA caution is to analyze ancient and modern DNA
degradation is a function of the age of the sam- samples in completely different laboratories.
ple and the conditions under which it was pre- Finally, after the DNA has been isolated, it must
served. Samples a few thousand years old will still be kept from subsequent opportunities for
typically yield very usable DNA, whereas sam- contamination.
ples exceeding 100,000 years in age may be so The first criticism typically leveled against re-
degraded, regardless of preservation condi- sults of ancient DNA analyses is the potential
tions, that no meaningful data can be obtained. for contamination. Guidelines have been pro-
Environmental conditions at the time the or- posed, but researchers have been slow in imple-
ganism died also play a large part. A woolly menting them, as they are difficult to follow.
mammoth frozen shortly after death will yield There is still considerable debate about the ve-
much more and better-preserved DNA than racity of many of the studies so far published,
will the bones of a turtle weathered for many and some DNA initially believed to be ancient
months or years before being buried. Insects was later found to originate in contamination
trapped in amber would seem to have very well from contemporary sources. In spite of some of
preserved DNA, as they were likely encased the problems with isolating and analyzing an-
while still alive, but the age of such fossils may cient DNA, it has produced some fruitful re-
be so great that the DNA is still degraded be- sults.
yond usefulness.
Of probably greater concern than DNA deg- Archaeological and Anthropological
radation is contamination with modern DNA. Discoveries
All fossils and ancient remains have the poten- Probably the most fruitful area of ancient
tial to be contaminated with all manner of DNA analysis for archaeologists has been in the
more recent molecules of DNA, from pollen or study of the origins of human diseases. Tradi-
bacteria to mold or the skin cells of the person tionally, determining whether an ancient hu-
extracting the DNA. Even minute quantities of man being suffered from a particular disease
DNA contamination can ruin the results of PCR relied on circumstantial evidence: stunted
analysis, which is capable of amplifying a DNA growth, bone scars, and other circumstances
sequence with only a few template molecules subject to interpretation. Recovery of ancient
from which to read. For these reasons, the con- bacterial DNA from Egyptian mummies has
ditions to which the sample was exposed prior helped establish the presence of skeletal tuber-
to collection must be taken into account. If the culosis as long ago as about 3000 b.c.e.
sample was encased in ice or rock, the probabil- Based on historical accounts, the plague,
ity of contamination is minimal, whereas if the caused by the bacterium Yersinia pestis, has long
sample was exposed to the air, contamination been considered the cause of a repeated series
can almost be assured. Thus, when collecting a of epidemics over the last two millennia. Unfor-
sample, the researcher must immediately place tunately, without any adequate medical records
it into an airtight, sterile container. to confirm plague epidemic accounts, confir-
Once DNA extraction begins, the specimen mation is not possible. In 1998, researchers in
must be completely protected from contamina- France unearthed the skeletons of individuals
tion by DNA from the researcher or anything from the sixteenth and eighteenth centuries
else in the environment. The work area must be that presumably died from the plague. Using
Ancient DNA 29
PCR to amplify a gene from Y. pestis from dental was discovered that the species of fish were not
pulp, they obtained proof that the plague ex- from the study area. Instead, they were fish that
isted at the end of the sixteenth century in had to have come from Egypt or the Levant,
France. Other diseases that have been success- hinting at potential ancient trade routes.
fully identified in this way include leprosy, Dipping more deeply into the past, research-
schistosomiasis, malaria, and Chagas disease. ers have isolated DNA from the bones of an-
In 2003 archaeologists discovered a mummy, cient humans from Australia, Africa, Europe,
accompanied by two others, that might be the and other parts of the world. The goal has been
famous wife of Akhenaton and co-ruler of to analyze mitochondrial DNA (mtDNA) se-
Egypt, Nefertiti. Extraction of DNA from all quences and use them to help answer questions
three mummies, to see if they are related, could about human origins. This sort of DNA is pre-
help determine whether the mummy is Nef- ferred because it evolves at an appropriate rate
ertiti. Although DNA evidence would not re- and is more abundant in cells, so it is more
move all doubt, added to circumstantial evi- likely to be present in ancient specimens. Al-
dence presented by some anthropologists and though the results thus far have not settled
historians, it would strengthen their case. some of the long-standing questions about hu-
Archaeologists excavating an ancient Roman man origins, they have shown that a remark-
and early Byzantine site in Turkey found fish re- able similarity exists between ancient and mod-
mains. When DNA was isolated and analyzed, it ern DNA sequences.
A salt crystal entrapping a 250-million-year-old bubble containing bacteria, excavated from 1,850 feet below ground near Carlsbad,
New Mexico, offers scientists Russell Vreeland (left) and William Rosenzwieg the opportunity to study ancient DNA. (AP/Wide
World Photos)
30 Ancient DNA
Ancient Dinosaur and Bacterial DNA yses will come only as more samples are ana-
It had long been assumed that obtaining lyzed and DNA is shown to be capable of surviv-
DNA from samples older than a few hundred ing so long, and even then there will still be
thousand years would not be possible. DNA room for skepticism. Working with such an-
millions of years old was assumed to be so de- cient samples and avoiding all possibility of
graded that the fragments would be too small contamination is extremely difficult.
even for PCR to pull out sequences to analyze. Studying rates of evolution in a population
In 1991, however, Edward Golenberg of Wayne over thousands of years has also been accom-
State University isolated DNA from fossil mag- plished using ancient DNA. Adlie penguins
nolia leaves that were approximately 18 million have lived in colonies in the same areas of Ant-
years old. Just a year later, in 1992, researchers arctica for many thousands of years. Excavating
in California isolated DNA from a fossil bee various colony sites, researchers have collected
trapped in amber and researchers at the Ameri- partially fossilized bones covering a range of
can Museum of Natural History (New York ages to almost seven thousand years old. By
City) isolated DNA from a termite trapped in comparing the DNA sequences of a portion of
amber. Although tantalizing, these studies have mtDNA among the different aged samples and
been questioned by those who suspect that the modern samples from live penguins, they have
DNA that was isolated represents contamina- estimated evolutionary rates of change. Be-
tion rather than true ancient DNA. In some cause these samples were only thousands of
cases, reanalysis has shown that the supposed years old, the results are much more reliable
ancient DNA was an artifact or a contaminant. than samples from fossils.
The likelihood that DNA could survive so long,
even in amber, has also been questioned.
In 1994, Ral Cano, at California Polytech- Future Prospects in Ancient DNA Research
nic State University, isolated 25-million-year- Some limitation in the field of ancient DNA
old DNA from bacteria in the gut of a bee research will never be overcome, but as more
trapped in amber. In 1999, Charles L. Green- research is done, methods of extraction and
blatt, at Hebrew University in Jerusalem, re- analysis of ancient DNA should improve. Also,
ported the isolation of DNA of several types as more samples are collected and analyzed,
of bacteria from 120-million-year-old amber. better methods for measuring the extent of
Comparisons of the DNA sequences of ribo- DNA degradation and for determining whether
somal RNA (rRNA) genes with modern bacte- contamination is present should be developed.
ria revealed significant differences, lending However, doubt about the ability of DNA to sur-
support to the claim that Greenblatt and his vive longer than 100,000 years, in the best of
colleagues had actually isolated ancient DNA conditions, has resulted in a drop in studies of
and not contaminants. very ancient DNA. It now appears that the most
A number of researchers have isolated DNA fruitful use of ancient DNA is from samples on
from dinosaur bones, ranging in age from 65 the order of a few thousands to tens of thou-
million to 80 million years old. The same sands of years old, rather than DNA millions of
doubts exist with these studies, particularly be- years old. Archaeologists, anthropologists, and
cause there is no pure, undegraded DNA from biologists studying relatively recent extinct ani-
ancient dinosaurs with which to compare the mals will probably be the primary researchers
extracted DNA. Certainly, if the DNA is com- analyzing ancient DNA.
pared with bacterial or fungal DNA sequences Bryan Ness
and there is a match, then the DNA can be con- See also: DNA Structure and Function;
sidered a contaminant. On the other hand, if Evolutionary Biology; Genetic Code; Molecu-
the DNA resembles modern reptile or bird lar Clock Hypothesis; Mutation and Mutagene-
DNA, it may represent a contaminant as well sis; Polymerase Chain Reaction; Punctuated
but may also be dinosaur DNA, as claimed. Equilibrium; RNA Structure and Function;
Confidence in the results of ancient DNA anal- RNA World.
Animal Cloning 31
Further Reading
Arndt, Allan, et al. Roman Trade Relation- Animal Cloning
ships at Sagalassos (Turkey) Elucidated by
Ancient DNA of Fish Remains. Journal of Ar- Field of study: Genetic engineering and
chaeological Science 30, no. 9 (2003): 1095- biotechnology
1105. Analysis of DNA isolated from ancient Significance: Animal cloning is the process of gen-
fish remains showed that the fish were from erating a genetic duplicate of an animal starting
another location and must have represented with one of its differentiated cells. Sheep, mice, cat-
foreign trade. tle, goats, pigs, and a cat have been cloned. While
Desalle, Robert, and David Lindley. The Science currently an inefficient process that may pose risks
of Jurassic Park and The Lost World. New to the clone, animal cloning offers the benefits of
York: HarperCollins, 1998. A critical look at replicating valuable animals.
the science in the first two films based on Mi-
chael Crichtons novels, especially easy to Key terms
read for nonscientists. asexual reproduction: reproduction not re-
Herrmann, Bernd, and Susanne Hummel, eds. quiring fusion of haploid gametes as a first
Ancient DNA: Recovery and Analysis of Genetic step
Material from Paleographic, Archaeological, Mu- clone: a genetic replica of a biological organ-
seum, Medical, and Forensic Speciments. New ism
York: Springer-Verlag, 1994. Written when differentiated cell: a somatic cell with a spe-
DNA fingerprinting was just coming to the cialized function
fore and films such as Jurrasic Park were in mitochondrial genome: DNA found in mito-
theaters, this collection of papers by first- chondria, coding for forty genes, involved in
generation researchers reflects the broad energy metabolism, and maternally inher-
applications of the technology, including ited
paleontological investigations. nuclear genome: DNA found in the nucleus,
Hummel, Susanne. Fingerprinting the Past: Re- coding for 30,000 genes in higher organ-
search on Highly Degraded DNA and Its Applica- isms, half inherited from each parent
tions. New York: Springer-Verlag, 2002. Man- telomere: a specialized structure at the chro-
ual about typing ancient DNA. mosome end, which shortens in somatic
Jones, Martin. The Molecule Hunt: Archaeology and cells with age
the Search for Ancient DNA. New York: Arcade,
2002. A broad overview of the history of ana- Clones and Cloning
lyzing ancient DNA and other biological mol- Asexual reproduction occurs in numerous
ecules. Includes a nice selection of the win- bacteria, fungi, and plants, as well as some ani-
ners and losers in the hunt for ancient DNA. mals, leading to genetically identical offspring
Pennisi, Elizabeth. A Shaggy Dog History. Sci- or clones. In addition, humans can assist in
ence 298, no. 5598 (2003): 1540-1542. Re- such reproduction. For instance, cuttings from
ports on discoveries using DNA extracted plants generate thousands of replicates. Di-
from ancient dog remains that point to an viding some animals, such as earthworms or
Old World origin for New World dogs. flatworms, allows them to regenerate. How-
Wayne, Robert K., Jennifer A. Leonard, and ever, most vertebrates, including all mammals,
Alan Cooper. Full of Sound and Fury: The reproduce sexually, requiring fertilization of
Recent History of Ancient DNA. Annual Re- an ovum by sperm. In such species, clones oc-
view of Ecology and Systematics 30 (1999): 457- cur, as in the case of identical twins, when an
477. A comprehensive overview of what has embryo splits into two early in development.
happened in this highly controversial field. This process can be instigated artificially using
Includes some excellent examples of cases microsurgical techniques to divide a harvested
in which DNA originally considered ancient early-stage embr yo and reimplanting the
was found to be recent. halves into surrogate dams (mothers). While
32 Animal Cloning
this can be considered animal cloning, the In theory, the process is straightforward. It
term should be reserved for cloning from consists of taking a differentiated cell from an
nonembryonic cells. adult animal, inserting its diploid nucleus into
a donor ovum whose own haploid nucleus has
Cloning Procedure been removed, initiating embryonic develop-
Animal cloning typically refers to mammals ment of this ovum, inserting the resultant em-
or other higher vertebrates and involves creat- bryonic mass into a receptive surrogate dam
ing a duplicate animal starting from a differen- and allowing it to proceed to term. In practice,
tiated cell. Although such a cell only has the the technique is difficult and was thought to be
ability to perform its specialized function, its impossible until 1997. It also appears fraught
nucleus retains all genetic information for the with species specificity. Various differentiated
organisms development. Animal cloning re- cells have been used as the starting source;
quires that such information be reprogrammed mammary cells were used in the first case, while
into an undifferentiated cell that can re-initiate skin fibroblasts and cumulus cells are now of-
the developmental process from embryo to ten used. The preparation of the anucleate
birth and beyond. ovum is an important step. A limitation to clon-
In 1997, the world was taken aback when a group of fer arthritis, a veterinarian noted that both the loca-
scientists headed by embryologist Ian Wilmut at the tion and the age of onset were uncommon. Then, in
Roslin Institute in Scotland announced the success- February, 2003, she was euthanized after the discov-
ful cloning of a sheep named Dolly. Scientists had al- ery of a progressive lung disease.
ready cloned cows and sheep, but they had used em- Dollys health problems have led to speculations
bryo cells. Dolly was the first vertebrate cloned from about premature aging in clones but are compli-
the cell of an adult vertebrate. cated by her unique experiences as well. As Wilmut
The feat was accomplished by removing cells from noted, in the early years following the announce-
the udder of a six-year-old ewe and placing them in a ment of her cloning, she became something of a ce-
laboratory dish filled with nutrients, where they were lebrity, which led to overfeeding by visitors and in
left to grow for five days. Then the nutrients were re- turn a period of obesity, later corrected. More signifi-
duced to 5 percent of what the cells needed to con- cant were the discovery of her arthritis and then her
tinue growing, which caused the cells to enter a state lung diseaseconditions not uncommon in sheep
resembling suspended animation, making them but that tend to emerge later (sheep typically live to
more receptive to becoming dedifferentiated. When be eleven or twelve years old).
the nuclei of these cells were placed in the ova of host Theories of premature aging are supported by the
sheep, the cytoplasm of each ovum directed the nu- fact that Dollys telomeres were shorter than normal.
cleus it received to enter an undifferentiated state, These cell structures function as caps that prevent
thus causing the cell to develop into an embryo. fraying at the ends of DNA cells. As a cell ages, its
Of an initial 277 adult cells introduced into sheep telomeres become progressively shorter, until finally
ova, thirteen resulted in pregnancy, and only one, they disappear altogether and are no longer able to
Dolly, was carried to full term. Dolly was a genetic protect the cell, which then dies.
replica of the sheep from whose udder the original Was Dolly older genetically than she was chrono-
cells were extracted. Environmental factors would logically? The answer to the question of whether
make Dolly, like any other clone, individual, but ge- Dolly was completely normal or aged prematurely
netically she would never have the individuality that as a result of being a clone must await full investiga-
an organism produced by usual reproductive means tion of her autopsy results, as well as tracking of her
would possess. Over the next six years, she gave birth offsprings lives and monitoring of other vertebrate
to several, apparently healthy, offspring. In 2002, at clones through their life spans.
the age of six, Dolly became lame in her left hind leg, R. Baird Shuman, updated by Christina J. Moose
a victim of arthritis. Although sheep commonly suf-
Animal Cloning 33
Cloned Animals
The first cloned animal was
a sheep named Dolly. While
she was the only live offspring
generated from 277 attempts,
Dolly, the first animal cloned from an adult vertebrate cell, in 1997. She was her birth showed that animal
euthanized in 2003 after complications from advanced arthritis and lung disease. cloning was possible. Shortly
(AP/Wide World Photos) thereafter, mice and cattle were
cloned. Reproducible cloning
of mice is more difficult than
ing dogs appears to be the difficulty in obtain- imagined, whereas more cattle were cloned in
ing ova suitable for nuclear transfer. The tech- the first five years after Dollys birth than any
nique for inserting the nucleus is crucial, as is other species. Goats, pigs, and a cat were subse-
the conversion to the undifferentiated embry- quently also cloned.
onic state. Transfer of the embryonic cells to a
receptive surrogate dam is generally a well- Problems and Potential Benefits
developed technology, although more than Prominent among the problems with animal
four viable embryos are necessary to maintain cloning is its inefficiency. Although this may
pregnancy in pigs. not be surprising as the technology is still un-
Furthermore, the genetic makeup of a puta- der development, no more than 2 percent of
tive clone must be verified, to ensure that it is embryos generated lead to viable offspring.
indeed a replica of its progenitor and not an Additionally, most cloned animals are larger
unintended offspring of either the donor of than normal at birth, often requiring cesarian
the ovum or the surrogate dam. DNA finger- delivery, and some have increased morbidity
printing via microsatellite analysis at a number and mortality. Some have had smaller telo-
of polymorphic sites is an unambiguous way to meres and shorter lives. Dolly exhibited this
establish its genetic identity. trait and lived for only six years (although she
was euthanized, she clearly would not have
Identicalness lived much longer)half of the average life
Such a clone is not absolutely identical, be- span. Conversely, some cloned mice do not ex-
cause of mitochondrial differences and envi- hibit shortened telomeres or premature aging,
ronmental effects. While the nuclear genome even through six consecutive cloned genera-
must be identical to its progenitor, the mito- tions. Further research will establish whether
chondrial genome of the clone will invariably these problems are inherent to cloning, are
be different, because it comes from the ovum consequences of some aspect of the current
used. While mitochondria make a minor con- procedure or are attributable to the small num-
tribution to the total genetic makeup, they can bers of cloned animals studied.
34 Animal Cloning
At a news conference in July, 1998, Dr. Ryuzo Yanagimachi holds in his hands the first cloned mouse and its parent. The cloning
occurred nearly simultaneously with the cloning of Dolly the sheep. (AP/Wide World Photos)
The benefits of animal cloning would in- tion Enzymes; Reverse Transcriptase; Shotgun
volve duplicating particularly valuable animals. Cloning; Telomeres; Transgenic Organisms;
Livestock with highly valued production char- Xenotransplants.
acteristics could be targets for cloning. How-
ever, the technique is likely to be most benefi- Further Reading
cial in connection with transgenesis, to replicate Patterson, Lesley, William Richie, and Ian
animals that yield a therapeutic agent in high Wilmut. Nuclear Transfer Technology in
quantities or organs suitable for transplanta- Cattle, Sheep and Swine. In Transgenic Ani-
tion into humans. If animal cloning can be mal Technology, A Laboratory Handbook, edited
made efficient and trouble-free, its potential by Carl A. Pinkert. 2d ed. London: Academic
benefits could be fully developed. Press, 2002. The detailed protocol needed
James L. Robinson to clone three livestock species, as well as the
See also: Biopharmaceuticals; cDNA Librar- limitations to increased efficiency.
ies; Cloning; Cloning: Ethical Issues; Cloning Pennisi, Elizabeth, and Gretchen Vogel. Ani-
Vectors; DNA Replication; DNA Sequencing mal Cloning: Clones: A Hard Act to Follow.
Technology; Genetic Engineering; Genetic En- Science 288 (2000): 1722-1727. The status of
gineering: Agricultural Applications; Genetic animal cloning, three years after the an-
Engineering: Historical Development; Genetic nouncement of Dolly. The problems, ques-
Engineering: Industrial Applications; Genetic tions, and concerns are presented in a highly
Engineering: Medical Applications; Genetic En- readable text.
gineering: Risks; Genetic Engineering: Social Wilmut, Ian, Keith Campbell, and Colin Tudge.
and Ethical Issues; Knockout Genetics and The Second Creation: The Age of Biological Con-
Knockout Mice; Mitochondrial Genes; Parthe- trol by the Scientists That Cloned Dolly. London:
nogenesis; Polymerase Chain Reaction; Restric- Headline, 2000. The story of the scientific
Anthrax 35
collaboration between an agricultural scien- of Genesis. In Exodus 9, the Lord instructs Mo-
tist and a cell biologist, of their perseverance ses to take handfuls of ashes of the furnace
and the serendipity that led to the first cloned and sprinkle it toward the heaven in the sight
sheep, Dolly. of the Pharaoh. Moses performed the deed
and it became a boil breaking forth with blains
Web Sites of Interest upon man and upon beast. This may repre-
ActionBioScience.org. http://www.actionbio sent the first use of anthrax as a biological
science.org/biotech/pecorino.html. Fea- weapon. Greek peasants tending goats suffered
tures the article Animal Cloning: Old Mac- from anthrax; the Greek word from which an-
Donalds Farm Is Not What It Used To Be thrax derives means coal, referring to the coal-
and several useful links to the animal clon- black center of the skin lesion.
ing debate. Anthrax became the first pathogenic bacil-
Roslin Institute. http://www.roslin.ac.uk. The lus to be seen microscopically when described
site of the oldest cloning group in the world, in infected animal tissue by Aloys-Antoine
founded in 1919, which cloned the first ani- Pollender in 1849. Studies by Robert Koch in
mal, Dolly the sheep. Includes information 1876 resulted in the four postulates that form
on genomics and animal breeding. the basis for the study of infectious disease cau-
sation. In 1881, Louis Pasteur demonstrated
the protective efficacy of a vaccine for sheep
made with his attenuated vaccine strain.
Anthrax
The Disease
Field of study: Bacterial genetics Anthrax is primarily a disease of herbivorous
Significance: Anthrax has plagued humankind animals that can spread to humans through as-
for thousands of years. Naturally occurring an- sociation with domesticated animals and their
thrax spores have caused disease in livestock and products. Herbivorous animals grazing in pas-
wildlife more often than in humans, but with the tures with soil contaminated with anthrax endo-
rise of genetic technologies anthrax has become spores become infected when the spores gain
amenable to manipulation as an agent of bioter- entry through abrasions around the mouth and
rorism and biowarfare. germinate in the surrounding tissues. Omni-
vores and carnivores can become infected by
Key terms ingesting contaminated meat. Human infection
plasmids: extrachromosomal DNA, found is often a result of a close association with herbi-
most commonly in bacteria, which can be vores, particularly goats, sheep, or cattle (in-
transferred between bacterial cells cluding their products of hair, wool, and hides).
polymerase chain reaction (PCR): a process The most common clinical illness in humans
in which a portion of DNA is selected and re- is skin infection (cutaneous anthrax), acquired
peatedly replicated when spores penetrate through cuts or abra-
single nucleotide polymorphism (SNP): sions. After an incubation period of three to
the difference in a single nucleotide be- five days, a papule develops, evolves into a vesi-
tween the DNA of individual organisms cle, and ruptures, leaving an ulcer that dries to
variable number tandem repeat (VNTR): form the characteristic black scab. Inhaled
the difference in the number of tandem re- spores reach the alveoli of the lung, where they
peats (short sequences of DNA repeated are engulfed by macrophages and germinate
over and over) between the DNA of individ- into bacilli. Bacilli are carried to lymph nodes,
ual organisms where release and multiplication are followed
by bloodstream invasion and the infections
History spread to other parts of the body, including the
A disease killing cattle in 1491 b.c.e., likely brain, where it causes meningitis. The symp-
to have been anthrax, is recounted in the Book toms of the illness, which begin a few days after
36 Anthrax
inhalation, resemble those of the flu and may positive, and rod-shaped. It produces spores
be associated with substernal discomfort. and exotoxins (toxins that are released from
Cough, fever, chills, and respiratory distress the cells). Spores are ellipsoidal or oval (1-2 mi-
with raspy, labored breathing ensue. The least crons) and located within the bacilli. The
common type of infection is that of the gastro- endospores have no reproductive significance,
intestinal tract. as only one spore is formed by each bacillus
An effective vaccine is available for preven- and a germinated spore yields a single bacillus.
tion, and antibiotics have been used when im- Spores form in soil and dead tissue and with no
mediate protection is needed. Antibiotics can measurable metabolism may remain dormant
also successfully treat the infection. Inhalational for years. They are resistant to drying, heat, and
anthrax is nearly always fatal if untreated, and many disinfectants.
even with treatment the mortality ranges from The genetic composition of B. anthracis dif-
40 to 80 percent. Mortality from treated cuta- fers little from the other Bacillus species, and
neous anthrax is less than 1 percent. studies have demonstrated remarkable similar-
ity within B. anthracis strains. The resting stage
The Anthrax Bacterium of sporulation may have contributed to the ex-
The Bacillus anthracis bacterium is large tremely similar DNA of all strains of B. anthra-
(1-1.2 3-10 microns), encapsulated, gram- cis. The circular chromosomal DNA is com-
Anthrax cells invading the spleen of a monkey, in an undated electronmicrograph from the U.S. Department of Defense Web site.
The United States and the Soviet Union developed biological weapons during the Cold War, and many of these lethal organisms
remain housed in facilities around the world. (AP/Wide World Photos)
Anthrax 37
posed of 5.2 million base pairs and codes for tacks, a sensitive and specific three-target (two-
metabolic function, cell repair, and the sequen- plasmid and one-chromosome) assay has been
tial process of sporulation. Comparative ge- developed for rapid detection and identifica-
nome sequencing has uncovered only four dif- tion of B. anthracis, including bioengineered
ferences between the single-copy chromosomal strains, from both patients and the environ-
DNA of two strains. In addition to the single- ment.
copy DNA, comprising the majority of the ge- H. Bradford Hawley
nome, a remaining portion consists of repeti- See also: Bacterial Genetics and Cell Struc-
tive DNA sequences that are either dispersed or ture; Bacterial Resistance and Super Bacteria;
clustered into satellites. The satellite repeats Biological Weapons; Plasmids; Smallpox.
occur in tandem. The number of tandem re-
peats varies among different strains; six chro- Further Reading
mosomal marker loci have been identified by Centers for Disease Control and Prevention.
multiple-locus variable number tandem repeat Bioterrorism-Related Anthrax: Emerging Infec-
(VNTR) analysis. tious Diseases 8 (October, 2002): 1013-1183.
In addition to its chromosome, B. anthracis Summarizes the investigation following the
has two large plasmids that carry genes neces- 2001 bioterrorism attacks in the United
sary for pathogenesis. The pXO1 plasmid has States.
181,654 base pairs and contains the structural Dixon, Terry C., et al. Anthrax. New England
genes for the anthrax toxins cya (edema fac- Journal of Medicine 341 (September 9, 1999):
tor), lef (lethal factor), and pagA (protective 815-826. Details the disease and its patho-
antigen). The pXO2 plasmid consists of 96,231 genesis.
base pairs and carries three genes required for Miller, Judith, Stephen Engelberg, and William
synthesis of the capsule. These plasmids con- Broad. Germs: Biological Weapons and Amer-
tain a much greater number of single nucleo- icas Secret War. New York: Simon & Schuster,
tide polymorphisms (SNPs) and VNTRs among 2001. This book, written by three New York
strains than the chromosomal genome. There Times reporters, explores the ideas and ac-
are a variety of reference strains, such as Pas- tions of scientists and politicians involved in
teur (which lacks the XO1 plasmid), Sterne the past, present, and future of germ war-
(which lacks the XO2 plasmid), and Ames fare. Forty-two pages of notes and a select
(which has both plasmids and is fully virulent). bibliography.
Read, Timothy D., et al. Comparative Genome
Bioterrorism Sequencing for Discovery of Novel Poly-
Anthrax spores can be easily packaged to act morphisms in Bacillus anthracis. Science 296
as aerosoled (airborne) agents of war, and the (June 14, 2002): 2028-2033. Describes the
genome may be bioengineered to alter the complete sequencing of the anthrax ge-
virulence or effectiveness of current vaccines. nome.
Knowledge of the genetic composition of B. an-
thracis has facilitated the investigation of an- Web Sites of Interest
thrax attacks. In 1993, the Aum Shinrikyo cult Centers for Disease Control, Public Health
aerosoled a suspension of anthrax near Tokyo, Emergency Preparedness and Response.
Japan. Molecular studies of the genome from http://www.bt.cdc.gov. This comprehensive
this strain revealed it to be devoid of the pXO2 site offers information on how to recognize
plasmid (Sterne strain), explaining why only a illness caused by anthrax exposure and
bad odor rather than illness was the fortunate more. Available in Spanish.
consequence. In 2001, analysis of material from Nature. http://www.nature.com. The online
letter-based attacks with anthrax in the United version of the premier science journal Na-
States demonstrated the source to be the Ames ture includes links to research articles on the
strain. Furthermore, as a result of the exten- genetics of anthrax, including Focus on An-
sive laboratory studies associated with these at- thrax.
38 Antibodies
regions and the adjacent C region by a recom- the blood, and become associated with lymph
bination event. The remaining segments are nodes and the spleen; and B cells, which are
cut from the chromosome and subsequently formed in bone marrow and move directly to
destroyed, resulting in a fusion gene encoding the circulatory and the lymph systems. B cells
a specific light chain of an antibody. In mature are genetically programmed to produce anti-
B cells, this gene is then transcribed and trans- bodies. Each B cell synthesizes and secretes
lated into polypeptides that form a light chain only one type of antibody, which has the ability
of an antibody molecule. Genes for the other to recognize with high affinity a discrete region
class of light chains as well as heavy chains are (epitope or antigenic determinant) of an anti-
also made up of regions that undergo recombi- gen. Generally, an antigen has several different
nation during B-cell maturation. These ran- epitopes, and each B cell produces a set of
dom recombination events in each B cell dur- different antibodies corresponding to one of
ing maturation lead to the production of the many epitopes of the same antigen. All of
billions of different antibody molecules. Each the antibodies in this set, referred to as poly-
B cell has, however, been genetically pro- clonal antibodies, react with the same antigen.
grammed to produce only one of the many pos- The immune system is more effective at con-
sible variants of the same antibody. trolling infections than the nonspecific defense
response (bodily defenses against infection
Production of Antibodies: Immune such as skin, fever, inflammation, phagocytes,
Response natural killer cells, and some other antimicro-
Immunity is a state of bodily resistance bial substancesthat are not part of the im-
brought about by the production of antibodies mune system proper). The immune system has
against an invasion by an antigen. The immune three characteristic responses to antigens: di-
response is mediated by white blood cells verse, which effectively neutralizes or destroys
known as lymphocytes that are made in the various foreign invaders, whether they are mi-
bone marrow. There are two types of lympho- crobes, chemicals, dust, or pollen; specific,
cytes: T cells, which are formed when lympho- which effectively differentiates between harm-
cytes migrate to the thymus gland, circulate in ful and harmless antigens; and anamnestic,
which has a memory component that remem- antibodies is released in response to an inva-
bers and responds faster to a subsequent en- sion by a foreign agent. Each member of this
counter with an antigen. The primary immune group of polyclonal antibodies will launch the
response involves the first combat with anti- assault against the foreign agent by recognizing
gens, while the secondary immune response in- different epitopes of the same antigen. The
cludes the memory component of a first as- polyclonal nature of antibodies has been well
sault. As a result, humans typically get some recognized in the medical field.
diseases (such as chicken pox) only once; other In the case of multiple myeloma (a type of
infections (such as cold and influenza) often cancer), one B cell out of billions in the body
recur because the causative viruses mutate, proliferates in an uncontrolled manner. Even-
thus presenting a different antigenic face to tually, this event compromises the total popula-
the immune system each season. tion of B cells of the body. The immune system
An antibody-mediated immune response in- will produce huge amounts of IgG originating
volves several stages: detection of antigens, acti- from the same B cell, which recognizes only
vation of helper T cells, and antibody produc- one specific epitope of an antigen; therefore,
tion by B cells. White blood cells known as this persons immune system produces a set of
macrophages continuously wander through antibodies referred to as monoclonal anti-
the circulatory system and the interstitial bodies. Monoclonal antibodies form a popula-
spaces between cells searching for antigen mol- tion of identical antibodies that all recognize
ecules. Once an antigen is encountered, the in- and are specific for one epitope on an antigen.
vading molecule is engulfed and ingested by a Thus, someone with this condition may suffer
macrophage. Helper T cells become activated frequent bacterial infections because of a lack
by coming in contact with the antigen on the of antibody diversity. Indeed, a bacterium whose
macrophage. In turn, an activated helper T cell antigens do not match the antibodies manufac-
identifies and activates a B cell. The activated T tured by the overabundant monoclonal B cells
cells release cytokines (a class of biochemical has a selective advantage.
signal molecules) that prompt the activated B The high-affinity binding capacity of anti-
cell to divide. Immediately, the activated B cell bodies with antigens has been employed in
generates two types of daughter cells: plasma both therapeutic and diagnostic procedures. It
cells (each of which synthesizes and releases ap- is, however, unfortunate that the effectiveness
proximately two thousand to twenty thousand of commercial preparations of polyclonal anti-
antibody molecules per second into the blood- bodies varies widely from batch to batch. In
stream during its life span of four to five days) some instances of immunization, certain epi-
and B memory cells (which have a life span of a topes of a particular antigen are strong stimula-
few months to a year). The B memory cells are tors of antibody-producing cells, whereas at
the component of the immune memory system other times, the immune system responds more
that, in response to a second exposure to the vigorously to different epitopes of the same
same type of antigen, produces antibodies in antigen. Thus one batch of polyclonal antibod-
larger quantities and at faster rates over a lon- ies may have a low level of antibody molecules
ger time frame than the primary immune re- directed against a major epitope and not be as
sponse. A similar cascade of events occurs when effective as the previous batch. Consequently, it
a macrophage presents an antigen directly to a is desirable to produce a cell line that will pro-
B cell. duce monoclonal antibodies with a high affin-
ity for a specific epitope on the antigen for
Polyclonal and Monoclonal Antibodies commercial use. Such a cell line would provide
Plasma cells originating from different B a consistent and continual supply of identical
cells manufacture distinct antibody molecules (monoclonal) antibodies. Monoclonal antibod-
because each B cell was presented with a spe- ies can be produced by hybridoma cells, which
cific portion of the same antigen by a helper T are generated by the fusion of cancerous B cells
cell or macrophage. Thus a set of polyclonal and normal spleen cells obtained from mice
Antibodies 41
immunized with a specific antigen. After initial and cost-effective manner. It has been demon-
selection of hybridoma clones, monoclonal an- strated that a hybrid IgA-IgG molecule pro-
tibody production is maintained in culture. In duced by transgenic plants prevented coloniza-
addition, the hybridoma cells can be injected tion of S. mutans in culture, which appears to
into mice to induce tumors that, in turn, will re- be how the antibody prevents colonization of
lease large quantities of fluid containing the this bacterium in vivo.
antibody. This fluid containing monoclonal It has been estimated that antibodies ex-
antibodies can be collected periodically and pressed in soybeans at a level of 1 percent of to-
may be used immediately or stored for future tal protein may cost approximately one hun-
use. Various systems used to produce mono- dred dollars per kilogram of antibody, which is
clonal antibodies include cultured lymphoid relatively inexpensive in comparison with the
cell lines, yeast cells, Trichoderma reese (ascomy- cost of traditional antibiotics. Transgenic
cetes), insect cells, Escherichia coli, and monkey plants have also been used as bioreactors for
and Chinese hamster ovary cells. Transgenic the large-scale production of antibodies with
plants and plant cell cultures have been ex- no extensive purification schemes. In fact, anti-
plored as potential systems for antibody expres- bodies have been expressed in transgenic to-
sion. bacco roots and then accumulated in tobacco
seeds. If this technology could be employed to
Impact and Applications obtain stable accumulation of antibodies in
The high-affinity binding capacity of anti- more edible plant organs such as potato tubers,
bodies may be used to inactivate antigens in it could potentially allow for long-term storage
vivo (within a living organism). The binding as well as a safe and easy delivery of specific anti-
property of antibodies may also be employed in bodies for immunotherapeutic applications. In
many therapeutic and diagnostic applications. addition, plant-produced antibodies may be
In addition, it is a very effective tool in both im- more desirable for human use than microbial-
munological isolation and detection methods. produced antibodies, because plant-produced
Monoclonal antibodies may outnumber all antibodies undergo eukaryotic rather than the
other products being explored by various bio- prokaryotic (bacterial) post-translational mod-
technology-oriented companies for the treat- ifications. Human glycosylation (a biochemical
ment and prevention of disease. For example, process whereby sugars are attached onto the
many strategies for the treatment of cancerous protein) is more closely related to that of plants
tumors as well as for the inhibition of human than that of bacteria.
immunodeficiency virus (HIV) replication are The potential use of antibody expression in
based on the use of monoclonal antibodies. plants for altering existing biochemical path-
HIV is a retrovirus (a virus whose genetic mate- ways has also been demonstrated. For example,
rial is ribonucleic acid, or RNA) that causes ac- germination mediated by phytochrome (a bio-
quired immunodeficiency syndrome (AIDS). chemical produced by plants) has been altered
Advances in plant biotechnology have made it by utilizing plant-produced antibodies. In addi-
possible to use transgenic plants to produce tion, antibodies expressed in plants have been
monoclonal antibodies on a large scale for ther- successfully used to immunize host plants
apeutic or diagnostic use. Indeed, one of the against pathogenic infection; for example, to-
most promising applications of plant-produced bacco plants have already been immunized
antibodies in immunotherapy is in passive im- with antibodies against viral attack. This ap-
munization (for example, against Streptococcus proach has great potential to replace the tradi-
mutans, the most common cause of tooth de- tional methods (use of chemicals) in control-
cay). Large doses of the antibody are required ling pathogens.
in multiple applications for passive immuno- Sibdas Ghosh and Tom E. Scola
therapy to be effective. Transgenic antibody- See also: Allergies; Autoimmune Disor-
producing plants may be one source that can ders; Biopharmaceuticals; Blotting: Southern,
supply huge quantities of antibodies in a safe Northern, and Western; Diabetes; Diphtheria;
42 Antisense RNA
transcription (pre-transcriptional gene si- form the mature primer needed for DNA repli-
lencing) or after a messenger RNA (mRNA) cation. Antisense RNA I can bind to RNA II,
has been transcribed (post-transcriptional preventing the formation of the necessary struc-
gene silencing ture. In the R1 plasmid, the CopA antisense
RNA interference (RNAi): Sequence-specific RNA can bind and prevent the translation of
degradation of messenger RNA (mRNA) the RNA transcript for replication initiation
caused by complementary double-stranded protein RepA. Thus, change in plasmid num-
RNA ber is controlled by changing levels of antisense
up-regulation: a process of gene expression RNA, modifying the ability of plasmids to repli-
in which the amount that a gene is tran- cate.
scribed and/or translated is increased Many plasmids use antisense RNA to ensure
their maintenance within bacteria. The R1 plas-
Discovery mid transcribes Hok toxin mRNA, but interac-
In addition to the three main types of tion with antisense Sok RNA prevents its trans-
RNAmessenger RNA (mRNA), transfer RNA lation. Sok RNA is less stable than Hok RNA, so
(tRNA), and ribosomal RNA (rRNA)there plasmid loss leads to Sok degradation but leaves
are numerous other types of RNA molecules. some Hok transcripts, which are translated into
Some have an effect, through complementary a toxin that kills the cell. This is an ingenious
binding, on mRNA molecules. When this kind way of selecting for plasmid propagation. Anti-
of RNA binds to an mRNA, it effectively blocks sense regulation has also been found in some
translation of the mRNA and can therefore be transposons and bacteriophages.
described as having an antisense action (that is, Bacteria use antisense RNA to regulate par-
it blocks the expression of the message in the ticular genes. Such RNA is often encoded in a
mRNA). Antisense RNA was first discovered in region different from that of the target and
1981 as a mechanism regulating copy number may affect multiple genes. For example, the
of bacterial plasmids. Other RNAs, such as OxyS RNA, induced by oxidative stress, inhibits
small nuclear and small nucleolar RNAs translation of fhlA mRNA (involved in formate
(snRNA and snoRNA), act in RNA splicing and metabolism). In conjunction with the protein
editing, with a catalytic effect guided by com- Hfq, OxyS RNA binds near the ribosome-bind-
plementary base pairing. ing site in fhlA mRNA, preventing translation.
Various forms of gene down-regulation were MicF RNA is induced under cellular stress and
discovered throughout the 1990s, including binds to the mRNA of membrane pore protein
plant post-transcriptional gene silencing (that ompF to prevent its translation.
is, preventing the mRNA from being trans- One of the first examples of antisense regu-
lated), gene silencing in fungi (that is, prevent- latory mechanisms in eukaryotes came from
ing transcription of a gene), and RNA interfer- the nematode Caenorhabditis elegans. Small anti-
ence in the nematode Caenorhabditis elegans. sense RNA molecules lin-4 and let-7 show im-
The importance of noncoding RNA molecules, perfect base-pairing to the 3 untranslated re-
including antisense RNA, is becoming clear. gion of their target gene mRNAs. This results in
They add a previously unknown level of genetic translational inhibition and is important for
complexity, and the extent of their influence is normal development. These small antisense
yet to be determined fully. RNAs are members of the microRNA (miRNA)
class of molecules, which are single-stranded
Natural Function RNA molecules, about 21 nucleotides long,
Antisense RNA is utilized in a number of found throughout eukaryotes. They are pro-
ways by bacterial plasmids. Replication of duced by cleavage of longer molecules (about
ColE1 plasmids requires an RNA preprimer, 60-100 nucleotides) which contain partial self-
called RNA II, that interacts with the origin of complementarity that produces a hairpin struc-
replication and forms a particular secondary ture. The function of most miRNAs is unknown.
structure. This allows an enzyme to cut and Antisense RNA has been implicated in other
44 Antisense RNA
Dr. Phillip A. Sharp, who with Richard J. Roberts won the 1993 Nobel Prize in Physiology or Medicine. Sharp acknowledges that the
discovery of antisense RNA and RNA interference has changed his cancer research. The process could theoretically offer ways of si-
lencing the genes associated with cancer. (AP/Wide World Photos)
processes. Imprinted genes are often associ- mans), and the steps involved are likely to be
ated with antisense transcripts from the same similar. RNAi begins by the recognition of long
locus, although their role is unclear. Double- double-stranded RNA molecules by the con-
stranded RNA may be capable of affecting served protein Dicer, which cuts these long
DNA chromatin structure through methyla- RNAs to produce small interfering RNAs
tion of homologous sequence. (siRNA, double-stranded RNA about 21-23 nu-
cleotides long with overhanging 3 ends). These
RNA Interference become part of the RNA-induced silencing com-
RNA interference (RNAi) causes sequence- plex (RISC), which uses the antisense strand of
specific gene silencing in response to the pres- the siRNA to recognize complementary RNA
ence of double-stranded RNA. The process is sequences. These sequences are then cut and
proposed to have evolved as a mechanism of degraded. Some organisms show amplification,
avoiding viral infection and limiting transpos- where siRNA stimulates production of more
able element replication, since both can in- double-stranded RNA to be processed by Dicer.
volve double-stranded RNA. Caenorhabditis elegans and plants show evidence
The process is present in a wide variety of eu- of a systemic response, whereby initial silencing
karyotes (including mice and probably hu- in one cell spreads to other cells.
Archaea 45
Therapeutic Applications
Many disease states are caused by abnormal Archaea
gene expression and are therefore potential
targets for gene therapy. One approach is to Field of study: Cellular biology
use antisense RNA or RNAi. For example, can- Significance: Archaea are diverse prokaryotic or-
cer cells often show overexpression of genes in- ganisms distinct from the historically familiar bac-
volved in growth and proliferation. These teria. Archaea have certain molecular properties
genes could be targeted by antisense RNA to previously thought to occur only in eukaryotes.
decrease the amount of gene product pro- Many archaea require severe conditions for
duced, in hopes of preventing tumor growth. growth, and their genetic processes have adapted to
RNAi could be used to target specific muta- these extreme conditions in ways that are not fully
tions. The mRNA from a mutant allele could be understood.
targeted for degradation in a heterozygous pa-
tient, allowing production of the correct pro- Key terms
tein from the wild-type allele alone. Antisense conjugation: the process by which one bacte-
techniques could be used to target viruses and rial cell transfers DNA directly to another
prevent their replication, or could be used to domain: the highest-level division of life, some-
correct aberrant splicing. Many of the pro- times called a superkingdom
cesses described above have been successfully extreme halophiles: microorganisms that re-
demonstrated in experimental systems such as quire extremely high salt concentrations for
cell culture or mouse models. optimal growth
Many issues need to be addressed before insertion sequence: a small, independently
antisense RNA therapeutics become feasible. A transposable genetic element
delivery system is needed to produce a long- methanogens: microorganisms that derive en-
lasting effect in the correct cell type. The fact ergy from the production of methane
that RNA interference appears to spread sys- prokaryotes: unicellular organisms with sim-
temically in some organisms may facilitate its ple ultrastructures lacking nuclei and other
application. The safety and effectiveness of intracellular organelles
such approaches also need to be tested. Never- small subunit ribosomal RNA (ssu rRNA):
theless, the approach is promising and poten- the RNA molecule found in the small sub-
tially very useful. unit of the ribosome; also called 16S rRNA
Peter J. Waddell and Michael J. Mclachlan (in prokaryotes) or 18S rRNA (in eukary-
See also: Gene Regulation: Eukaryotes; otes)
Human Genetics; Model Organism: Caenorhab-
ditis elegans; Noncoding RNA Molecules; RNA Gene Sequences Measure the Diversity of
Structure and Function; RNA Transcription Prokaryotes
and mRNA Processing; RNA World; Viral Ge- Prokaryotic microorganisms have been on
netics. earth for as many as 3.8 billion years and have
diverged tremendously in genetic and meta-
Further Reading bolic terms. Unfortunately, the magnitude of
Brantl, S. Antisense-RNA Regulation and RNA this divergence has made it difficult to measure
Interference. Biochimica et Biophysica Acta the relatedness of prokaryotes to one another.
1575 (2002): 15-25. A detailed survey of the In the 1970s, Carl R. Woese addressed this
wide variety of ways in which antisense RNAs problem using a method of reading short se-
operate. quences of ribonucleotides from a highly con-
Shuey, D. J., D. E. McCallus, and T. Giordano. served RNA molecule, the small subunit ribo-
RNAi: Gene Silencing in Therapeutic In- somal RNA (ssu rRNA). Because this RNA is
tervention. Drug Discovery Today 7 (2002): present in all organisms and has evolved very
1040-1046. A look at challenges ahead for us- slowly, any two organisms have at least a few of
ing RNAi in a medical setting. these short nucleotide sequences in common.
46 Archaea
of replication. As in bacteria, the genes are genes for the DNA mismatch repair proteins
densely packed and often grouped into clusters found in all other organisms.
of related genes transcribed from a common
promoter. The promoters themselves, however, Unique Genetic Properties?
resemble the TATA box/BRE element combi- This last observation raises an important
nation of eukaryotic DNA polymerase II (Pol II) question: Has an evolutionary history distinct
promoters, and the RNA polymerases have the from all conventional genetic systems, com-
complex subunit composition of eukaryotes bined with the special demands of life in un-
rather than the simple composition found in usual environments, resulted in unique genetic
bacteria. Furthermore, archaea initiate tran- properties in archaea? Although basic genetic
scription by a simplified version of the process assays can be performed in only a few species,
seen in eukaryotic cells: Transcription factors the results help identify which genetic proper-
(TATA-binding protein and a TFIIB) first bind ties of cellular organisms are truly universal
to regions ahead of the promoter, then recruit and which ones may have unusual features in
RNA polymerase to attach and begin transcrip- archaea.
tion. Introns are rare in archaea, however, and The methanogen Methanococcus voltae trans-
do not interrupt protein-encoding genes. Also, fers short pieces of chromosome from one cell
the regulation of transcription in archaea seems to another, using particles that resemble bacte-
to depend heavily on the types of repressor and rial viruses (bacteriophages). This means of
activator proteins found in bacteria. gene transfer has been seen in only a few bacte-
ria. In other methanogens, researchers have
Genomes of Archaea used more conventional genetic phenomena,
The availability of complete DNA sequences such as antibiotic-resistance genes, plasmids,
now enables archaeal genomes to be compared and transposable elements, to develop tools for
to the genomes of bacteria and eukaryotes. cloning or inactivating genes. As a result, new
One pattern that emerges from these compari- details about the regulation of gene expression
sons is that most of the archaeal genes responsi- in archaea and the genetics of methane forma-
ble for the processing of information (synthesis tion are now coming to light.
of DNA, RNA, and proteins) resemble their The extreme halophile Halobacterium salin-
eukaryotic counterparts, whereas most of the arum exhibits extremely high rates of spontane-
archaeal genes for metabolic functions (biosyn- ous mutation of the genes for its photosyn-
thetic pathways, for example) resemble their thetic pigments and gas vacuoles. This genetic
bacterial counterparts. The genomes of archaea instability reflects the fact that insertion se-
also reveal probable cases of gene acquisition quences transpose very frequently into these
from distant relatives, a process called lateral and other genes. A distantly related species,
gene transfer. Haloferax volcanii, has the ability to transfer
A third pattern to emerge from genome chromosomal genes by means of conjugation.
comparisons is that some archaea are missing Although many bacteria engage in conjuga-
genes thought to be important or essential. For tion, the mechanism used by H. volcanii does
example, the genomes of at least two methano- not resemble the typical bacterial system, since
genic archaea do not encode an enzyme that no plasmid seems to be involved, and there is
charges transfer RNA (tRNA) with cysteine. no apparent distinction between donor strain
These archaea instead use a novel strategy for and recipient strain in the transfer of DNA.
making cysteinyl-tRNA: Some of the seryl tRNA Genetic tools for the archaea from geother-
made by these cells is converted to cysteinyl mal environments are less well developed, but
tRNA by a specialized enzyme. Even more in- certain selections have made it possible to
triguing is the much longer list of archaeaall study spontaneous mutation and homologous
of which happen to be hyperthermophiles, recombination in some species of Sulfolobus. At
which grow optimally at 80 degrees Celsius the normal growth temperatures of these aero-
(176 degrees Fahrenheit) or abovethat lack bic archaea, 75-80 degrees Celsius (167-176 de-
48 Artificial Selection
grees Fahrenheit), spontaneous chemical de- biology text provides an accurate and well-
composition of DNA is calculated to be about illustrated overview of the biological diver-
one thousand times more frequent than in the sity of the archaea.
organisms previously studied by geneticists. In Olsen, Gary, and Carl R. Woese. Archaeal
spite of this, Sulfolobus acidocaldarius exhibits Genomics: An Overview. Cell 89 (1997):
the same frequency of spontaneous mutation 991-994. This mini-review article, along with
as Escherichia coli and significantly lower pro- several accompanying articles, summarizes
portions of base-pair substitutions and dele- for specialists numerous molecular differ-
tions. This indicates especially effective mecha- ences and similarities between archaea and
nisms for avoiding or accurately repairing DNA bacteria or eukaryotes, based on the first
damage, including mismatched bases, despite archaeal genomes to be sequenced.
the fact that no mismatch repair genes have Woese, Carl. R. Archaebacteria. Scientific
been found in Sulfolobus species. Also, S. acido- American 244 (1981): 98-122. A clear, though
caldarius, like H. volcanii, has a mechanism of somewhat dated, description of the archaea
conjugation that does not require a plasmid and the various lines of evidence for their
or distinct donor and recipient genotypes. The status as a third form of life.
transferred DNA recombines efficiently into
the resident chromosome, as indicated by fre-
quent recombination between mutations
spaced only a few base pairs apart.
Finding two similar and unusual mechanisms
of conjugation in two dissimilar and distantly Artificial Selection
related archaea (H. volcanii and S. acidocal- Fields of study: Evolutionary biology;
darius) raises questions regarding the possible Population genetics
advantages of this capability. Population ge- Significance: Artificial selection is the process
netic theory predicts that organisms that re- through which humans have domesticated and
produce clonally (as bacteria and archaea do) improved plants and animals. It continues to be
would benefit from occasional exchange and the primary means whereby agriculturally impor-
recombination of genes, because this acceler- tant plants and animals are modified to improve
ates the production of beneficial combinations their desirability. However, artificial selection is
of alleles. Such recombination may be particu- also a threat to genetic diversity of agricultural or-
larly important for archaea such as Haloferax ganisms as uniform and productive strains re-
and Sulfolobus species, whose extreme environ- place the many diverse, locally produced varieties
ments are like islands separated by vast areas that once existed around the globe.
that cannot support growth. For these organ-
isms, frequent DNA transfer between cells of
the same species may provide an efficient way Key terms
to enhance genetic diversity within small, iso- genetic merit: a measure of the ability of a
lated populations. parent to contribute favorable characteris-
Dennis W. Grogan tics to its progeny
See also: Antisense RNA; Bacterial Genet- genetic variation: a measure of the availabil-
ics and Cell Structure; Gene Regulation: Bacte- ity of genetic differences within a popula-
ria; Lateral Gene Transfer; Noncoding RNA tion upon which artificial selection has po-
Molecules. tential to act
heritability: a proportional measure of the
Further Reading extent to which differences among organ-
Madigan, Michael T., John M. Martinko, and isms within a population for a particular
Jack Parker. Brock Biology of Micro-organisms. character result from genetic rather than en-
10th ed. Upper Saddle River, N.J.: Prentice vironmental causes (a measure of nature
Hall, 2003. Chapter 13 of this popular micro- versus nurture)
Artificial Selection 49
Natural vs. Artificial Selection tightly in the head of a grass such as wheat is an
Selection is a process through which organ- advantage to the farmer, as it makes harvesting
isms with particular genetic characteristics leave easier. That same characteristic would be a dis-
more offspring than do organisms with alterna- advantage to wild wheat because it would limit
tive genetic forms. The process may occur be- seed dispersal.
cause the genetic characteristics confer upon
the organism a better ability to survive and ulti- Early Applications
mately produce more offspring than individu- Artificial selection was probably conducted
als with other characteristics (natural selec- first by early farmers who identified forms of
tion), or it may be caused by selective breeding crop plants that had characteristics that fa-
of individuals with characteristics valuable to vored cultivation. Seeds from favored plants
humans (artificial selection). Natural and arti- were preferentially kept for replanting. Any
ficial selection may act in concert, as when a ge- characteristics that were to some degree herita-
netic characteristic confers a disadvantage di- ble would have had the tendency to be passed
rectly to the organism. Dwarfism in cattle, for on to the progeny through the selected seeds.
example, not only directly reduces the survival Some favored characteristics may have been
of the affected individuals but also reduces the controlled by a single gene and were therefore
value of the animal to the breeder. Conversely, quickly established, whereas other favored
natural selection may act in opposition to artifi- characteristics may have been controlled by a
cial selection. For example, a genetic charac- large number of genes with individually small
teristic that results in the seed being held effects, making them more difficult to estab-
The beefalo is created by breeding a cow and a bison, and then breeding the offspring again to a cow. Such hybridization, in both
plants and animals, is a form of artificial selection that has been practiced by humans for thousands of years to meet agricultural
needs. (AP/Wide World Photos)
50 Artificial Selection
lish. Nevertheless, seeds selected from the best gene sequences promised to allow researchers
plants would tend to produce offspring that to bypass the time-consuming data-recording
were better than average, resulting in gradual programs upon which genetic progress of the
improvement in the population. It would not 1990s relied.
have been necessary to have knowledge of the
mechanisms of genetics to realize the favorable Diversity vs. Uniformity
effects of selection. Likewise, individuals who The ultimate limit to what can be achieved
domesticated the first animals for their own use by selection is the exhaustion of genetic vari-
would have made use of selection to capture ants. One example of the extremes that can be
desirable characteristics within their herds and accomplished by selection is evident in dog
flocks. The first of those characteristics was breeding: The heaviest breeds weigh nearly
probably docile behavior, a trait known to be one hundred times as much as the lightest
heritable in contemporary livestock popula- breeds. Experimental selection for body weight
tions. in insects and for oil content in corn has re-
sulted in variations of similar magnitudes.
From Pedigrees to Genome Maps However, most modern breeding programs
Technology to improve organisms through for agricultural crops and livestock seek to de-
selective breeding preceded an understanding crease variability while increasing productivity.
of its genetic basis. Recording of pedigrees and Uniformity of the products enhances the effi-
performance records began with the formal ciency with which they can be handled me-
development of livestock breeds in the 1700s. chanically for commercial purposes. As indige-
Some breeders, notably Robert Bakewell, be- nous crop and livestock varieties are replaced
gan recording pedigrees and using progeny by high-producing varieties, the genetic varia-
testing to determine which sires had superior tion that provides the source of potential fu-
genetic merit. Understanding of the principles ture improvements is lost. Widespread use of
of genetics through the work of Gregor Mendel uniform varieties may also increase the suscep-
enhanced but did not revolutionize applica- tibility to catastrophic losses or even extinction
tions to agricultural plant and animal improve- from an outbreak of disease or environmental
ment. condition. The lack of biodiversity in the wake
Development of reliable methods for testing of such species loss could threaten entire eco-
the efficiency of artificial selection dominated systems and human beings themselves.
advances in the fields of plant and animal ge- William R. Lamberson
netics during the first two-thirds of the twenti- See also: Eugenics; Eugenics: Nazi Ger-
eth century. Genetic merit of progeny was ex- many; Evolutionary Biology; Gene Therapy;
pected to be equal to the average genetic merit Genetic Engineering: Agricultural Applica-
of the parents. More effective breeding pro- tions; Genetic Engineering: Historical Devel-
grams are dependent on identifying potential opment; Genomes; Genome Libraries; Hardy-
parents with superior genetic merit. Com- Weinberg Law; High-Yield Crops; Inbreeding
puters and large-scale databases have greatly and Assortative Mating; Natural Selection;
improved selection programs for crops and Polyploidy; Population Genetics; Pedigree
livestock. Genetic change on the order of 2 per- Analysis; Punctuated Equilibrium; Quantita-
cent per generation became possible. How- tive Inheritance; Sociobiology; Speciation.
ever, selection to improve horticultural species
and companion animals continued to rely Further Reading
largely on the subjective judgment of the Lurquin, Paul F. The Green Phoenix: A History of
breeder to identify superior stock. Plant and Genetically Modified Plants. New York: Colum-
animal genome-mapping programs would fa- bia University Press, 2001. Gives equal
cilitate the next leap forward in genetic im- weight to the science behind developing im-
provement of agricultural organisms. Selec- proved crop strains and the multinational
tion among organisms based directly on their corporations marketing the results.
Autoimmune Disorders 51
Rissler, Jane, and Margaret Mellon. The Ecologi- antigens: foreign substances recognized by
cal Risks of Engineered Crops. Cambridge, the immune system that result in the pro-
Mass.: MIT Press, 1996. A scientific and pol- duction of antibodies and lymphocytes di-
icy assessment of the dangers. The authors rected specifically against them
both of whom work for the Union of Con- immune system: the system that normally re-
cerned Scientistsnot only outline the risks sponds to foreign agents by producing anti-
but also make suggestions for ways to mini- bodies and stimulating antigen-specific lym-
mize them. phocytes, leading to destruction of these
Tudge, Colin. The Engineer in the Garden: Genes agents
and Genetics, from the Idea of Heredity to the Cre- lymphocytes: sensitized cells of the immune
ation of Life. New York: Hill and Wang, 1995. system that recognize and destroy harmful
A British science journalist follows the his- agents via antibody and cell-mediated re-
tory of human manipulation of genetics to sponses that include B lymphocytes from the
explore the social ramifications of artificial bone marrow and T lymphocytes from the
selection, which has resulted in genetic ad- thymus
vances that have not been adequately ex- major histocompatibility complex (MHC):
posed to ethical and policy considerations. a system of protein markers on a cells outer
Library Journal praised the book as a good membrane following infection with a virus,
balance between overall breadth of coverage malignant cell, or foreign cell that signals
and the intelligent, readable synthesis of the the immune system to destroy the cell
myriad issues of genetic research.
Zohary, Daniel, and Maria Hopf. Domestication Autoimmune Disorders and Immune
of Plants in the Old World: The Origin and System Dysfunction
Spread of Cultivated Plants in West Asia, Europe, Autoimmune disorders involve a large group
and the Nile Valley. 3d ed. New York: Oxford of chronic and potentially life-threatening dis-
University Press, 2001. A thorough review of eases that are initiated by an individuals own
information on the beginnings of agricul- immune system attacking the organs or tissues
ture, particularly utilizing new molecular bi- of the individuals own body. The main func-
ology findings on the genetic relations be- tion of the immune system is to defend against
tween wild and domesticated plant species. invading microorganisms such as bacteria,
fungi, viruses, protozoa, and parasites by pro-
ducing antibodies or lymphocytes that recog-
nize and destroy the harmful agent. The ability
Autoimmune Disorders to distinguish normal body constituents (self)
from foreign substances (nonself) is crucial to
Fields of study: Diseases and syndromes; appropriate immune functioning. Loss of this
Immunogenetics ability to distinguish between self and nonself
Significance: Autoimmune disorders are chronic can lead to serious damage to the affected or-
diseases that arise from a breakdown of the im- gans and tissues.
mune systems ability to distinguish between the Autoimmunitythe inaccurate recognition
bodys own cells and foreign substances. Autoim- of a normal body component as foreign, fol-
mune disorders can be caused by both genetic and lowed by the mounting of an autoimmune re-
environmental factors and cause an individuals sponseresults when normal autoantigens on
immune system to react against the organs or tis- body cells stimulate the development of auto-
sues of the individuals own body. antibodies. These autoantibodies are most of-
ten the result of a genetic defect during viral
Key terms and bacterial infections or from environmental
antibodies: molecules in blood plasma re- or chemical factors; they may also, according to
sponsible for recognizing and binding to some researchers, be a natural consequence of
antigens the aging process.
52 Autoimmune Disorders
History and Classification of Autoimmune mune disorders often requires both a genetic
Disorders susceptibility and additional stimuli such as ex-
The concept of autoimmune disorders was posure to a toxin. Of the numerous theories
first proposed in 1901, but it was not until the proposed for the cause of autoimmunity devel-
1950s that autoimmunity was experimentally opment, three models have received the most
created in animals via immunization. By the consideration by clinical researchers. The
1960s, it was recognized that autoimmunity clonal deletion theory suggests that autoimmu-
was a direct or indirect cause of numerous hu- nity develops if autoreactive T or B cell clones
man ailments. Many diseases formerly classi- are not eliminated during the fetal period or
fied as collagen-vascular diseases (collagenoses) very soon after birth. The body normally does
were later classified as autoimmune disorders. not react to its own fetal or neonatal antigens,
Autoimmune disorders are generally catego- which are recognized because the correspond-
rized as organ-specific diseases and non-organ- ing T and B cell clones are eliminated from the
specific (also called systemic) diseases. Organ- immune system. In the unfortunate event that
specific autoimmune diseases involve an attack forbidden clones of autoreactive cells remain
directed against one main organ and have been active, antibodies are produced that are di-
documented for essentially every organ in the rected against its own antigens, and autoimmu-
body. Common examples include multiple scle- nity develops, frequently involving the loss of
rosis (brain), insulin-dependent diabetes mel- the helper T cells ability to regulate B-cell
litus (pancreas), Graves disease (thyroid), Ad- function. A second theory suggests that some
disons disease (adrenal glands), pernicious antigens that are normally nonimmunogenic
anemia (stomach), myasthenia gravis (mus- (hidden antigens) somehow become autoim-
cles), autoimmune hemolytic anemia (blood), munogenic and stimulate the immune system
primary biliary cirrhosis (liver), pemphigus to react against itself. A third theory suggests
vulgaris (skin), and glomerulonephritis (kid- that autoimmunity can be initiated by an exog-
neys). Non-organ-specific autoimmune diseases enous antigen, assuming that the antibodies
involve an attack by the immune system on sev- produced to fight it cross-react with a similar
eral body areas, potentially causing diseases determinant on the bodys own cells.
such as systemic lupus erythematosus, rheuma-
toid arthritis, polyarteritis nodosa, scleroderma, Diagnosis and Treatment
ankylosing spondylitis, and rheumatic fever. Diagnosis of autoimmune disorders gener-
Some evidence suggests that other condi- ally begins with the often difficult task of docu-
tions (such as certain types of eye inflammation menting autoantibodies and autoreactive T
and male and female infertility) may be auto- cells. A condition suspected to be caused by
immune related. Allergies involve hypersensi- autoimmunity can also be confirmed by a num-
tivity reactions that result in immune reactions ber of other direct and indirect methods, such
that can lead to inflammation and tissue dam- as a favorable response to immunosuppressive,
age. Environmental antigens such as pollen, corticosteroid, or anti-inflammator y drug
dust mites, food proteins, and bee venom may treatment along with several other immuno-
cause allergic reactions such as hay fever, logic techniques.
asthma, and food intolerance in sensitive indi- Treatment strategies lag behind the ability
viduals via the antibody class known as immu- to diagnose autoimmune disorders. Initial man-
noglobulin E (IgE). Medications such as anti- agement involves the control and reduction of
biotics may also be recognized as chemical both pain and loss of function. Correction of
antigens, causing adverse allergic reactions. deficiencies in hormones such as insulin or thy-
Immunologists do not know the precise ori- roxin caused by autoimmune damage to glands
gin of most autoimmune diseases. What re- is often performed first. Replacing blood com-
searchers have shown is that most autoimmune ponents by transfusion is also considered, but
diseases occur more frequently in females than treatment effectiveness is often limited by the
in males and that the development of autoim- lack of knowledge of the precise disease mecha-
Autoimmune Disorders 53
Helicobacter pylori, which causes stomach ulcers, is only one example of one of the many forms of bacteria. The inset shows a single
bacterim. (AP/Wide World Photos)
56 Bacterial Genetics and Cell Structure
such as F pili in E. coli, are involved in the ex- bacteria can be induced to engage in a unidi-
change of genetic material from one bacterium rectional (one-way) exchange of genetic mate-
to another in a process called conjugation. rial via conjugation, first observed in 1946 by
Some bacterial strains have one or more biochemists Joshua Lederberg and Edward
flagella, which allow them to be motile (capa- Tatum. The unidirectional nature of the gene
ble of movement). Any bacterium may have transfer was discovered by William Hayes in
one or more of these surface structures. 1953. He found that one bacterial cell was a
Research in molecular genetics is continu- donor cell while the other was the recipient.
ing to expand insight into bacterial classifica- In the 1950s, molecular biologists Franois Ja-
tion and gene function. Many researchers have cob and Elie Wollman used conjugation and a
been actively sequencing the genomes of bacte- technique called interrupted mating to map
ria from a broad spectrum. The number of spe- genes onto the bacterial chromosome. By break-
cies that have been sequenced is now in the ing apart the conjugation pairs at intervals and
hundreds and includes many human patho- analyzing the times at which donor genes en-
gens, such as those that cause tuberculosis, bac- tered the recipient cells, they were able to de-
terial pneumonia, ulcers, bacterial influenza, termine a correlation between time and the
leprosy, and Lyme disease. The genomes of a distance between genes on a chromosome. The
wide range of nonpathogenic bacteria have use of this technique led to a complete map of
also been sequenced. Comparisons among the the sequence of genes contained in the chro-
genomes that have been sequenced is begin- mosome. It also led to a surprise: It was use of
ning to show extensive evidence that bacteria interrupted mating with E. coli that first dem-
of different species have transferred genes onstrated the circularity of the bacterial chro-
back and forth many times in the past, thus mosome. The circular structure of the chromo-
making it difficult to trace their evolutionary some was in striking contrast to eukaryotic
lineages. chromosomes, which are linear.
virulent type S bacteria were recovered from manufacture viral proteins. Bacteriophages, or
their blood. An unknown agent apparently phages, infect bacteria by attaching themselves
transformed avirulent type R into virulent type to a bacterium and injecting their genetic ma-
S. Griffith called the agent the transforming terial into the cell. Sometimes, during the as-
principle. It was his belief that the transform- sembly of new viral particles, a piece of the host
ing principle was a protein. cells DNA may be enclosed in the viral capsid.
Sixteen years later, in 1944, bacteriologists When the virus leaves the host cell and infects a
Oswald Avery, Colin MacLeod, and Maclyn second cell, that piece of bacterial DNA enters
McCarty designed an experiment that showed the second cell, thus changing its genetic
conclusively that the transforming principle makeup. Generalized transduction (the trans-
was DNA rather than protein. They showed fer of a gene from one bacterium to another)
that R bacteria could be transformed to S bacte- was discovered by Joshua and Esther Lederberg
ria in a test tube. They then progressively puri- and Norton Zinder in 1952. Using E. coli and a
fied their extract until only proteins and the bacteriophage called P1, the Lederbergs and
two nucleic acids, RNA and DNA, remained. Zinder were able to show that transduction
They placed some of the mixture onto agar could be used to map genes to the bacterial
plates (glass dishes containing a gelatin growth chromosome.
medium). At this point, transformation still
occurred; therefore, it was clear that one of Hershey-Chase Bacteriophage
these three molecules was the transforming Experiments
agent. They treated their extract with protein- The use of bacteriophages has been instru-
degrading enzymes, which denatured (de- mental in confirming DNA as the genetic mate-
stroyed) all the proteins in the extract. Despite rial of living cells. Alfred Hershey and Martha
the denaturing of the proteins, transformation Chase devised a series of experiments using E.
still occurred when some of the extract was coli and the bacteriophage T2 that conclusively
plated; had protein been the transforming established DNA as genetic material in 1953.
agent, no transformation could have occurred. Bacteria are capable of manufacturing all es-
Protein was eliminated as the transforming sential macromolecules by utilizing material
agent. The next step was to determine which of from their environment. Hershey and Chase
two nucleic acids was responsible for the trans- grew cultures of E. coli in a growth medium en-
formation of the R strain into the S strain. They riched with a radioactive isotope of phospho-
introduced RNase, an enzyme that degrades rus, phosphorus 32. DNA contains phospho-
RNA, to the extract. The RNA was destroyed, rus; as the succeeding generations of bacteria
yet transformation took place. RNA was thus pulled phosphorus from the growth medium
eliminated. At this point, it was fairly obvious to manufacture DNA, each DNA strand also
that DNA was the transforming agent. To con- carried a radioactive label. T2 phages were
clusively confirm this, they introduced DNase used to infect the cultures of E. coli. When the
to the extract. When the DNA was degraded by new T2 viruses were assembled in the bacte-
the enzyme, transformation did not take place, rial cells, they too carried the radioactive label
showing that DNA was the transforming agent. phosphorus 32 on their DNA. A second culture
Another way that genetic material can be ex- of E. coli was grown in a medium enriched with
changed between bacteria is by transduction. radioactive sulfur 35. Proteins contain sulfur
Transduction requires the presence of a bacter- (but no phosphorus). T2 viruses were used to
iophage (a virus that infects bacteria). A virus is infect this culture. New viruses contained the
a simple structure consisting of a protein coat sulfur 35 label on their protein coats.
called a capsid that contains either RNA or Since the T2 phage consists of only protein
DNA. Viruses are acellular, nonliving, and ex- and DNA, one of these two molecules had to be
tremely small. To reproduce, they must infect the genetic material. Hershey and Chase in-
living cells and use the host cells internal struc- fected unlabeled E. coli with both types of radio-
tures to replicate their genetic material and active T2 phages. Analysis has shown that the
58 Bacterial Genetics and Cell Structure
An example of a bacterial colony formed by a pathogenic strain of Escherichia coli, displayed by microbiologist Jay Lewis shortly
after an outbreak of food poisoning in Washington state in 1996. (AP/Wide World Photos)
phosphorus 32 label passed into the bacterial rial DNA. In nature, only bacteria contain spe-
cells, while the sulfur 35 label was found only in cialized enzymes called restriction enzymes. Re-
the protein coats that did not enter the cells. striction enzymes are capable of cutting DNA at
Since the protein coat did not enter the bacte- specific sites called restriction sites. The func-
rial cell, it could not influence protein synthe- tion of restriction enzymes in bacteria is to pro-
sis. Therefore, protein could not be the genetic tect against invading viruses. Bacterial restric-
material. The Hershey-Chase experiment con- tion enzymes are designed to destroy viral DNA
firmed DNA as the genetic material. without harming the host DNA. Hundreds of
different restriction enzymes have been iso-
Restriction Enzymes and Gene Expression lated from bacteria, and each is named for the
Using the aforementioned methods, it has bacterium from which it comes. The discovery
been possible to construct a complete genetic and isolation of restriction enzymes led to a
map showing the order in which genes occur new field of biological endeavor: genetic engi-
on the chromosome of E. coli and other bacte- neering.
ria. Certain genes are common to all bacteria. Use of these enzymes has made gene cloning
There are also several genes that are shared by possible. Cloning is important to researchers
bacteria and higher life-forms, including hu- because it permits the detailed study of individ-
mans. Further research showed that genes can ual genes. Restriction enzymes have also been
be either inserted into or deleted from bacte- used in the formation of genomic libraries (a
Bacterial Genetics and Cell Structure 59
collection of clones that contains at least one produced. From these populations, human
copy of every DNA sequence in the genome). proteins, such as insulin, can be recovered.
Genomic libraries are valuable because they Many proteins used against disease are man-
can be searched to identify a single DNA re- ufactured in this manner. Some examples of re-
combinant molecule that contains a particular combinant DNA pharmaceutical products that
gene or DNA sequence. are already available or in clinical testing in-
Bacterial studies have been instrumental in clude atrial natriuretic factor, which is used to
understanding the regulation of gene expres- combat heart failure and high blood pressure;
sion, or the translation of a DNA sequence first epidermal growth factor, which is used in burns
to a molecule of messenger RNA (mRNA) and and skin transplantation; factor VIII, which is
then to a protein. Bacteria live in environments used to treat hemophilia; human growth hor-
that change rapidly. To survive, they have mone, which is used to treat dwarfism; and
evolved systems of gene regulation that can ei- several types of interferons and interleukins,
ther turn on or turn off a gene in response which are proteins that have anticancer prop-
to environmental conditions. Franois Jacob erties.
and Jacques Monod discovered the lac operon, Bacterial hosts produce what are called the
a regulatory system that permits E. coli to re- first generation of recombinant DNA prod-
spond rapidly to changes in the availability of ucts. There are limits to what can be produced
lactose, a simple sugar. Other operons, such as in and recovered from bacterial cells. Since
the tryptophan operon, were soon discovered bacterial cells are different from eukaryotic
as well. An operon is a cluster of genes whose cells in a number of ways, they cannot process
expression is regulated together and involves or modify most eukaryotic proteins, nor can
the interaction of regions of DNA with regula- they add sugar groups or phosphate groups,
tory proteins. The discovery of operons in bac- additions that are often required if the protein
teria led to searches for them in eukaryotic is to be biologically active. In some cases, hu-
cells. While none has been found, several other man proteins produced in prokaryotic cells
methods of regulating the expression of genes do not fold into the proper three-dimensional
in eukaryotes have been described. shape; since shape determines function in pro-
teins, these proteins are nonfunctional. For
Impact and Applications this reason, it may never be possible to use bac-
Diabetes mellitus is a disease caused by the teria to manufacture all human proteins. Other
inability of the pancreas to produce insulin, a organisms are used to produce what are called
protein hormone that is part of the critical sys- the second generation of recombinant DNA
tem that controls the bodys metabolism of products.
sugar. Prior to 1982, people who suffered from The impact of the study of bacterial struc-
diabetes controlled their disease with injec- tures and genetics and the use of bacteria in
tions of insulin that had been isolated from biotechnology, cannot be underestimated. Bac-
other animals, such as cows. In 1982, human in- terial research has led to the development of an
sulin became the first human gene product to entirely new branch of science, that of molecu-
be manufactured using recombinant DNA. lar biology. Much of what is currently known
The technique is based on the knowledge that about molecular genetics, the expression of
genes can be inserted into the bacterial chro- genes, and recombination comes from research
mosome; that once inserted, the gene product, involving the use of bacteria. Moreover, bacte-
or protein, will be produced; and that once ria have had and will continue to have applica-
produced, the protein can be purified from tions in the production of pharmaceuticals and
bacterial extracts. Human proteins are usually the treatment of disease. The recombinant DNA
produced by inserting a human gene into a technologies developed with bacteria are now
plasmid vector, which is then inserted into a being used with other organisms to produce
bacterial cell. The bacterial cell is cloned until medicines and vaccines.
large quantities of transformed bacteria are Kate Lapczynski, updated by Bryan Ness
60 Bacterial Genetics and Cell Structure
See also: Archaea; Bacterial Resistance and genetics and then presenting the molecu-
Super Bacteria; Biopharmaceuticals; Cholera; lar genetics of mycobacteria in sections on
Chromosome Walking and Jumping; Cloning; genomes and genetic exchange, gene ex-
Diabetes; Diphtheria; Gene Regulation: Bac- pression, metabolism, and genetic strate-
teria; Gene Regulation: Lac Operon; Gene Reg- gies.
ulation: Viruses; Genetic Code, Cracking of; Russell, Peter J. Fundamentals of Genetics. 2d ed.
Lateral Gene Transfer; Model Organism: Es- San Francisco: Benjamin Cummings, 2000.
cherichia coli; Molecular Genetics; Plasmids; Re- Introduces the three main areas of genetics:
striction Enzymes; Transposable Elements. transmission genetics, molecular genetics,
and population and quantitative genetics.
Further Reading Reflects advances in the field, such as the
Birge, Edward A. Bacterial and Bacteriophage Ge- structure of eukaryotic chromosomes, alter-
netics. 4th ed. New York: Springer, 2000. Ex- native splicing in the production of mRNAs,
amines how genetic investigations and ma- and molecular screens for the isolation of
nipulations of bacteria and bacteriophages mutants.
have made vital contributions to the basic Schumann, Wolfgang, S. Dusko Ehrlich, and
understanding of living cells and to the de- Naotake Ogasawara, eds. Functional Analysis
velopment of genetic engineering and bio- of Bacterial Genes: A Practical Manual. New
technology. York: Wiley, 2001. Follows two teams of labo-
Drlica, Karl. Understanding DNA and Gene Clon- ratories that analyze thousands of newly dis-
ing: A Guide for the Curious. New York: John covered bacterial genes to try to discover
Wiley & Sons, 2003. A basic overview de- their functions. Addresses the biology of Ba-
signed to help lay readers understand mo- cillus subtilis.
lecular biology and recombinant DNA tech- Thomas, Christopher M., ed. The Horizontal
nology. Good illustrations and graphics. Gene Pool: Bacterial Plasmids and Gene Spread.
Goldberg, Joanna B., ed. Genetics of Bacterial Amsterdam: Harwood Academic, 2000. In-
Polysaccharides. Boca Raton, Fla.: CRC Press, ternational geneticists, biologists, and bio-
1999. Gives background on the fields his- chemists discuss the various contributions
tory, polysaccharide diversity, research gaps, plasmids make to horizontal gene pools:
and nomenclature issues. Nine chapters by replication, stable inheritance, and transfer
international researchers present the ge- modules; the phototypic markers they carry;
netic analysis of polysaccharides from vari- how they evolve; how they contribute to
ous bacteria pathogens to humans and one their host population; and approaches for
symbiotic with legumes. studying and classifying them.
Hacker, J., and J. B. Kaper, eds. Pathogenicity Is- Watson, James D., et al. Recombinant DNA: A
lands and the Evolution of Pathogenic Microbes. Short Course. New York: Scientific American
2 vols. New York: Springer, 2002. Explores Books, 1983. A classic account by one of
pathogenicity islands, plasmids, and bacte- three men who shared a Nobel Prize in Phys-
riophages, which are able to carry genes iology or Medicine for describing the molec-
whose products are involved in pathogenic ular structure of DNA.
processes. Shows how such elements and
their products play an important role in
pathogenesis due to the intestinal E. coli as Web Site of Interest
well to Shigellae. E. coli Genome Project, University of Wiscon-
Hatfull, Graham F., and William R. Jacobs, Jr., sin. http://www.genome.wisc.edu. The ge-
eds. Molecular Genetics of Mycobacteria. Wash- nome research center that sequenced the
ington, D.C.: ASM Press, 2000. Surveys all organisms complete K-12 genome now
aspects of mycobacterial genetics in the maintains and updates that sequence as well
context of new genomic information, start- as those of other strains and other patho-
ing with the development of mycobacterial genic Enterobacteriaceae.
Bacterial Resistance and Super Bacteria 61
(the treatment of disease with chemical com- drug out of the cell after it has entered. Such
pounds). For a drug such as an antibiotic to be systems are found in pathogenic Escherichia coli,
a magic bullet, it must have a specific target Pseudomonas aeruginosa, and Staphylococcus
that is unique to the disease-causing agent and aureus. These pumps are usually nonspecific
cannot harm the host in the process of curing and can cause bacteria to become resistant to
the disease. In 1910, Ehrlich discovered that more than one antibiotic at a time. Another
arsphenamine (Salvarsan), a derivative of ar- method of resistance is through chemical mod-
senic, could be used to treat syphilis, a common ification of the drug. Penicillin is inactivated by
sexually transmitted disease in the early twenti- breaking a chemical bond found in its ring
eth century. Until that time syphilis had no structure. Other drugs are inactivated by the
known cure. The use of Salvarsan did cure some addition of other chemical groups. Finally, the
patients of syphilis, but, since it was a rat poi- target of the drug can be altered in such a man-
son, it killed other patients. Generally speak- ner that it is no longer affected by the drug.
ing, antimicrobials have specific targets (or For example, Mycobacterium tuberculosis, which
modes of action) within bacteria. They target causes tuberculosis, became resistant to the
the following structures or processes: synthesis drug rifampin by altering the three-dimensional
of the bacterial cell wall, injury to the plasma structure of a specific protein.
membrane, and inhibition of synthesis of pro-
teins, DNA, RNA, and other essential metabo- Antibiotic Misuse and Drug Resistance
lites (all of these substances are building blocks The misuse of antibiotics over several de-
for the bacteria). A good antibiotic will have a cades has caused many strains of bacteria to be-
target that is unique to the bacteria so the host come resistant. For some bacterial infections,
(the patient) will not be harmed by the drug. only one or no effective drugs are available for
Bacteria and fungi are, of course, resistant to treatment. Many different factors of misuse,
the antibiotics they naturally produce. Other overuse, and abuse of antibiotics have led to
bacteria have the ability to acquire resistances drug-resistant diseases. Perhaps one of the
to antimicrobials, and this drug resistance oc- most important factors in the emergence of
curs either through a mutation in the DNA or drug-resistant bacteria is the overprescription
resistance genes on plasmids or transposons. or inappropriate use of antibiotics. Another
Plasmids are small, circular pieces of DNA that major factor is misuse by the patient. After sev-
can exist within or independently of the bacte- eral days of taking an antibiotic, a patient may
rial chromosome. Transposons, or jumping begin to feel better and decide not to finish all
genes, are pieces of DNA that can jump from of the prescription. By not completing the full
one bacterial species to another and be inte- course of treatment, the patient merely kills the
grated into the bacterial chromosome. The bacteria that are sensitive to the antibiotic, leav-
spread of plasmids and transposons that carry ing the resistant bacteria to grow, multiply, pass
antibiotic resistance genes has led bacteria to on their resistant genes, and cause the same in-
become resistant to many, if not all, currently fection. This time, another antibiotic (if there
available antibiotics. is one available that is effective) must be used.
Several antimicrobial resistance mechanisms Another contributing factor is the ease with
allow bacteria to become drug resistant. The which the newest and best antibiotics may be
first mechanism does not allow the drug to en- obtained in many countries. In several coun-
ter the bacterial cell. A decrease in the perme- tries in Central America, for example, one can
ability of the cell wall will inhibit the antimicro- walk into the local pharmacy and receive any
bial drug from reaching its target. An alteration antibiotic without a prescription. Another fac-
in a penicillin-binding protein (pbp), a protein tor in the worldwide spread of drug-resistant in-
found in the bacterial cell wall, will allow the fectious diseases is the ease of travel. Infected
cell to tie up the penicillin. Also, the pores in people can carry bacteria from one continent
the cell wall can be altered so the drug cannot to another in a matter of hours and infect any-
pass through. A second strategy is to pump the one with whom they come in contact.
Bacterial Resistance and Super Bacteria 63
The use of antibiotics is not limited to hu- Emerging Resistant Infections and Super
mans. They also play an important role in agri- Bacteria
culture. Antibiotics are added to animal feed The misuse of antibiotics over the decades
on farms to help keep herds healthy, and they has led to more infectious diseases becoming
are also used on fish farms for the production resistant to the current arsenal of drugs. Some
of fish for market. Antibiotics are used to treat diseases that could be treated effectively in the
domestic animals such as cats, dogs, birds, and 1970s and 1980s can no longer be controlled
fish and are readily available in pet stores to with the same drugs. Two very serious prob-
clear up fish aquariums. This widespread use of lems have emerged: vancomycin-resistant en-
antibiotics allows bacteria in all environmental terococci and multidrug-resistant tuberculosis.
niches the possibility of becoming resistant to The enterococcus is naturally resistant to many
potentially useful drugs. types of antibiotics, and the only effective treat-
Multiple-Resistant Bacteria
They lurk in schools, nursing homes, and hospitals Triclosan is a good example of the potent antibac-
perhaps even in your home. Often, you cannot see terial and antifungal agents that are increasingly
them to avoid them. Increasingly, they are a global used to produce germ-free consumer products.
health problem. What are these unseen purveyors of Until recently, triclosan was considered a broad-
disease? Antibacterial soaps. spectrum antiseptic rather than a true antibiotic. As
Antibacterial soaps contain antibacterials, a sub- a general biocide, triclosan was not expected to have
class of antimicrobials, which kill or inhibit the a specific target in the bacterial cell. However, Stuart
growth of bacteria and other microorganisms. Anti- Levy and his colleagues at Tufts University School of
septics are antimicrobial agents that are sufficiently Medicine determined that triclosan specifically in-
nontoxic to be applied to human tissue. Antibiotics terferes with an enzyme important in the synthesis of
are chemicals that inhibit a specific pathway or en- plasma membrane lipids. As triclosan kills off nor-
zyme in a bacterium and are critical to the treatment mal bacteria, it could make way for the growth of
of a bacterial infection. When bacteria are exposed strains with triclosan-insensitive enzymes. More trou-
to sublethal concentrations of an antibiotic, resis- bling, one of the front-line antibiotics commonly
tance can develop through the elimination of nor- used to treat tuberculosis, isoniazid, targets the same
mal bacteria, allowing the resistant ones to survive enzyme, raising the possibility that the use of tri-
and reproduce. The question has been whether ex- closan will lead to new drug-resistant strains of Myco-
posure to antibacterial products can promote antibi- bacterium tuberculosis.
otic resistance. The answer is that the use of antibac- Consumers are convinced that use of products
terial products may actually increase the prevalence with antimicrobial chemicals will lower their risk of
of antibiotic-resistant bacteria. infection. While this has not been demonstrated
Antibiotic resistance is irreversible and unavoid- scientifically, effective handwashing has been dem-
able, due to the selective pressure on bacteria to be- onstrated to prevent illness. However, the key to
come resistant. This selection is in large part a re- effective handwashing is the length of time (15-30
sult of the widespread use of antibiotics to increase seconds) spent scrubbing, not the inclusion of anti-
growth rates in livestock, as well as unnecessary and bacterials in the soap. Regular soap, combined with
improper use of antibiotics to restore and maintain scrubbing action, physically dislodges and removes
human health. The indiscriminate use or overuse of microorganisms. The constant exposure of bacteria
antibiotics has been widely blamed for the appear- to sublethal concentrations of triclosan promotes
ance of so-called super bacteriabacteria that are development of resistance; the substitution of anti-
unaffected by more than one antibiotic. In addition, bacterial soap for proper handwashing techniques
a widely used antibacterial agent found in tooth- will eventually render triclosan ineffective. In the
paste, kitchen utensils and appliances, clothing, cat battle of the soaps, plain wins.
litter, and toys could cause resistant strains of bacte- Laurie F. Caslake
ria to develop.
64 Bacterial Resistance and Super Bacteria
ment has been vancomycin. With the appear- Impact and Applications
ance of vancomycin-resistant enterococci, There is little encouraging news about the
however, there are no reliable alternative treat- availability of new antibiotics. The crisis of
ments. The fear that vancomycin resistance will super bacteria has altered the view that few new
spread to other bacteria such as staphylococci antibiotics would be needed. Pharmaceutical
seems well founded: A report from Japan in companies are scrambling to discover new anti-
1997 indicated the existence of a strain of microbial compounds and modify existing
staphylococcus that had become partially resis- antibiotics. Policy decisions of the 1970s and
tant to vancomycin. If a strain of methicillin- 1980s requiring more and larger clinical trials
resistant Staphylococcus aureus (MRSA) also be- for antibiotics before they are approved for use
comes resistant to vancomycin, there will be no by the Food and Drug Administration have in-
effective treatment available against this super creased the price of antibiotics and the amount
bacterium. of time it takes to market them. It may take up
A second problem is the appearance of to ten years from the time of discovery for an
multidrug-resistant tuberculosis. Mycobacterium antibiotic to be approved for use. The scientific
tuberculosis is a slow-growing bacterium that re- community has therefore had to meet the in-
quires a relatively long course of antibiotic crease of drug-resistant bacterial strains with
therapy. Tuberculosis (TB) is spread easily, and fewer and fewer new antibiotics.
it is a deadly disease. In the United States in The emergence of antibiotic-resistant bacte-
1900, tuberculosis was the number-one cause of ria and super bacteria is a serious global health
death. In the 1990s, it was still a leading cause concern that will lead to a more prudent use of
of death worldwide. Treatment of multidrug- available antibiotics. It has also prompted phar-
resistant tuberculosis requires several antibiot- maceutical companies to search for potentially
ics taken over a period of at least six months, new and novel antibiotics in the ocean depths,
with a success rate of approximately 50 percent; outer space, and other niches. Rational drug
on the other hand, susceptible strains of TB designor RDD, drug design based on knowl-
have a cure rate of nearly 100 percent. edge of how bacteria become drug resistant
Another contributing factor to the emer- will also be important. Exactly how scientists
gence of drug-resistant infectious diseases is and physicians will be able to combat super bac-
the lack of basic knowledge about some bacte- teria is a question that remains to be answered.
ria. Funding for basic genetic research on tu- Until a more viable solution is found, prudent
berculosis was reduced dramatically in the use of antibiotics, surveillance of drug-resistant
mid-twentieth century when it appeared that infections, and well-orchestrated worldwide
TB would be eradicated just as smallpox had monitoring and containment of emerging dis-
been. The appearance of multidrug-resistant eases appear to be the answers.
tuberculosis caught scientists and physicians Mary Beth Ridenhour
unprepared. Little was known about the genet- See also: Archaea; Bacterial Genetics and
ics of tuberculosis or how drug resistance oc- Cell Structure; Chromosome Walking and
curred. Jumping; DNA Replication; Emerging Dis-
Another concern about drug-resistant in- eases; Gene Regulation: Bacteria; Gene Regu-
fections is how to control them. Hospitals are lation: Lac Operon; Lateral Gene Transfer;
vigilant, and, in some cases, very proactive in Mutation and Mutagenesis; Model Organism:
screening for drug-resistant infections. People Escherichia coli; Natural Selection; Plasmids;
can be asymptomatic carriers (that is, they Transposable Elements.
carry the disease-causing organism but are
still healthy) of a disease such as methicillin- Further Reading
resistant Staphylococcus aureus and could infect Franklin, T. J., and G. A. Snow. Biochemistry of
other people without knowing it. The role of Antimicrobial Action. New York: Chapman and
the infection-control personnel is to find the Hall, 2001. Provides an explanation of the
source of the infection and remove it. chemistry of antimicrobials and how bacte-
Behavior 65
ria may become resistant to their effects. positive genetic traits are encouraged, by
Levy, Stuart. The Antibiotic Paradox: How the Mis- controlling, in some manner, who is allowed
use of Antibiotics Destroys Their Curative Powers. to reproduce
Cambridge, Mass.: Perseus, 2002. Provides an genome: the entire set of genes required by an
overview of antibiotic resistance in bacteria. organism; a set of chromosomes
Levy also discusses mechanisms of resistance, heritability: the probability that a specific
reasons for the spread of antimicrobial resis- gene or trait will be passed from parent to
tance, and ways to combat this spread. offspring, rendered as a number between
Murray, Patrick, ed. Manual of Clinical Microbi- zero and 100 percent, with zero percent be-
ology. Washington, D.C.: ASM Press, 2003. ing not heritable and 100 percent being
Presents a direct approach to organizing in- completely heritable
formation with thorough but concise treat- linkage: a relation of gene loci on the same
ments of all the major areas of microbiology, chromosome; the more closely linked two
including new microbial discoveries, chang- loci are, the more often the specific traits
ing diagnostic methods, and emerging ther- controlled by these loci are expressed to-
apeutic challenges facing clinicians. gether
Tortora, Gerard. Microbiology: An Introduction. neurotransmitter: a chemical messenger
7th ed. San Francisco: Benjamin Cummings, that transmits a nerve impulse between neu-
2001. An accessible introduction to the basic rons
principles of microbiology, the interaction
between microbe and host, and human dis- Brain Biology
eases caused by microorganisms. Provides As the first organ system to begin develop-
an overview of antibiotics and how bacterial ment and the last to be completed, the verte-
resistances to antibiotics occur. brate nervous systembrain, spinal cord, and
nerveswith the brain at the control, remains
Web Site of Interest something of an enigma to biologists. It is based
National Center for Infectious Diseases. http:// on neurons, special cells that generate and
www.cdc.gov/ncidod. Searchable on antibi- transmit bioelectrical impulses. The vertebrate
otic resistance and other keywords to pro- brain consists of as many as three major areas:
vide access to research articles. the brain stem, the cerebellum, and the cere-
brum. A reptilian brain consists of only the
brain stem, while the mammalian brain has all
three, including a well-developed cerebrum
Behavior (the two large hemispheres on top). The brain
stem controls basic body functions such as
Field of study: Population genetics breathing and heart rate, while the cerebrum
Significance: One of the long-standing questions is the ultimate control center. Consisting of
pondered by biologists is, to what extent do genes billions of neurons (commonly called brain
control the way we behave? By the mid-1990s, re- cells), the cerebrum controls functions such as
searchers had identified human genes that had memory, speech, hearing, vision, and analyti-
been linked to such behavioral characteristics as cal skills.
depression, homosexuality, schizophrenia, and al- The brain is an exceedingly complex net-
coholism; however, such findings were complicated work of billions of neurons. As messages enter
by methodological questions and by the problem of the brain stem from the spinal cord, groups of
distinguishing between the effects of genetic and neurons either respond directly or transfer in-
environmental factors. formation to higher levels. In order to commu-
nicate with other neurons, each individual neu-
Key terms ron generates impulses much like the impulse
eugenics: a process in which negative genetic that carries a voice over a telephone line, and
traits are removed from the population and this message travels from the beginning to the
66 Behavior
end of each neuron. At the end of one neuron of daylight hours is not reached, the genes will
and the beginning of the next in line, a small not be activated, and sexual behavior will not
open space occurs. This space is filled with flu- increase.
ids, and the message is carried across to the Each neuron making up the intricate net-
next neuron by a chemical known as a neuro- works and circuits throughout the cerebrum
transmitter. Neurotransmitters may be of sev- (80 percent of the human brain) has protein
eral biochemical classifications, including ace- receptors (chemoreceptors) that respond to
tylcholines, amines, amino acids, and peptides. specific signaling molecules. The production
An individual neuron and an entire neuronal of the receptors and signaling molecules used
circuit may fire or not fire an impulse based on for any type of brain activity is directly tied to
the messages carried by these neurotransmit- genes. A slightly different gene may lead to a
ters. For example, the signal for pain is trans- slightly different signaling molecule or recep-
mitted from neuron to neuron by a peptide- tor and thus a slightly different cell (neuron)
based neurotransmitter known as substance response. A larger difference among genes
P, while another peptide transmitter (endor- may lead to a larger difference among signal-
phin) acts as a natural painkiller. Thought, ing molecules or receptors and thus a larger
memory, and behavior, then, are produced by variation in cell response. Since human behav-
the activity along neuronal circuits. A genetic ior involves the response of neurons and neu-
link occurs here, since neurotransmitters are ron networks in the brain to specific signals,
expressed either directly or indirectly based on and since the response of neurons occurs be-
information in genes. cause of the interaction between a signaler and
By birth, the collection of approximately a receptor built by specific genes, the genetic
21,200 genes in humans has directed the devel- link seems straightforward: input, signal, re-
opment of the nervous system. At birth, the sponse, behavior. However, when the slight
brain consists of approximately 100 billion neu- variations between genes are added to the con-
rons and trillions of supporting glial cells to siderable variation among noncoding or regu-
protect and nourish neurons. However, the in- latory sequences of DNA, the genetic connec-
tricate wiring between these neurons is yet to tion to behavior becomes much less direct.
be determined. Studies from the 1980s and Since a gene is under the control of one or sev-
1990s suggested that the critical networking eral regulatory sequences that in turn may be
and circuit formation between these billions of under the control of various environmental in-
neurons that control later brain function are puts, the amount of genetic variation among
determined not from genes but from environ- individuals is compounded by two other criti-
mental input and experiences from birth until cal factors: the environmental variations under
the brain is fully developed around age seven. which the brain develops and the daily environ-
mental variations to which the individual is ex-
Genes and Behavior posed. A convenient way to think of genetics
Genes make proteins, and proteins cause and behavior is to consider that genes simply al-
biochemical responses in cells. The behavior of low humans to respond to a specific stimulus by
an animal takes place under the combined in- building the pathway required for a response,
fluences of its genes, expressed through the ac- while behavior is defined by the degree and the
tions of proteins, and its environment. A good manner of human response.
example is the phenomenon of mating seasons
in many animals. As day length gradually in- Eugenics
creases toward spring and summer, a critical The concept of eugenics was born during
length is reached that signals the release of hor- the evolution and study of basic genetics in the
mones that result in increased sexual activity, early twentieth century. Eugenics is the catego-
with the ultimate goal of seasonal mating. The rization of a specific human behavior to an un-
production and activity of hormones involve derlying genetic cause. Human characteristics
genes or gene products. If the critical number such as alcoholism and laziness were thought
Behavior 67
to be caused entirely by inherited genes. Since marker. Thus, geneticists are not directly iden-
then, research has provided a much clearer pic- tifying the genes involved, but are identifying
ture of a genetic-behavior link. People inherit the approximate locations of the genes. Unfor-
specific genes to build specific pathways that al- tunately, the more genes control a trait, the
low them to respond in certain ways to environ- harder it is to identify QTLs. Environmental ef-
mental input. With variations possiblefrom fects can also mask the existence of QTLs, caus-
the gene to gene regulators to the final cellular ing some people to have the trait that lack a
responseit is virtually impossible to discon- QTL and others to lack the trait but have a
nect the nature vs. nurture tie that ultimately QTL. In spite of these difficulties, QTLs have
controls human behavior. Genes are simply the been identified for a number of behavioral
tools by which the environment shapes and re- traits, such as aggression, depression, and a
shapes human behavior. There is a direct cor- number of other mental disorders.
relation between gene and protein: Change
the gene, change the protein. However, there Single-Gene Behavioral Traits
is no direct correlation between gene and be- Although behavioral traits controlled by a
havior: Changing the gene does not necessar- single gene have been identified, they probably
ily change the behavior. Behavior is a multi- require interaction with other genes in order
faceted, complex response to environmental to produce the specific characteristics of the
influences that is only partially related to ge- behavior. On top of this are laid environmental
netic makeup. Most studies conducted on hu- effects. The most dramatic case of a single gene
mans based on twin and other relative data sug- that controls a complex behavior was the dis-
gest that most behavioral characteristics have covery in 2002 of the gene that controls honey-
between a 30 and 70 percent genetic basis, leav- bee social status. This same gene is found in
ing considerable room for environmental in- fruit flies and affects how actively fruit flies seek
fluence. For example, studies of twins indicate food. Bees with a more actively expressed form
that homosexuality may be as much as 50 per- of the gene (called the for gene) were much
cent genetic, leaving 50 percent under environ- more likely to forage than bees with a less ac-
mental control. tive for gene. Not surprisingly, the for gene pro-
Another important fact is that almost no be- duces a protein that acts as a cell-signaling mol-
haviors are controlled by a single gene locus, ecule.
and the more complex the behavior, the more In humans, only a few behavioral traits are
likely that it is controlled by several to many clearly controlled by a single gene. The best ex-
genes. Hence, not only do environmental ef- amples include Huntingtons disease (a rare,
fects cloud the picture; each gene involved in autosomal dominant gene), early-onset Alzhei-
more complex behavioral traits represents just mers disease (also a rare, autosomal dominant
a small part of the genetic basis for the trait. gene), and fragile X syndrome (actually involves
The study of the genetic basis for complex two genes). The remaining traits, discussed be-
traits, therefore, involves the search for quanti- low, actually represent multigene traits where
tative trait loci (QTLs), rather than for single one primary QTL has been identified as pri-
genes. Searching for QTLs requires that a large marily responsible.
number of genetic markers be identified in the Several genes were identified during the late
human genome, and the Human Genome Pro- 1980s and early to mid-1990s with possible
ject has provided numerous such markers. A direct behavioral links. A gene has been identi-
QTL is identified by looking for linkage be- fied that seems to be involved in neurotic be-
tween a specific genetic marker and the trait haviors associated with anxiety, depression, hos-
being studied. Linkage occurs when a marker is tility, and impulsiveness. This gene produces a
close to one of the genes that control the trait. protein that transports a chemical called sero-
Practically speaking, this means that individu- tonin, across neuronal membranes. Serotonin
als with the behavioral trait have the marker, is a neurotransmitter and is the chemical that is
and those who do not have the trait lack the affected by the antidepressant drug Prozac and
68 Behavior
Proteins and Simple Dominant and homozygous state, c chc ch. This occurs because
Recessive Alleles the c ch allele codes for a pigment enzyme that is
In order to understand how certain geno- partially defective. The partially defective en-
types are expressed as phenotypes, knowledge zyme works much more slowly than the normal
of the biochemistry behind gene expression is enzyme, and the smaller amount of pigment
essential. It is known that the various sequences produced leads to the gray phenotype. When
of nitrogenous bases in the DNA of genes code this allele is heterozygous with the fully defec-
for the amino acid sequences of proteins. How tive c allele, c chc, there is only half as much of an
the proteins act and interact in an organism de- enzyme that works very slowly. As one might ex-
termines that organisms phenotype. pect, there is less pigment produced, and the
Simple dominant and recessive alleles are phenotype is an even lighter shade of gray
the easiest to understand. For example, in the called light chinchilla. The enzyme concentra-
genetic disease phenylketonuria (PKU), two al- tion does affect the rate of the reaction and, ul-
leles of the PKU locus exist: p+, which codes for timately, the amount of product made. This
phenylalanine hydroxylase, an enzyme that phenomenon is known as incomplete, or par-
converts phenylalanine (a common amino tial, dominance. Genes for the red pigments in
acid in proteins) to tyrosine (another common such flowers as four-oclocks and snapdragons
amino acid); and p, which is unable to code for show incomplete dominance, as do the hair,
the functional form of the enzyme. Individuals skin, and eye pigment genes of humans and the
with two normal alleles, p+p+, have the enzyme purple pigment genes of corn kernels.
and are able to perform this conversion. How- Sometimes a mutation occurs that creates an
ever, individuals with two abnormal alleles, pp, enzyme with a different function instead of cre-
do not have any of this enzyme and are unable ating a defective enzyme. The B allele in the
to make this conversion. Since phenylalanine is ABO blood-group gene codes for an enzyme
not converted to tyrosine, the phenylalanine that adds galactose to a short sugar chain that
accumulates in the organism and eventually exists on the blood cells surface forming the B
forms phenylketones, which are toxic to the antigen. The A allele codes for an enzyme that
nervous system and lead to mental retardation. adds N-acetylgalactosamine to the same previ-
The heterozygote, p+p, has one normal and one ously existing sugar chain, forming the A anti-
abnormal allele. These individuals have phe- gen. Anyone with two B alleles, I BI B, makes only
nylalanine and tyrosine levels within the nor- the B antigen and is type B. Those with two A al-
mal range, since the enzyme can be used over leles, I AI A, make only the A antigen and are type
and over again in the conversion. In other A. Heterozygotes, I AI B, have the enzymes to
words, even when there is only one normal al- make both antigens, and they do. Since they
lele present, there is enough enzyme produced have both antigens on their blood cells, they
for the conversion to proceed at the maximum are classified as type AB. This phenomenon is
rate. known as codominance and is also seen in
Many other inborn errors of metabolism fol- other blood-type genes.
low this same pattern. In the case of albinism, Biochemistry can also explain other single-
for example, afflicted individuals are missing gene phenomena such as the pigmentation
the enzyme necessary to produce the brown- pattern seen in Siamese cats and Himalayan
black melanin pigments. Galactosemics are rabbits. The Siamese-Himalayan allele codes
missing an essential enzyme for the breakdown for an enzyme that is so unstable that it falls
of galactose. apart and is completely nonfunctional at the
normal body temperature of most mammals.
Other Single-Gene Phenomena Only at cooler temperatures can the enzyme re-
Many other genetic phenomena can be ex- tain its stability and function. Since mammals
plained by looking at the biochemistry behind have lower temperatures at their extremities, it
them. For example, the chinchilla coat muta- is there that the enzyme produces pigment; at
tion in rabbits causes a gray appearance in the more centrally located body areas, it cannot
72 Biochemical Mutations
purple because it has both of the enzymes in bridization. Surveys the structure, evolution,
the pathway. Interbreeding the AaBb progeny and mutational instability of the human ge-
gives a ratio of 9 purple to 7 white. nome and human genes, and examines map-
Human pigmentation is another case in ping of the human genome, study of genetic
which many genes are involved. In this case, the diseases, and dissection and manipulation
various genes determine how much pigment is of genes.
produced by nonalbino individuals. Several
gene loci are involved, and the contributions of
each allele of these loci is additive. In other
words, the more functional alleles one has, the Bioethics
darker the pigmentation; the fewer one has,
the lighter. Since many of the genes involved Field of study: Bioethics; Human genetics
for skin, eye, and hair color are independent, and social issues
ranges of color in all three areas are seen that Significance: Bioethics is the practice of helping so-
may or may not be the same. In addition, there ciety and, more specifically, families, patients, and
are genes that code for enzymes that produce medical teams, make tough health care decisions.
chemicals that modify the expression of the This branch of philosophy focuses on helping indi-
pigment genes (for example, to change blue viduals decide what is right for them while ad-
eyes to gray, convert hazel eyes to green, or dressing the needs of families, health care provid-
change brown hair to auburn). This gives rise ers, and society.
to the great diversity of pigmentation seen in
humans today. Add to these many possible ex- Key terms
pression patterns at the biochemical level the genetic testing: the use of the techniques of
effect of the environment, and it is clear why genetics research to determine a persons
such great variation in phenotypic expression risk of developing, or status as a carrier of, a
is possible. disease or other disorder
Richard W. Cheney, Jr. informed consent: the right of patients to
See also: Chemical Mutagens; Chromo- know the risks of medical treatment and to
some Mutation; Classical Transmission Genet- determine what is done to their bodies
ics; Complete Dominance; Dihybrid Inheri-
tance; Epistasis; Inborn Errors of Metabolism; The Emergence of Bioethics
Incomplete Dominance; Monohybrid Inheri- As early as the mid-1960s, advances in genet-
tance; Mutation and Mutagenesis; Oncogenes; ics and reproduction, life support, and trans-
Phenylketonuria (PKU); Tumor-Suppressor plantation technologies spurred an increased
Genes. focus on ethical issues in medicine and scien-
tific research. From the late 1960s through the
Further Reading mid-1970s, bioethicists were preoccupied with
Neumann, David, et al. Human Variability in Re- the moral difficulties of obtaining voluntary,
sponse to Chemical Exposures: Measures, informed consent from human subjects in sci-
Modeling, and Risk Assessment. Boca Raton, entific research. They concentrated on the de-
Fla.: CRC Press, 1998. Addresses genetic evi- velopment of ethical guidelines in research
dence for variability in the human response that would ensure the protection of individuals
to chemicals associated with reproductive vulnerable to exploitation, including mentally
and developmental effects, the nervous sys- or physically handicapped individuals, prison-
tem and lungs, and cancer. ers, and children. Beginning in the mid-1970s
Strachan, Tom, and Andrew Read. Human Mo- and continuing through the mid-1980s, bio-
lecular Genetics. 2d ed. New York: Wiley, 1999. ethicists became increasingly involved in dis-
Provides introductory material on DNA and cussions of the definitions of life, death, and
chromosomes and describes principles and what it means to be human. In the mid-1980s,
applications of cloning and molecular hy- practitioners began to focus on cost contain-
74 Bioethics
President George W. Bush established the Presi- way to advance research while guarding against
dents Council on Bioethics by executive order on abuse. The minority favored regulating cloned em-
November 28, 2001. Its mission was to advise the bryos used in biomedical research, including federal
chief executive on bioethical issues emerging from licensing, oversight, and time limits on the length of
advances in biomedical science and technology. Spe- time for development of cloned embryos.
cifically mentioned in the councils mission were President Bush stated his strong opposition to hu-
embryo and stem cell research, assisted reproduc- man cloning in a speech in August, 2001. The Hu-
tion, cloning, and end-of-life issues. Other ethical man Cloning Prohibition Act of 2003, which banned
and social issues identified for discussion included all forms of human cloning, including cloning to
the protection of human research subjects and the create a pregnancy and cloning for medical re-
appropriate use of biomedical technologies. The search, passed the House of Representatives in Feb-
council, chaired by Leon Kass, consisted of eighteen ruary of 2003 by a vote of 241 to 155. It also made it a
members appointed by the president, who were eligi- crime to receive or import a cloned human embryo
ble for reappointment. Included in that group were or any product derived from a cloned human em-
scientists, physicians, ethicists, social scientists, law- bryo, punishable by $1 million in fines and ten
yers, and theologians. The council was scheduled years imprisonment. This part of the law essentially
to terminate two years after its creation unless ex- made it illegal to harvest embryonic stem cells for
tended. medical research.
Deeply controversial issues constituted the sub- Stem cellsundifferentiated cells that have the
ject matter of the inquiries undertaken by the coun- potential to grow into any type of tissueare created
cil. Debate among its members as well as discussions in the first days of pregnancy. Scientists hope to di-
on the floors of the Senate and House of Representa- rect stem cells to grow a variety of tissues for use in
tives were strongly divisive, producing heated argu- transplantation to treat serious illnesses such as can-
ment and disagreement. The councils members cer, heart disease, and diabetes. Embryos have been
were particularly divided on the issue of human clon- valued in research for their ability to produce these
ing, producing two recommendations for national stem cells, but the harvesting process requires the
policy. Both recommendations would ban cloning to destruction of days-old embryos (a procedure con-
produce children, and ten of the eighteen council demned by the Catholic Church, President Bush,
members recommended a four-year moratorium on anti-abortion activists, and womens rights organiza-
human cloning for biomedical research while the is- tions). Other research, however, points to similar
sue continued to be studied. Declining to call for an promise using stem cells harvested from adults, so
outright ban on cloning, the divided council stated that no embryos are destroyed.
that prudent and sensible regulation was the best Marcia J. Weiss
ment in health care and the allocation of scarce reproductive materialstheir eggs or sperm
medical resources. to create embryos or fetuses without their ex-
Bioethicists worry about such matters as the plicit consent.
guarantee of privacy, especially when compul- Beginning in 1992, the Joint Commission on
sory testing for genetic disorders is involved, Accreditation of Health Care Organizations,
and about the limits of a persons right to the U.S. agency that accredits hospitals and
threaten the health of others versus the per- health care institutions, required these organi-
sonal right to freedom of choice. For example, zations to establish committees to formulate
the dissemination of information about ge- ethics policies and address ethical conflicts and
netic predispositions to chronic, costly, or inca- issues. Centers for the study of biomedical eth-
pacitating conditions can result in the denial of ics such as the Society for Health and Human
insurance coverage, job opportunities, and ad- Values and the Park Ridge Center for the Study
mittance to educational programs. Bioethicists of Health, Faith, and Ethics became important
also debate such matters as the use of peoples forums for public debate and research.
Bioethics 75
The overriding principle of bioethics and tors typically considered before a person un-
U.S. law is to respect each persons right to de- dergoes genetic testing include the nature of
cide, free of coercion, what treatments or pro- the test, the timing of the test, and the options
cedures he or she will undergo, except when that having the test results will bring. Testing
the person making the decision is not compe- can be done prenatally to detect disorders in fe-
tent because of youth, mental retardation, or tuses; it can also be done before conception to
medical deterioration. Other important rights determine whether a prospective parent is a
discussed by bioethicists include a patients carrier of a gene for a particular disorder or dis-
right to know that medical practitioners are ease. Tests can also provide information about
telling the truth and the right to know the risks whether an adult is susceptible to or even in a
of proposed medical treatment. presymptomatic state for a genetic disorder.
Practicing bioethicists help patients to focus
Impact and Applications on whether genetic testing will help them with
Advances in genetics and genetic testing have the nature and severity of any disorders they or
created a host of dilemmas for bioethicists, pa- their children may have, the degree of disabil-
tients, and the health care establishment. For ity or discomfort they may face, the costs and
example, as the ability to forecast and under- rigors of treatment, and the options that might
stand the genetic code progresses, people will be opened or closed as a result of testing. The
have to decide whether knowing the future, key for consumers of genetic testing is whether
even if it cannot be altered or changed, is a the information obtained can be provided in
good thing for them or their children. time and at a time when it can help to guide
Bioethicists help people to decide whether treatments or family planning. Some affected
genetic testing can be valuable for them. Fac- persons need only to make lifestyle changes or
Leon Kass of the University of Chicago was appointed head of the Presidents Council on Bioethics in November, 2001. Professor
Kass and a panel of scientists, doctors, lawyers, and ethicists advised the Bush administration on policy issues surrounding stem
cell and other research in biology, medicine, and genetics. (AP/Wide World Photos)
76 Bioethics
take medications to help prevent or manage a and insurance justificationsand the way in
disease; others learn that they or their off- which this interaction profoundly affects
spring are at risk for, or even likely to develop, decision making, patient health, and treat-
serious and often untreatable disorders. Know- ment.
ing ones genetic fate may be more of a burden Comstock, Gary L., ed. Life Science Ethics. Ames:
than a person wants, particularly if there is Iowa State Press, 2002. Introduces ethical
nothing that can be done to change or alter the reasoning in the area of humankinds rela-
risks the person faces. Bioethicists act as guides tionship with nature and presents twelve fic-
through the complicated and often wrenching tional case studies as a means to show the ap-
decision process. plication of ethical reasoning.
Fred Buchstein Danis, Marion, Carolyn Clancy, and Larry R.
See also: Bioinformatics; Biological Deter- Churchill, eds. Ethical Dimensions of Health
minism; Cloning: Ethical Issues; Criminality; Policy. New York: Oxford University Press,
DNA Fingerprinting; Eugenics; Eugenics: Nazi 2002. The three authors, from varied profes-
Germany; Forensic Genetics; Gene Therapy; sions within the medical field, attempt to
Gene Therapy: Ethical and Economic Issues; identify the goals of health care, examine
Genetic Counseling; Genetic Engineering: So- how to connect ethical considerations with
cial and Ethical Issues; Genetic Screening; Ge- the making of health policy, and discuss spe-
netic Testing; Genetic Testing: Ethical and cific areas of ethical controversy such as re-
Economic Issues; Human Genetics; In Vitro source allocation, accountability, the needs
Fertilization and Embryo Transfer; Insurance; of vulnerable populations, and the conduct
Miscegenation and Antimiscegenation Laws; of health services research.
Patents on Life-Forms; Paternity Tests; Prena- Evans, John Hyde. Playing God? Human Genetic
tal Diagnosis; Race; Stem Cells; Sterilization Engineering and the Rationalization of Public
Laws. Bioethical Debate. Chicago: University of Chi-
cago Press, 2002. Provides a framework for
Further Reading understanding the public debate, and de-
Bulger, Ruth Ellen, Elizabeth Heitman, and tails the various positions of the debates
Stanley Joel Reiser, eds. The Ethical Dimen- players, including eugenicists, theologians,
sions of the Biological and Health Sciences. 2d ed. and bioethicists.
New York: Cambridge University Press, Kass, Leon R. Life, Liberty, and the Defense of Dig-
2002. Designed for graduate students who nity: The Challenge for Bioethics. San Francisco:
will be conducting research in the medical Encounter Books, 2002. Examines genetic
and biological sciences. Provides essays, research, cloning, and active euthanasia,
readings, and questions to stimulate think- and argues that biotechnology has left hu-
ing about ethical issues and implications. manity out of its equation, often debasing
Caplan, Arthur. Due Consideration: Controversy in human dignity rather than celebrating it.
the Age of Medical Miracles. New York: Wiley, Kristol, William, and Eric Cohen, eds. The Fu-
1997. A leading bioethicist analyzes the ture Is Now: America Confronts the New Genetics.
moral questions regarding scientific ad- Lanham, Md.: Rowman & Littlefield, 2002.
vancements, among them cloning, assisted Brings together classic writings (George Or-
suicide, genetic engineering, and treating well, Aldous Huxley) as well as more recent
illnesses during fetal development. essays and congressional testimony about
Charon, Rita, and Martha Montello, eds. Stories human cloning, genetic engineering, stem
Matter: The Role of Narrative in Medical Ethics. cell research, biotechnology, human nature,
New York: Routledge, 2002. Explores the and American democracy.
narrative interaction of the medical field May, Thomas. Bioethics in a Liberal Society: The Po-
the written and verbal communication in- litical Framework of Bioethics Decision Making.
volved in doctors notes, patients stories, Baltimore: Johns Hopkins University Press,
the recommendations of ethics committees, 2002. Takes the debate about biomedical
Biofertilizers 77
ethics into the political realm, analyzing how ganization specializes in bioethics, and its
the political context of liberal constitutional site contains news postings, articles on bio-
democracy shapes the rights and obligations ethics and different aspects of genetic sci-
of both patients and health care profession- ence, and announcements of events and
als. publications.
ONeill, Onora. Autonomy and Trust in Bioethics.
New York: Cambridge University Press,
2002. Examines issues surrounding repro-
ductive and principled autonomy, trust, con- Biofertilizers
sent, and the media and bioethics.
Singer, Peter. Unsanctifying Human Life: Essays Field of study: Genetic engineering and
on Ethics. Edited by Helga Kuhse. Malden, biotechnology
Mass.: Blackwell, 2002. Singer is one of to- Significance: Biofertilizers were used in agricul-
days major bioethicists. Here he examines ture long before chemical fertilizers became preva-
the role of philosophers and philosophy in lent during and after the Industrial Revolution.
such questions as the moral status of the em- The depleted soil fertility and contamination of
bryo, animal rights, and how we should live. ecosystems caused by the extensive use of chemical
Veatch, Robert M. The Basics of Bioethics. 2d ed. fertilizers, however, has prompted the redevelop-
Upper Saddle River, N.J.: Prentice Hall, ment of biofertilizers, which are designed to work
2003. In a textbook designed for students, according to basic principles at work in nature,
Veatch presents an overview of the main the- taking advantage of plants and other organisms
ories and policy questions in biomedical eth- to maintain healthy soil.
ics. Includes diagrams, case studies, and defi-
nitions of key concepts. Key terms
algae: minute plants that live in fresh water;
Web Sites of Interest they are used as biofertilizers because of
American Journal of Bioethics Online. http:// their high productivity and ability to fix at-
www.bioethics.net. Provides sections on mospheric nitrogen
cloning basics, animal cloning, stem cells, nodule: a symbiotic relationship between bac-
U.S. federal and state laws, the cloning de- teria and plant roots that causes the conver-
bate, news, and more. sion of nitrogen gas into a form readily ac-
Kennedy Institute of Ethics, Georgetown Univer- cessible by plants
sity. http://www.georgetown.edu/research/ symbiosis: a mutually beneficial association
kie. Links to many resources on bioethics as between two living organisms
well as a bioethics library that in turn leads
to resources on human genetics and ethics. Overview
National Information Resource on Ethics and Biofertilizers are living microorganisms that
Human Genetics. http://www.georgetown work either alone or in association with matter
.edu/research/nrcbl/nirehg. Supports links and other organisms to enhance the fertility of
to databases, annotated bibliographies, and soil. For many centuries, biofertilizers were
articles about the ethics of genetic testing used in organic farming in countries such as
and human genetics. China, India, and Egypt until modernization
Presidents Council on Bioethics. http:// resulted in a move toward the use of environ-
bioethics.gov. Government arm that advises mentally destructive chemical fertilizers. Or-
on ethical issues surrounding biomedical ganic agriculture integrates livestock, aquatic
science and technology. Includes links to organisms, plants, and the scientific enhance-
bioethics literature and other resources on ment of natural processes to maintain ecologi-
ethics and human genetics. cal equilibrium, thus maximizing the produc-
The Hastings Center. http://www.thehastings tion of foods and goods through complete
center.org. This independent nonprofit or- recycling of all resources. Biofertilizers may in-
78 Biofertilizers
clude microorganisms, nitrogen-fixing algae, mal, but if they are grown too densely, they may
green manure, plant residues, and sewer sludge. become weeds and suffocate aquatic animals.
Biofertilizers not only provide an alternative
method of farming but may also provide the Green Manure, Plant Residues, and
only way to reduce environmental contamina- Treated Sewer Sludge
tion and soil fertility depletion caused by chem- Some crops, particularly legumes, are grown
ical fertilizers. and harvested to be used as green manure to
restore the soils fertility. They may be used di-
Microorganisms and Algae rectly or mixed with microorganisms. Green
Microorganisms must be applied to the soil manure releases nutrients slowly and provides
or mixed with seeds and other ingredients be- long-term fertility for soil. After grains are har-
fore they can establish a symbiotic relationship vested for food, plant residues are processed
with a plants root system. They have been into fertilizer in one of two ways. They may be
shown to stabilize manure, increase the amount burned to extract energy, after which the ashes
of nitrogen in the soil, increase root surface are applied to the soil. Alternatively, they may
area for absorption, and control the leaking of be fermented in a sealed underground tank to
nitrogen into the groundwater. Another type of make methane to be used as natural gas or
association between plant roots (particularly ethanol, which may become an increasingly im-
legumes) and nitrogen-fixing bacteria is a sym- portant fuel source. Genetically engineered
biotic relationship called a nodule. Nodules microbes convert fiber-rich crop residues such
are natural factories that produce ample fer- as wheat straw and corn stalks into ethanol.
tilizers by converting nitrogen into ammonium, Solid residue left over after fermentation is
a form of nitrogen that may be used directly by used as a biofertilizer. The fermentation ap-
plants or deposited slowly into the soil, thus en- proach is promising because it is environmen-
hancing its fertility. While continuous applica- tally friendly and also creates alternative en-
tion of chemical fertilizers depletes the soils ergy sources, additional income, and market
natural fertility and destroys beneficial micro- opportunities for farmers.
organisms, natural fertilizers produced by nod- Even though sewer sludge has been used as a
ules alleviate the contamination to the ecosys- fertilizer in developing countries for some
tem. Unfortunately, nodules are formed only time, people are more resistant to it because of
between legumes and bacteria, thus limiting the animal and human wastes present in the
their use. Genetically engineered bacteria are sludge. Proper treatments must be in place to
being used to improve the efficiency of nitro- get rid of possible heavy metals or pathogens.
gen fixation, and some researchers have at- More research is needed on sewer sludge be-
tempted to transfer genes responsible for form- fore it is considered for wide use as a fertilizer.
ing such symbiotic relationships from legumes Ming Y. Zheng
to other plant species. See also: Biopesticides; Genetic Engi-
Algae are minute plants that are almost en- neering; Genetic Engineering: Agricultural
tirely aquatic. They grow and reproduce very Applications; Genetically Modified (GM)
rapidly during the growing season but die off Foods; High-Yield Crops; Quantitative Inheri-
during the nongrowing season. Such a boom tance; Transgenic Organisms.
and bust life cycle provides the soil with sub-
stantial amounts of nutrients through the deg- Further Reading
radation of dead algae and the deposit of the Bethlenfalvay, G. J., and R. G. Linderman.
nitrogen fixed by algae during the growing sea- Mycorrhizae in Sustainable Agriculture. Madi-
son. Two types of algae, azospirillum and azoto- son, Wis.: American Society of Agronomy,
bacter, have been used as biofertilizers in rice 1992. Provides excellent discussions on the
fields for centuries in Southeast Asia. Algae are knowledge and importance of mycorrhizae
the only plants that are able to fix nitrogen by to plants and the soil.
themselves. The cost of raising algae is mini- Chrispeels, M. J., and D. E. Sadava. Plants, Genes,
Bioinformatics 79
striction enzyme cloning strategies, and even tive information, such as the organism from
entire in silico experiments. This greatly accel- which it comes, its location on the genome, the
erates the work of researchers but also changes person or organization that produced the se-
the daily lives of many biologists so that they quence, and a unique identification number
spend more time working with computers and (accession number) so that it can be refer-
less time working with test tubes and pipettors. enced in scientific literature. This additional
The rapid accumulation of enormous amounts annotation information can also be stored as
of molecular sequence data and their cryptic texteven in the same file with the sequence
and subtle patterns have created a need for informationbut there must be a consistent
computerized databases and analysis tools. format, a standard.
Bioinformatics provides essential support In addition to maintaining basic flat-file
services to modern molecular genetics for or- structures for text data, it is useful to maintain
ganizing, analyzing, and distributing data. As sequence data in relational databases, which al-
DNA sequencing and other molecular genetic low for much faster searching across multiple
technologies become more automated, data query terms and the linkage of sequence data
are generated ever more rapidly, and comput- files with other relevant information. The most
ing systems must be designed to store the data sophisticated and widely used relational data-
and make them available to scientists in a use- base system for bioinformatics is the Entrez sys-
ful fashion. The use of these vast quantities of tem at the National Center for Biotechnology
data for the discovery of new genes and genetic Information (NCBI). Entrez is a relational data-
principles relies on the development of sophis- base that includes cross-links between all of
ticated new data-mining tools. The challenge the DNA sequences in GenBank. GenBank ex-
of bioinformatics is in finding new approaches changes data with the DNA DataBank of Japan
to deal with the volume and complexity of the and the European Molecular Biology Labora-
data, and in providing researchers with access tory on a daily basis to ensure that all three cen-
both to the raw data and to sophisticated and ters maintain the same set of data, and all peer-
flexible analysis tools in order to advance re- reviewed journals require the submission of
searchers understanding of genetics and its sequence data to GenBank prior to publication
role in health and disease. of research articles; publicly funded sequencing
projects, such as the Human Genome Project,
Database Design submit new sequence data to GenBank as it is
The DNA sequence data collected by auto- collected, so that the scientific community can
mated sequencing equipment can be repre- have immediate access to it. Entrez also includes
sented as a simple sequence of letters: G, A, T, all of the derived protein sequences (transla-
and Cwhich stand for the four nucleotide tions from cDNAs and predicted coding se-
bases on one strand of the DNA molecule (gua- quences in genomic DNA), the scientific litera-
nine, adenine, thymine, and cytosine). These ture in MedLine/PubMed, three-dimensonal
letters can easily be stored as plain text files on a protein structures from the Protein Data Base
computer. Similarly, protein sequences can also (PDB), and human genetic information from
be stored as text files using the twenty single- the Online Mendelian Inheritance in Man
letter abbreviations for the amino acids. (OMIM) database. Relational databases are
There is a significant advantage to storing even more important for more complex types
DNA and protein sequence as plain text files, of genomic data, such as gene expression micro-
also known as flat files. Text files take up mini- arrays and genetic variation and genotyping
mal amounts of hard-drive space, can be used data sets.
on any type of computer and operating system,
and can easily be moved across the Internet. Key Algorithms
However, a text file with a bunch of letters rep- Some of the key algorithms used in bio-
resenting a DNA or protein sequence is essen- informatics include sequence alignment (dy-
tially meaningless without some basic descrip- namic programming), sequence similarity
Bioinformatics 81
Steven Brenner, of the University of California at Berkeley, next to a computer running bioinformatics software in November, 2001.
He advocates distributing information freely as open source code, claiming that this is the best way to debug bioinformatics software
and advance research. (AP/Wide World Photos)
variation: genetic tests either for alleles of well- entries in GenBank; however, these links are
studied genes or for anonymous single nucleo- not reciprocal. Someone looking at a GenBank
tide polymorphisms (SNPs) identified from cDNA sequence in the Entrez browser would
genome sequence data. As these genotyping have no way of knowing that a corresponding
technologies are improved, it is becoming pos- protein entry is present in a database dedicated
sible to collect data in an automated fashion for to Drosophila genetics or to G-protein coupled
many genetic loci from a single DNA sample, or receptor mutants. It is never possible for scien-
to test a single genetic locus on many thou- tists to be certain that they have collected all of
sands of DNA samples in parallel. These new the relevant information about a molecule of
data types require new database designs and interest from all online databases.
the inclusion of new types of algorithms (from Stuart M. Brown
statistics, population genetics, and other disci- See also: cDNA Libraries; DNA Finger-
plines) in bioinformatics data-management so- printing; DNA Sequencing Technology; For-
lutions. ensic Genetics; Genetic Testing: Ethical and
Economic Issues; Genetics, Historical Develop-
Integration ment of; Genomic Libraries; Genomics; Hu-
The biggest challenge facing bioinformatics man Genome Project; Icelandic Genetic Data-
is the integration of various types of data in a base; Linkage Maps; Proteomics.
form that allows scientists to extract meaning-
ful insights into biology from the masses of Further Reading
information in molecular genetic databases. Baxevanis, Andreas D., and B. F. Francis
Genome browsers are one example of this chal- Ouellette. Bioinformatics: A Practical Guide to
lenge. It is extremely difficult to provide a dis- the Analysis of Genes and Proteins. 2d ed. Ho-
play that allows someone to view all of the boken, N.J.: John Wiley & Sons, 2003. This
relevant information about a gene or a chro- book provides a sound foundation of basic
mosomal region, including the identity of en- concepts of bioinformatics, with practical
coded proteins, protein structure and func- discussions and comparisons of both com-
tional information, involvement in metabolic putational tools and databases relevant to
and regulatory pathways, developmental and biological research. The standard text for
tissue-specific gene expression, evolutionary most graduate-level bioinformatics courses.
relationships to proteins in other organisms, Claverie, Jean-Michel, and Cedric Notredame.
DNA motifs bound by regulatory proteins, ge- Bioinformatics for Dummies. Hoboken, N.J.:
netic synteny with other species (that is, having John Wiley & Sons, 2003. A practical intro-
genes with loci on the same chromosome), duction to bioinformatics: computer tech-
phenotypes of mutations, and known alleles nologies that biochemical and pharmaceuti-
and SNPs and their frequency in various popu- cal researchers use to analyze genetic and
lations. biological data. This reference addresses
Another, much more modest, goal would be common biological questions, problems,
simply to alert a person viewing a DNA or pro- and projects while providing a UNIX/Linux
tein sequence in one database of the existence overview and tips on tweaking bioinformatic
of additional information about that entity in applications using Perl.
other databases. At the present time, such cross- Krawetz, Stephen A., and David D. Womble. In-
database links are inconsistent and unreliable. troduction to Bioinformatics: A Theoretical and
The NCBI cross-references its own databases Practical Approach. Totowa, N.J.: Humana
from DNA to proteins to three-dimensional Press, 2003. Aimed at undergraduates, grad-
structures to PubMed articles to genomes. Most uate students, and researchers. Four sec-
special subject databases, such as those that fo- tions: Biochemistry: Cell and Molecular
cus on a particular species or on a particular Biology, Molecular Genetics, Unix Oper-
type of molecule, link DNA and protein se- ating System, and Computer Applica-
quences back to the corresponding reference tions.
Biological Clocks 83
Mount, David W. Bioinformatics: Sequence and Ge- personality changes, and deterioration of
nome Analysis. Cold Spring Harbor, N.Y.: higher mental functions
Cold Spring Harbor Laboratory Press, 2001. circadian rhythm: a cycle of behavior, ap-
A textbook written for the biologist who proximately twenty-four hours long, that is
wants to acquire a thorough understanding expressed independent of environmental
of popular bioinformatics programs and changes
molecular databases. It does not teach pro- free-running cycle: the rhythmic activity of
gramming but does explain the theory be- an individual that operates in a constant en-
hind each of the algorithms. vironment
Nucleic Acids Research 31, no. 1 (2003). This Huntingtons disease: an autosomal domi-
widely respected journal produces a special nant genetic disorder characterized by loss
issue in January of each year devoted en- of mental and motor functions in which
tirely to online bioinformatics databases. symptoms typically do not appear until after
The articles represent the definitive state- age thirty
ment by the directors of each of the major suprachiasmatic nucleus (SCN): a cluster of
public databases of molecular biology data several thousand nerve cells that contains a
regarding the types of information and anal- central clock mechanism that is active in the
ysis tools in their databases and plans for de- maintenance of circadian rhythms
velopment in the immediate future.
Types of Cycles
Web Sites of Interest Biological clocks control a number of physi-
Bioinformatics Organization. http://www.bio ological functions, including sexual behavior
informatics.org. Provides a helpful tutorial and reproduction, hormonal levels, periods of
on bioinformatics. activity and rest, body temperature, and other
European Bioinformatics Institute. http://www activities. In humans, phenomena such as jet
.ebi.ac.uk. Maintains databases concerning lag and shift-work disorders are thought to re-
nucleic acids, protein sequences, and macro- sult from disturbances to the innate biological
molecular structures, as well as postings of clock.
news and events and descriptions of ongoing The most widely studied cycles are circadian
scientific projects. rhythms. These rhythms have been observed in
a variety of animals, plants, and microorgan-
isms and are involved in regulating both com-
plex and simple behaviors. Typically, circadian
Biological Clocks rhythms are innate, self-sustaining, and have a
cyclicity of nearly, but not quite, twenty-four
Field of study: Human genetics and social hours. Normal temperature ranges do not alter
issues them, but bursts of light or temperature can
Significance: Biological clocks control those peri- change the rhythms to periods of more or less
odic behaviors of living systems that are a part of than twenty-four hours. Circadian rhythms are
their normal function. The rhythms may be of a apparent in the activities of many species, in-
daily, monthly, yearly, or even longer periodicity. cluding humans, flying squirrels, and rattle-
In some cases, the clocks may be programmed to snakes. They are also seen to control feeding
regulate processes that may occur at some point behavior in honeybees, song calling in crickets,
in the lifetime of the individual, such as those and hatching of lizard eggs.
processes related to aging. Altered or disturbed What is known about the nature of the biolog-
rhythms may result in disease. ical clock? The suprachiasmatic nucleus (SCN)
consists of a few thousand neurons or special-
Key terms ized nerve cells that are found at the base of the
Alzheimers disease: a disorder characterized hypothalamus, the part of the brain that con-
by brain lesions leading to loss of memory, trols the nervous and endocrine systems. The
84 Biological Clocks
SCN appears to play a major role in the regula- A semidominant autosomal mutation,
tion of circadian rhythms in mammals and af- CLOCK, in the mouse produces a circadian
fects cycles of sleep, activity, and reproduction. rhythm one hour longer than normal. Mice
The seasonal rhythm in the SCN appears to be that are homozygous (have two copies) for
related to the development of seasonal depres- the CLOCK mutation develop twenty-seven- to
sion and bulimia nervosa. Light therapy is ef- twenty-eight-hour rhythms when initially placed
fective in these disorders. Blind people, whose in darkness and lose circadian rhythmicity com-
biological clocks may lack the entraining ef- pletely after being in darkness for two weeks.
fects of light, often show free-running rhythms. No anatomical defects have been seen in associ-
Genetic control of circadian rhythms is indi- ation with the CLOCK mutation.
cated by the findings of single-gene mutations
that alter or abolish circadian rhythms in sev- Biological Clocks and Aging
eral organisms, including the fruit fly (Drosoph- Genes present in the fertilized egg direct
ila) and the mouse. A mutation in Drosophila and organize life processes from conception
affects the normal twenty-four-hour activity until death. There are genes whose first effects
pattern so that there is no activity pattern at all. may not be evident until middle age or later.
Other mutations produce shortened (nineteen- Huntingtons disease (also known as Hunting-
hour) or lengthened (twenty-nine-hour) cy- tons chorea) is such a disorder. An individual
cles. The molecular genetics of each of these who inherits this autosomal dominant gene is
mutations is known. programmed around midlife to develop in-
A squirrel hibernates in the hands of University of Minnesota biochemist Matt Andrews. Because the ground squirrel possesses the
ability to put its body into this form of stasis, it is nearly immune to strokes. The genetics of such biological clocks may one day lead to
better treatments for strokes in humans. (AP/Wide World Photos)
Biological Clocks 85
voluntary muscle movement and signs of men- review of research on organisms from algae
tal deterioration. Progressive deterioration of to primates, expanding traditional geronto-
body functions leads to death, usually within fif- logical and geriatric issues to intersect with
teen years. It is possible to test individuals early behavioral, developmental, evolutionary,
in life before symptoms appear, but such tests, and molecular biology. Illustrated.
when no treatment for the disease is available, Hamer, Dean, and Peter Copeland. Living with
are controversial. Our Genes: Why They Matter More than You
Alzheimers disease (AD) is another disor- Think. New York: Doubleday, 1998. Links
der in which genes seem to program processes DNA and behavior and contains a good
to occur after middle age. AD is a progressive, chapter on biological clocks and aging.
degenerative disease that results in a loss of in- Medina, John J. The Clock of Ages: Why We Age,
tellectual function. Symptoms worsen until a How We AgeWinding Back the Clock. New
person is no longer able to care for himself or York: Cambridge University Press, 1996. A
herself, and death occurs on an average of book written especially for the general
eight years after the onset of symptoms. AD reader. Covers aging on a system-by-system
may appear as early as forty years of age, al- basis and includes a large section on the ge-
though most people are sixty-five or older netics of aging.
when they are diagnosed. Age and a family his- Nelson, James Lindemann, and Hilde Linde-
tory of AD are clear risk factors. Gene muta- mann Nelson. Alzheimers: Answers to Hard
tions associated with AD have been found on Questions for Families. New York: Main Street
human chromosomes 1, 14, 19, and 21. Al- Books, 1996. Reviews Alzheimers disease
though these genes, especially the apolipopro- for the lay reader, guides caregivers through
tein e4 gene, increase the likelihood of a person the difficult moral and ethical problems as-
getting AD, the complex nature of the disorder sociated with the disease, and discusses sup-
is underscored when it is seen that the muta- port services.
tions account for less than half of the cases of Zallen, Doris Teichler. Does It Run in the Family?
AD and that some individuals with the muta- A Consumers Guide to DNA Testing for Genetic
tion never get AD. Disorders. New Brunswick, N.J.: Rutgers Uni-
versity Press, 1997. Focuses on the practical
Impact and Applications aspects of obtaining genetic information,
Evidence has accumulated that human activ- clearly explaining how genetic disorders are
ities are regulated by biological clocks. It has passed along in families. Provides useful in-
also become evident that many disorders and formation on genetic disorders, including
diseases, and even processes that are associ- Huntingtons disease and Alzheimers dis-
ated with aging, may be affected by abnormal ease.
clocks. As understanding of how genes control
biological clocks develops, possibilities for im-
proved therapy and prevention should emerge. Web Sites of Interest
It may even become possible to slow some of National Institute of Mental Health, How Bio-
the harmful processes associated with normal logical Clocks Work. http://www.nimh.nih
aging. .gov/publicat/bioclock.cfm. An introductory
Donald J. Nash site that focuses on the molecular basis of
See also: Aging; Alzheimers Disease; Bio- the biological clock. Includes references for
logical Determinism; Cancer; Developmental further study.
Genetics; Huntingtons Disease; Telomeres. National Science Foundation, Center for Bio-
logical Timing. http://www.cbt.virginia .edu/
Further Reading cbtdocs. This site covers the science of bio-
Finch, Caleb Ellicott. Longevity, Senescence, and logical clocks and provides a biological tim-
the Genome. Reprint. Chicago: University of ing tutorial.
Chicago Press, 1994. Provides a comparative
86 Biological Determinism
tween groups. In addition, the correlation be- tional genes that influence behavior, society
tween two entities (such as genes and behavior) must guard against using this information as
does not necessarily imply a causal relationship justification for the mistreatment or elimina-
(for example, the incidences of ice cream con- tion of groups that are perceived as inferior
sumption and drowning are correlated only or undesirable by the majority.
because both increase during the summer). Lee Anne Martnez
Complex, multifaceted behaviors such as intel- See also: Aggression; Aging; Alcoholism;
ligence and violence are often reified, or treated Altruism; Behavior; Bioethics; Biological
as discrete concrete entities (as IQ and impulse Clocks; Cloning: Ethical Issues; Criminality;
control, respectively), in order to make claims Developmental Genetics; Eugenics; Eugenics:
about their genetic basis. Combined with the Nazi Germany; Gender Identity; Genetic Engi-
cultural and social bias of scientific researchers, neering: Social and Ethical Issues; Genetic
reification has led to many misleading claims Screening; Genetic Testing: Ethical and Eco-
regarding the biological basis of social structure. nomic Issues; Heredity and Environment; Hu-
Biological and cultural evolution are gov- man Genetics; Intelligence; Miscegenation
erned by different mechanisms. Biological and Antimiscegenation Laws; Natural Selec-
evolution occurs only between parents and off- tion; Race; Sociobiology; Twin Studies; XYY
spring (vertically), while cultural evolution oc- Syndrome.
curs through communication without regard
to relationship (horizontally) and thus can oc- Further Reading
cur quickly and without underlying genetic Begley, Sharon. Gray Matters. Newsweek,
change. Moreover, the socially fit (those who March 27, 1995. Discusses the differences
are inclined to reproduce wealth) are not nec- between the brains of males and females.
essarily biologically fit (inclined to reproduce Gould, Stephen Jay. The Mismeasure of Man.
themselves). The reductionist attempt to gain New York: Norton, 1996. Refutes Richard
an understanding of human culture through Herrnstein and Charles Murrays argument
its biological components does not work well and presents an engaging historical over-
in a system (society) shaped by properties that view of how pseudoscience has been used to
emerge only when the parts (humans) are put support racism and bigotry.
together. Cultures cannot be understood as Herrnstein, Richard, and Charles Murray. The
biological behaviors any more than biological Bell Curve: Intelligence and Class Structure in
behaviors can be understood as atomic interac- American Life. New York: Simon and Schus-
tions. ter, 1994. Asserts that IQ plays a statistically
important role in the shaping of society by
Impact and Applications examining such sociological issues as school
Throughout history, biological determin- dropout rates, unemployment, work-related
ism has been used to justify or reinforce racism, injury, births out of wedlock, and crime.
genocide, and oppression, often in the name of Moore, David S. Dependent Gene: The Fallacy of
achieving the genetic improvement of the hu- Nature vs. Nurture. New York: W. H. Freeman,
man species (for example, the racial health 2001. Few books examine the ways the genes
of Nazi Germany). Gould has noted that claims and the environment interact to produce ev-
of biological determinism tend to be revived erything from eye color to behavioral ten-
during periods when it is politically expedient dencies. This book lays to rest the popular
to do so. In times of economic hardship, many myth that some traits are purely genetic and
find it is useful to adopt an us against them at- others purely a function of environment;
titude to find a group to blame for social and rather, all traits are the result of complex, de-
economic woes or to free themselves from the pendent interactions of bothinteractions
responsibility of caring for the biologically in- that occur at all stages of biological and psy-
ferior underprivileged. As advances in molec- chological development. An informed argu-
ular genetics lead to the identification of addi- ment against simplistic determinism.
88 Biological Weapons
Rose, Steven. The Rise of Neurogenetic Deter- recombinant DNA: DNA prepared by trans-
minism. Nature 373 (February, 1995). Dis- planting and splicing genes from one spe-
cusses how advances in neuroscience have cies into the cells of another species
led to a resurgence of the belief that genes smallpox: an acute, highly infectious, often fa-
are largely responsible for deviant human tal disease characterized by fever followed by
behavior. the eruption of pustules
Sussman, Robert, ed. The Biological Basis of Hu-
man Behavior: A Critical Review. 2d ed. New Early History
York: Simon and Schuster, 1998. Fifty-nine Biological warfare antedates by several cen-
essays examine genetics, the various inter- turies the discovery of the gene. Just as the his-
pretations of the early evolution of human tory of genetics did not begin with Gregor Men-
behavior, new attempts to link human physi- del, whose pea-plant experiments eventually
cal variation to behavioral differences be- helped found modern genetics, the history of
tween people, modern evolutionary psy- biological warfare began long before the Japa-
chology, and the influences of hormones nese dropped germ-filled bombs on several
and the brain on behavior. Chinese cities during World War II. For exam-
ple, the Assyrians, six centuries before the com-
mon era, knew enough about rye ergot, a fun-
gus disease, to poison their enemies wells. The
Biological Weapons ancient Greeks also used disease as a military
weapon, and the Romans catapulted diseased
Fields of study: Genetic engineering and animals into enemy camps. A famous medieval
biotechnology; Human genetics use of biological weapons occurred during the
Significance: Just as twentieth century discoveries Tatar siege of Kaffa, a fortified Black Sea port,
in chemistry and physics led to such devastating then held by Christian Genoans. When Tatars
weapons as poison gases and nuclear bombs, so started dying of the bubonic plague, the survi-
humanity in the twenty-first century faces the pros- vors catapulted cadavers into the walled city.
pect that the biotechnological revolution will lead Many Genoans consequently died of the plague,
to the development and use of extremely deadly bio- and the remnant who sailed back to Italy con-
logical weapons. tributed to the spread of the Black Death into
Europe.
Key terms Once smallpox was recognized as a highly
anthrax: an acute bacterial disease that af- contagious disease, military men made use of
fects animals and humans and that is espe- it in war. For example, the conquistador Fran-
cially deadly in its pulmonary form cisco Pizarro presented South American na-
biological weapon (BW): the military or ter- tives with smallpox-contaminated clothing, and,
rorist use of such organisms as bacteria and in an early case of ethnic cleansing, the British
viruses to cause disease and death in people, and Americans used deliberately induced small-
animals, or plants pox epidemics to eliminate native tribes from
bioterrorist: an individual or group that co- desirable land.
ercively threatens or uses biological weap- As scientists in the nineteenth and twentieth
ons, often for ideological reasons centuries learned more about the nature and
ethnic weapons: genetic weapons that target modes of reproduction of such diseases as an-
certain racial groups thrax and smallpox, germ warfare began to
genetic engineering: the use of recombinant become part of such discussions as the First In-
DNA to alter the genetic material in an or- ternational Peace Conference in The Hague
ganism (1899). The worldwide revulsion against the
immune system: the biological defense mecha- chemical weapons used in World War I, along
nism that protects the body from disease- with a concern that biological weapons would
causing microorganisms be more horrendous, led to the Geneva Proto-
Biological Weapons 89
Anthrax colonies grow on culture in a petri dish in Mexico City, where in 2001 two germ banks housed dozens of these cultures vir-
tually unguarded. (AP/Wide World Photos)
col (1925), which prohibited the first use of nities as San Francisco. When news of these
germ weapons, but not their development. secret tests was made public, many questioned
their morality. Extensive criticism of the re-
From Germ Warfare to Genetic Weapons search and development of these weapons, to-
With the accelerating knowledge about the gether with the realization that these weapons
genetics of various disease-causing microorgan- posed a threat to the attackers as well as the at-
isms, several countries became concerned with tacked, led President Richard Nixon to end the
the threat to their security posed by the weap- American biological weapons program formally
onizing of these pathogens. Although several in 1969.
states signed the Geneva Protocol in the late Abhorrence of biological weapons extended
1920s, others signed only after assurances of to the world community, and in 1972 the Biolog-
their right to retaliate. The United States, ical and Toxin Weapons Convention (BTWC)
which did not ratify the treaty until 1975, did a treaty that prohibited the development, pro-
extensive research on germ weapons during duction, and stockpiling of bacteriological
the 1950s and 1960s. American scientists were weaponswas signed in Washington, D.C., Lon-
able to make dry infectious agents that could don, and Moscow and was put into force in
be packed into shells and bombs, and estimates 1975. Although it was eventually signed by most
were made that ten airplanes with such bombs members of the United Nations, the nations
could kill or seriously disable tens of millions of that signed the pact failed to reach agreement
people. Unknown to Congress and the Ameri- on an inspection system that would control the
can people, tests using apparently harmless mi- proliferation of these weapons. A pivotal irony
crobes were performed on such large commu- of the BTWC is that while most of the world was
90 Biological Weapons
renouncing germ warfare, biologists were learn- and botulinum bacteria to Iraq, whose scien-
ing how to manipulate DNA, the molecule that tists later acknowledged that they had used
carries genetic information, in powerful new these microbes to make tons of biological
ways. This knowledge made possible the cre- weapons during the 1980s.
ation of superbugs, infectious agents for With the demise of the Soviet Union and in-
which there are no cures. creasing violence in the Balkans and Middle
Some scientists warned the public and inter- East, politicians became fearful that experts
national agencies about these new germ weap- who had dedicated their careers to making bio-
ons. Other investigators discovered that Ameri- logical weapons would now sell their knowl-
can researchers were creating infectious agents edge to rogue nations or terrorist groups. In-
that would confuse diagnosticians and defeat deed, deadly pathogens were part of world
vaccines. Similarly, Soviet researchers on an is- trade, since the line separating legitimate and
land in the Aral Sea, described as the worlds illegitimate research, defensive and offensive
largest BW test site, were producing germ BWs, was fuzzy. In the 1980s members of a reli-
weapons that could be loaded on missiles. gious cult spread salmonella, a disease-causing
When Boris Yeltsin became president of Russia, bacterium, in an Oregon town, causing more
he discovered that the secret police and mili- than seven hundred people to become very ill.
tary officials had misinformed him about BW The same company that sold salmonella to this
programs, in which deadly accidents had oc- religious cult also sold pathogens to the Univer-
curred. Also troubling was the spread of biolog- sity of Baghdad. Bioterrorism had become
ical agents to such countries as Iraq. American both a reality and a threat.
and French companies legally shipped anthrax
In 1996, U.N. inspectors supervise the destruction of growth media for biological weapons in Iraq. (AP/Wide World Photos)
Biological Weapons 91
Key terms
Agrobacterium tumefaciens: a species of bacteria
that is able to transfer genetic information
into plant cells
Bacillus thuringiensis: a species of bacteria that
produces a toxin deadly to caterpillars,
moths, beetles, and certain flies Image not available
baculovirus: a strain of virus that is capable of
causing disease in a variety of insects
transformation: the process of transferring a
foreign gene into an organism
transgenic organism: an organism synthesiz-
ing a foreign protein; the gene of which was
obtained from a different species of organ-
ism
Bacillus thuringiensis
Hungry insects are the bane of gardeners.
This problem is worsened for farmers, whose
livelihoods depend on keeping fields free of
destructive insects. Although effective, chemi-
Although the biopesticide Bt has been genetically integrated
cal pesticides have a variety of drawbacks. The into crops to make them resistant to insects and other pests,
increasing popularity of organically grown pro- there is evidence that new pests are emerging and old pests,
duce that is untreated by chemicals suggests such as the bollwormagainst which the Bt crops were engi-
that consumers are wary that human-made pes- neered to protectare evolving their own resistance to the Bt
ticides may hold hidden dangers. In response toxin. Here a farmer in India displays the bollworm damage to
to consumers worries over chemical-pesticide his Bt cotton. (AP/Wide World Photos)
Biopesticides 93
Researchers have long had a concern as to the effect Since then, additional studies indicate a less sig-
of chemical insecticides on nontarget species. Tar- nificant effect of Bt toxins on nontarget species. The
get species frequently display resistance to chemical dispersal of Bt pollen is not believed to occur more
controls due to large effective population sizes and than a few meters from the edges of the treatment
prior histories of exposure to chemical agents which area, and even at these distances the levels have been
favors the increase in resistance alleles in a popula- shown to be sublethal. Research involving monarchs
tion. The exact opposite is typically true for non- and swallowtail butterflies (Papilio species) has indi-
target species that occupy the treatment area. When cated that lethality is not elevated at low-level Bt
biopesticides such as the Cry1ab endotoxins, de- exposure, although there is evidence of reduced
rived from the soil bacterium Bacillus thuringiensis growth rates. Furthermore, only a fraction of the
(Bt), were first proposed as control agents, many sci- nontarget organisms population would be exposed
entists believed that the collateral effects on non- at a given time, and frequently the larval periods of
target species would be significantly limited. the target and nontarget organisms do not overlap.
Initially these toxins were sprayed on crops, thus This evidence suggests that biopesticides are not pro-
potentially increasing the exposure of nontarget spe- ducing the observed decrease in nontarget popula-
cies. Even with the development of transgenic crops tions.
such as corn, it was possible for Bt to move from the It is likely that there may be a limited effect of bio-
treatment area to the feeding grounds of nontarget pesticides on nontarget species, and most research-
species through pollen dispersal. One of the first ers agree that additional research needs to be con-
documented accounts of Bt-induced mortality in a ducted. The genetics of Bt resistance have been
nontarget species was provided in 1999 by research- determined for a number of insects, although for
ers at Cornell University. They demonstrated that others the exact mechanism has remained elusive.
the pollen from Bt-treated corn increased mortality However, the greatest threat to the nontarget organ-
among monarch butterflies (Danaus plexippus) when isms rests with habitat destruction. A decrease in the
applied to the surfaces of milkweed plants, the but- population size due to reduced resources may serve
terflys primary food source. In this study, monarchs to weaken the population and enhance the sublethal
exposed to Bt had a slower rate of growth and in- effects of biopesticide production. The physiological
creased mortality. It was suggested that field mon- effect and population genetics of Bt susceptibility
archs could also be exposed to corn pollen con- in nontarget species will need to be examined in
taining Bt endotoxins. Given the popularity of the some detail to prove to the public the value of bio-
monarch and the noticeable decline in North Amer- pesticides.
ican populations during the 1990s, it appeared that Michael Windelspecht
the future of biopesticides was dim.
inactive proenzyme. After it is digested, en- cotton plants that generated their own Bt toxin.
zymes in the insects gut cleave the protein into The toxin gene was first isolated from Bt cells
an active, toxic fragment. The active toxin binds and ligated (enzymatically attached) into a Ti
to receptors in the insects midgut cells and plasmid. A Ti plasmid is a circular string of
blocks those cells from functioning. Only cater- double-stranded DNA that originates in the
pillars (tobacco hornworms and cotton boll- Agrobacterium tumefaciens bacteria. The A. tume-
worms), beetles, and certain flies have the gut faciens has the ability to take a portion of that Ti
biochemistry to activate the toxin. The toxin plasmid, called the T-DNA, and transfer it and
does not kill insects that are not susceptible, whatever foreign gene is attached to it into a
nor does it harm vertebrates in any way. plant cell. Cotton plants were exposed to the A.
The drawbacks of Bt are its expense and its tumefaciens carrying the toxin gene and were
short-lived effect. In the early 1990s, scientists transformed. The transgenic plants synthesized
overcame these two drawbacks through applied the Bt toxin and became resistant to many
genetic engineering. They produced transgenic forms of larvae.
94 Biopesticides
At the University of Floridas Institute of Food and Agricultural Sciences, Dov Borovsky has developed a diet pill for mosquitoes
that causes them to starve to death. It may help eradicate mosquitoes and the diseases they transmit. (AP/Wide World Photos)
Many crystal toxins have been isolated from tage is their strong specificity against moths,
various strains of Bt. These toxins make up a sawflies, and beetles but not against beneficial
large collection of proteins active against pests insects. Also, viruses, unlike bacteria, tend to
from nematodes to aphids. Researchers are in persist in the environment for a longer period.
the process of reengineering the toxin genes to Finally, baculoviruses are ideal for use in devel-
improve upon their characteristics and to de- oping countries because they can be produced
sign better methods of transporting genes cheaply and in great quantity with no health
from one Bt strain to another. risks to workers. One limitation of baculovirus
is that it must be administered in a precise tem-
Other Biopesticides poral and spatial framework to be effective.
Several species of fungi have been found to Knowledge of insect behavior after hatching,
be toxic to insects, including Verticillium lecanii the insect populations distribution within the
and Metarhizium anisopliae. Scientists have just crop canopy, and the volume of foliage in-
begun to study these fungi, which are not yet gested by each larva is essential. For example,
commercially available to farmers. moths usually do the most damage at the late
In the mid-1990s, a viral biopesticide called larval stage. To minimize crop damage from
baculovirus became widely popular. Baculo- moths, one must spray baculovirus as early as
viruses are sprayed onto high-density pest possible before the insects reach that late stage.
populations just like chemical pesticides. Bacu- One final biopesticide approach has been to
loviruses have several advantages over conven- make transgenic plants that manufacture pro-
tional pesticides. The most important advan- teins isolated from insect-resistant plant spe-
Biopesticides 95
cies. Tomatoes naturally make an enzyme in- crops as well as an overview of new technolo-
hibitor that deters insects by keeping their gies for future genetic engineering.
digestive enzymes (trypsin and chymotrypsin) Cory, Jenny, and David Bishop. Use of Baculo-
from functioning. These inhibitors were iso- viruses as Biological Insecticides. Molecular
lated by Clarence Ryan at the University of Biotechnology, March, 1997. Presents a com-
Washington. Ryan transformed tobacco plants plete discussion of baculoviruses.
with two different forms of inhibitor (inhibi- Deacon, J. W. Microbial Control of Plant Pests and
tors I and II from tomato). The tomato pro- Diseases. Washington, D.C.: American Soci-
teins were effectively produced in tobacco and ety for Microbiology, 1983. Good if brief
made the transgenic plants resistant to tobacco monograph for a broad perspective on bio-
hornworm larvae. control agents.
Entwhistle, Philip F., Jenny S. Cory, Mark J.
Biopesticide Resistance Bailey, and Steven R. Higgs. Bacillus Thur-
As with chemical pesticides, over time insect ingiensis, an Environmental Biopesticide: Theory
populations grow resistant to biopesticides. Bt- and Practice. New York: Wiley, 1994. Addresses
resistant moths can now be found around the the use of one of the oldest and best-known
world. Resistance arises when pesticides are too biopesticides, including its manufacture and
effective and destroy more than 90 percent of a use in developing nations.
pest population. The few insects left are often Gibbons, Anne. Moths Take the Field Against
very resistant to the pesticide, breed among Biopesticides. Science, November 1, 1991.
themselves, and create large, resistant popula- Discusses resistance to biopesticides and its
tions. implications.
Entomologists have suggested strategies for Hall, Franklin R., and Julius J. Menn, eds. Biopes-
avoiding pesticide-resistant insect populations. ticides: Use and Delivery. Totowa, N.J.: Humana
One strategy suggests mixing biopesticide-- Press, 1999. A guide to development, appli-
producing and nonproducing plants in the same cation, and use of biopesticides as a comple-
field, thereby giving the pesticide-susceptible mentary or alternative treatment to chemi-
part of the insect population places of refuge. cal pesticides. Reviews their development,
These refuges would allow resistant and nonre- mode of action, production, delivery systems,
sistant insects to interbreed, making the overall and market prospects and discusses current
species less resistant. Other strategies include registration requirements for biopesticides
synthesizing multiple types of Bt toxin in a sin- as compared with conventional pesticides.
gle plant to increase the toxicity range and re- Koul, Opender, and G. S. Dhaliwal, eds. Micro-
duce resistance, making other biological toxins bial Biopesticides. New York: Taylor & Francis,
besides Bt in a single plant, and reducing the 2002. International experts on biopesticides
overall exposure time of insects to the biopesti- explore developments in using those based
cides. on bacteria, fungus, viruses, and nematodes,
James J. Campanella discussing their advantages and disadvan-
See also: Biofertilizers; Genetic Engineer- tages and their role in genetic engineering.
ing: Agricultural Applications; Genetic Engi- _______. Phytochemical Biopesticides. Amsterdam,
neering: Risks; Genetic Engineering: Social and Netherlands: Harwood Academic, 2001. Ad-
Ethical Issues; Genetically Modified (GM) dresses advances made on phytochemical
Foods; High-Yield Crops; Population Genetics. biopesticides, covering behavioral, chemical,
biochemical, and molecular aspects. Topics
Further Reading include the role of phytochemical biopesti-
Carozzi, Nadine, and Michael Koziel, eds. Ad- cides in integrated pest management (IPM),
vances in Insect Control: The Role of Transgenic the potential uses of phytochemical pesti-
Plants. Bristol, Pa.: Taylor & Francis, 1997. cides in deciduous temperate fruit crops, and
Presents technologies that have proved suc- prospects and problems with phytochemical
cessful for engineering of insect-tolerant biopesticides.
96 Biopharmaceuticals
Web Site of Interest particular disease. Since there was no real un-
U.S. Environmental Protection Agency. http:// derstanding of the underlying problem, a ratio-
www.epa.gov/pesticides. Government site nal approach to drug selection and design was
with a link to information on biopesticides, difficult if not impossible. One philosophy of
including the Federal Insecticide, Fungi- medicine that developed to address this prob-
cide, and Rodenticide Act, enacted to moni- lem was called the doctrine of similitudes, in
tor the harmful effects of toxic pesticides on which treatments were based on similarities of
humans and the environment and ensure in- structure with disease manifestation. For exam-
dustry compliance. ple, the leaves of St Johns wort look similar to
damaged skin, so it was thought that extracts
from this plant would be beneficial for treating
cuts and burns.
Biopharmaceuticals It was not until the twentieth century that
the underlying genetic basis for disease was dis-
Fields of study: Diseases and syndromes; covered. The discovery that DNA is the genetic
Genetic engineering and biotechnology material and provides the instructions to make
Significance: Biopharmaceuticals encompass a proteins was revolutionary. In the mid-1900s it
class of drugs that are designed by combining ge- was demonstrated that sickle-cell disease was
netics with biotechnology. Biopharmaceutical caused by a single nucleotide change from an A
products are typically derived from proteins, such (adenine) to a T (thymine) in the hemoglobin
as enzymes or antibodies, and are genetically engi- beta-chain gene. This small change alters the
neered in an attempt to treat a specific disease. shape of a red blood cell from a biconcave disc
They differ from traditional pharmaceuticals, to a sharply pointed crescent. Even though this
which are usually simpler compounds that are pro- finding showed it was possible to identify ge-
duced by chemical synthesis. netic mutations, there was still no way to manip-
ulate or make changes to the genetic informa-
Key terms tion itself.
clinical trial: an experimental research The advent of recombinant DNA technol-
study used to determine the safety and effec- ogy in the 1970s provided the first chance to
tiveness of a medical treatment or drug engineer, or manipulate, genes. Restriction en-
humanized antibody: a human antibody that zymes became an important tool of this tech-
has been engineered to contain a portion of nology. Restriction enzymes were first found in
a nonhuman variable region with known bacteria, where they function to protect the cell
therapeutic activity from foreign DNA by cutting it up. Restriction
pharmacogenomics: the field of science that enzymes cut DNA at specific sequences, which
examines how variations in genes alter the are usually palindromes of the letters that sig-
metabolism and effectiveness of drugs nify the four nucleotides that make up DNA:
guanine (G), adenine (A), thymine (T), and
History of Biopharmaceuticals cytosine (C). Most restriction enzymes cut the
Drugs have been used by humans for thou- DNA in such a way that an overhang, called a
sands of years. The Sumerians are the first peo- sticky end, is created. Since DNA readily recom-
ple known to have compiled medical informa- bines with complementary strands, these sticky
tion in a written form that outlined symptoms ends can be used to splice different pieces of
and treatments for different diseases more DNA together. The resulting sequence is called
than three thousand years ago. Most ancient recombinant DNA.
cultures used medicines derived from plants With the ability to engineer DNA now possi-
and animals. These drugs are different from ble, scientists looked again to bacteria to pro-
modern biopharmaceuticals in many ways, but vide a way to convert that DNA into protein.
the most significant difference is that there was Bacteria are ideal for protein production be-
no engineering used to shape the drugs for a cause they reproduce quickly, are easy to ma-
Biopharmaceuticals 97
nipulate, and can be grown in large quantities. protein. All of these approaches can provide
Many bacteria contain circular pieces of DNA clues as to what may be important targets for
apart from their genome, called plasmids. treatment of the disease.
These plasmids can be readily transferred be- A better understanding of the disease at the
tween bacteria and are also inherited by the genetic and molecular levels facilitates an at-
daughter cells when a bacterium divides. With tempt at designing a biopharmaceutical to
the use of restriction enzymes, plasmids can be treat the disease. Once a disease is understood,
taken from bacteria and engineered to contain it becomes possible to target a key pathway or
a foreign gene. The resulting recombinant plas- protein involved in the disease. The resultant
mid can be put back in bacteria, transforming drug and the way that it is used clinically will
them into protein factories that work nonstop vary from disease to disease. For example,
transcribing and translating the recombinant type I diabetes is caused by a deficiency in the
gene. The first biopharmaceutical produced in hormone insulin. Without insulin, the body
bacteria was recombinant human insulin, which is not able to regulate the level of glucose in
was marketed in 1982. the blood. Lack of insulin is easily corrected
The future for biopharmaceuticals looks by a simple injection of recombinant human
bright. In 1991, there were only fourteen bio- insulin, the first biopharmaceutical. Another
pharmaceuticals approved for use by the U.S. example of a biopharmaceutical that is cur-
Food and Drug Administration (FDA). By 2001, rently in use is the enzyme tissue plasminogen
nearly three hundred had been approved for activator (tPA). Most heart attacks are caused
use, with an additional fifty in phase III clinical by a blood clot blocking the flow of blood
trials, and by 2003 more than 330 major compa- through a coronary artery. Formation and re-
nies in the United States were working to pro- moval of blood clots is a highly regulated and
duce and develop biopharmaceuticals. well-understood process. The enzyme tPA is
known to be one of the key players in blood clot
Design of Biopharmaceuticals removal. This knowledge led to the develop-
A popular method for identifying disease- ment of recombinant tPA, which can be pro-
related genes is called genomics. This method vided by injection or infusion to heart attack
uses gene chip analysis to screen thousands of patients. Once in the bloodstream, the tPA
genes in a single experiment. This approach is breaks up the coronary artery clots and re-
dramatically faster and more efficient than tra- stores blood flow to the heart, preventing any
ditional methods and can be used for any dis- further muscle damage.
ease, even those that are not hereditary.
Once the genomic information is obtained, Clinical Trials
it is used to build a broad understanding of Before a biopharmaceutical can be used to
how a disease gene functions and what role it treat disease, it must undergo a clinical trial to
plays in the cell. This information is gathered test its safety and effectiveness. There are four
through the use of experimental models, ge- phases to a clinical trial. Phase I trials involve
netic analysis, biochemical analysis, and struc- studies on a small number of patients (fewer
tural analysis. Experimental models can range than one hundred) to determine drug safety
from cell culture to transgenic mice and pro- and dosage. Phase II trials involve more pa-
vide physiological information about the dis- tients (up to five hundred) to determine ef-
ease. Genetic analysis provides information fectiveness and additional safety information,
about where and when the gene is expressed. such as potential side effects. Phase III trials are
At the molecular level, biochemical analysis the most extensive and involve large numbers
provides information about protein-protein in- of people (between one thousand and three
teractions, post-translational modifications, and thousand) to establish risk-benefit information
enzymatic activity. Structural analysis yields ex- and comparisons with other currently used
tremely detailed information about the physi- treatments. Phase IV trials determine the drugs
cal arrangement of the atoms that make up the optimal use in a clinical setting. In 2003, the en-
98 Blotting: Southern, Northern, and Western
tire process of drug designfrom discovery to Ethical and Economic Issues; Genetic Engi-
clinical trialscost approximately $802 mil- neering; Genetic Engineering: Medical Appli-
lion and took an average of twelve years. Many cations; Genetic Engineering: Risks; Genetic
years of research and millions of dollars are Engineering: Social and Ethical Issues; Geneti-
wasted, because only one in five thousand po- cally Modified (GM) Foods; Molecular Genet-
tential drugs actually makes it to market. ics; Synthetic Genes; Transgenic Organisms;
Xenotransplants.
Biopharmaceuticals Today
Two examples of approved biopharmaceuti- Further Reading
cals are Aralast and Campath. Aralast is mar- Collins, F., and V. McKusick. Implications of
keted by Baxter and was approved for use by the Human Genome Project for Medical Sci-
the FDA in 2003. Aralast is the trade name for ence. JAMA 285, no. 5 (2001): 540-541.
the recombinant human protein known as Overviews the significant impact of the Hu-
alpha-1 proteinase inhibitor (A1PI). A1PI defi- man Genome Project on medical research,
ciency results in the destruction of lung tissue, including specific examples of drug design.
which can lead to emphysema. Aralast is given Wu-Pong, S., and Y. Rojanasakul. Biopharmaceu-
to patients intravenously each week and helps tical Drug Design and Development. Totowa,
protect them against future lung damage. The N.J.: Humana Press, 1999. Outlines the pro-
second drug, Campath, is marketed by Millen- cess of biopharmaceutical design, including
nium Pharmaceuticals and was approved by basic molecular biology, major classes of bio-
the FDA in 2001. Campath is the trade name pharmaceuticals, and clinical trials.
for a humanized antibody against the CD52
antigen found on lymphocytes. The antibody is Web Site of Interest
used to treat chronic lymphocytic leukemia American Chemical Society, The Pharmaceuti-
and works by destroying lymphocytes through cal Century. http://pubs.acs.org/journals/
agglutination and complement activation. pharmcent. Posts articles about the science
The current trend in pharmaceutical re- of biopharmaceuticals, including the role
search is the production of designer drugs played by genetics and the Human Genome
through the new field of pharmacogenomics. Project in the development of new drugs.
Instead of giving a patient a drug that works for
the average person with the average form of a
disease, a patient will be given a drug that is spe-
cifically matched to his or her genetic profile Blotting: Southern,
and to his or her particular form of the disease. Northern, and Western
Currently 100,000 people die each year be-
cause of adverse drug reactions. With the use of Field of study: Techniques and
pharmacogenomics it will be possible to deter- methodologies
mine a patients genetic profile prior to treat- Significance: Blotting is a technique that allows
ment and avoid adverse drug reactions. Re- identification of a specific nucleic acid or amino
search in pharmacogenomics will also increase acid sequence even when it is mixed in with all of
the pool of drugs available to treat disease. Cur- the other material from a cell. This allows the rapid
rently, many drugs never make it to market be- identification of the changes associated with mu-
cause they work for only a small subset of pa- tant alleles.
tients. Pharmacogenomic research will allow
these specific patients to be identified and en- Key terms
able previously abandoned drugs to be used to blotting: the transfer of nucleic acids or pro-
treat disease. teins separated by gel electrophoresis onto a
Matthew J. F. Waterman filter paper, which allows access by mole-
See also: Cloning; Cloning: Ethical Issues; cules that will interact with only one specific
Cloning Vectors; Gene Therapy; Gene Therapy: sequence
Blotting: Southern, Northern, and Western 99
dioactive, single-stranded DNA is added. Since proteins, he named the system Western blot-
the added DNA could stick nonspecifically to ting. This system of naming has been expanded:
the nitrocellulose, the paper is pretreated with A technique for detecting viral DNA in tree
unrelated DNA, such as sheared salmon DNA, leaves was named the Midwestern blot and a
which will bind the available nitro groups but variant of the Northern blot developed in Is-
not react with the probe. rael was named the Middle Eastern blot.
A large molar excess of probe must be used Since proteins are generally smaller than
to drive the hybridization reaction (reforming DNA fragments, they are usually separated on
the hybrid of two matching antiparallel polyacrylamide gels, which have a much smaller
strands together), which means that it is neces- pore size than agarose gels. It is therefore nec-
sary to make sure that enough probe is avail- essary to use electrical current to pull the pro-
able in the solution to randomly run into the teins out of the gel. The nitrocellulose is pressed
correct sequence on the paper and reanneal to onto the gel with a porous plastic pad. The gel
it. The hybridization is done at an elevated tem- is then placed in a buffer tank and electrodes
peratureoften 50-65 degrees Celsius (122- are placed on either side. When a voltage is ap-
149 degrees Fahrenheit), so that only strands plied, the current that flows through the gel
that match exactly will stay together and those carries the proteins onto the nitrocellulose.
with short, random matches will come apart. Af- The reactive side chains of the nitrocellulose
ter overnight hybridization, the paper is washed also bind proteins very effectively, so they are
multiple times with a detergent-salt solution, all retained on the paper. The specific probe
which removes the DNA that did not hybridize. used to detect a protein is an antibody that ei-
The paper is placed against a piece of X-ray ther can be radioactively labeled or can have an
film, and the radioactive emissions from the enzymatic side chain attached, which will pro-
probe darken the film next to them. When the duce light or a colored dye when the appropri-
film is developed, a pattern of bands appears ate chemicals are added. Since the antibody is a
that corresponds to the position in the original protein, it could also stick nonspecifically to
gel of the DNA piece for which the researcher the paper, so the blot is pretreated with a gen-
was probing. eral protein such as serum albumin before the
antibody is added.
Expanded Techniques to Study RNA
and Proteins Blotting in Genetic Analysis
The basic method of blotting has been ex- The ability to detect individual molecules in
panded to include the study of RNA and pro- a large background has been very important
teins. James Alwine developed a very similar for genetic analyses. For instance, restriction
method to transfer messenger RNA (mRNA) fragment length polymorphism (RFLP) analy-
that had been separated on an agarose gel. sis is a method that uses the change in the size
Since the mRNA started as single-stranded, of a DNA fragment in the genome, generated
there was no need to treat the gel with dena- by restriction enzyme digestion as a genetic
turant. However, to block the formation of in- marker. The isolation of many disease genes,
ternal double-stranded regions, which could including the one causing Huntingtons dis-
alter the migration during electrophoresis, the ease, depended on RFLP mapping to localize
gel contained an organic solvent. Other than the gene. It would not be possible to detect the
that, the two methods are very similar. Although changes in a single DNA fragment out of the
the DNA transfer system was named the South- millions generated by digesting the human ge-
ern blot in honor of Ed Southern, Alwine de- nome without having the Southern blot to pick
cided to defer the credit and called his system out the correct piece. Many other mutations
the Northern blot to indicate that it was related that change a specific region of DNAsuch as
but in a different direction. deletions, inversions, and duplicationsare of-
Similarly, when W. N. Burnette developed a ten detected by changes in a Southern blot pat-
system for transferring and detecting specific tern. The sensitivity of hybridization can be
Breast Cancer 101
tuned to a level where probes that differ by only See also: Antibodies; DNA Sequencing
a single nucleotide will not attach efficiently. Technology; Gel Electrophoresis; Genetic Test-
This allows the rapid identification of the posi- ing; Huntingtons Disease; Immunogenetics;
tions of point mutations. When polymerase Model Organisms; Polymerase Chain Reaction;
chain reaction (PCR) is used to amplify DNA Repetitive DNA; RFLP Analysis.
from a crime scene or to detect human immu-
nodeficiency virus (HIV) in the bloodstream, Further Reading
the presence of DNA pieces on a gel is not suffi- Alwine, J. C., D. J. Kemp, and G. R. Stark.
cient proof that the correct DNA has been Method for Detection of Specific RNAs in
found. The DNA must be blotted and probed Agarose Gels by Transfer to Diazobenyloxy-
with the expected sequence to confirm that it is methyl-Paper and Hybridization with DNA
the correct piece. Probes. Proceedings of the National Academy of
Northern blot analysis allows scientists to see Sciences 74 (1977): 5350. The original de-
how mRNA is altered in different mutants. scription of Northern blotting.
Northern blots can indicate if a mutant allele is Southern, E. M. Detection of Specific Se-
no longer transcribed or if the level of mRNA quences Among DNA Fragments Separated
produced has been dramatically decreased or by Gel Electrophoresis. Journal of Molecular
increased. Deletions or insertions will also show Biology 98, no. 3 (1975): 503-517. The origi-
up as shortened or lengthened messages. Alter- nal description of Southern blotting and of
native splicing can be seen as multiple bands blotting in general. This is one of the most
on a Northern blot which hybridize to the same often cited articles in biology research.
probe. Point mutations that do not detectably
alter the mRNA can still dramatically alter the
protein product. Changes of a single amino
acid can alter the electrophoretic mobility and
the difference in apparent molecular weight Breast Cancer
can often only be detected by Western blot.
These changes can also alter protein stability, Field of study: Diseases and syndromes
which can be detected as decreased protein lev- Significance: While the majority of breast cancers
els showing up on the Western. The ability to are caused by acquired mutations, about 5 percent
detect changes at the DNA, RNA, and protein of all breast cancers are caused by inherited muta-
level through blotting techniques has greatly tions that greatly increase the chances of devel-
increased the ability of scientists to study ge- oping the disease. Germ-line mutations in the
netic alterations. BRCA1 and BRCA2 genes are associated with
most of these inherited breast cancers.
Future Directions
Blotting techniques are the most generally Key terms
efficient methods for detecting specific pro- BRCA1 and BRCA2 genes: the genes associ-
teins or nucleic acids. Most improvements in ated with most inherited breast cancers
the past years have been aimed at speeding up cell cycle: the sequence of events of a divid-
the transfer process using vacuums or pressure ing cell
or the hybridization process by changing the exon: the coding sequence (part of a messen-
conditions. The next step will be developing ger RNA, or mRNA) that specifies the amino
silicon chips that can interact with specific nu- acid sequence of the protein produced dur-
cleic acid or amino acid sequences and produce ing translation
an electrical output when they hybridize with germ-line mutation: a heritable change in
the correct sequence. This will diminish the the genes of an individuals reproductive
time required to confirm a sequence from sev- cells, often linked to hereditary diseases
eral hours to minutes. p53 gene: a tumor-suppressor gene, the first
J. Aaron Cassill gene identified in an inherited breast cancer
102 Breast Cancer
tumor-suppressor gene: a gene that produces are termed sporadic. It is estimated that about
a protein product that limits cell division 5 to 10 percent of all breast cancers are familial.
and therefore acts to inhibit the uncontrolled Approximately 80 to 85 percent of these can be
cell growth of cancers attributed to mutations in the BRCA1 or BRCA2
gene.
Genes Associated with Breast Cancer The first gene identified in an inherited
Approximately one in eight women develops breast cancer was p53, which is mutated in Li-
breast cancer over the course of her lifetime. Fraumeni syndrome. It is a tumor-suppressor
In the United States there are approximately gene that encodes a protein transcription fac-
180,000 new cases of breast cancer yearly. By tor that stops the cell cycle until DNA repair has
2002, more than forty different genes had been occurred; a defective p53 gene no longer stops
found to be altered in breast cancers. Those cell division, and unrepaired DNA can be repli-
breast cancers that are not familial (inherited) cated, resulting in accumulated mutations in
the cell. About 1 percent of women who de-
velop breast cancer before the age of thirty
have germ-line mutations in p53. Families with
Breast Cancer Sites this syndrome have extremely high rates of
brain tumors and other cancers in both chil-
dren and adults.
Some gene mutations may predispose an in-
dividual to develop breast cancer. For example,
there is an increased incidence of breast cancer
41% 14% associated with the ataxia telangiectasia (AT)
34% gene and the HRAS1 gene. A mutated form of
6% the AT gene is found in the rare recessive he-
5% reditary disorder ataxia telangiectasia, which
has a very wide range of symptoms, including
Breast cancer sites cerebellar degeneration, immunodeficiency,
and incidence of balance disorder, high risk of blood cancers,
occurence extreme sensitivity to ionizing radiation, and
an increased risk of breast cancer. Individuals
Pectoral with one mutated copy of the AT gene have an
muscle increased risk of cancer. The AT gene was iden-
Fat lobules tified as a phosphatidylinositol-3 kinase (an en-
Breast zyme that adds a phosphate group to a lipid
glandular molecule) that transmits growth signals and
tissue other signals from the cell membrane to the
cell interior. The AT gene was found to be simi-
lar in sequence to other genes that are known
Nipple to have a role in blocking the cell cycle in cells
whose DNA is damaged by ultraviolet light or X
rays. It is possible that the mutated AT gene
does not stop the cell from dividing, and the
damaged DNA may lead to cancers. It is dis-
turbing to note that individuals with a mutated
AT gene may be more sensitive to ionizing radi-
Milk ducts ation. It must be determined if these individu-
als should then avoid low X-ray doses, such as
those received from a mammogram used to de-
(Hans & Cassidy, Inc.) tect the early stages of breast cancer.
Breast Cancer 103
Prior to the discoveries of BRCA1 and BRCA2, there were many hints that susceptibility to at least some breast
cancers was inherited. The time line below shows some of the discoveries leading up to the discoveries of
BRCA1 and BRCA2 as well as later discoveries about breast cancer genes.
1966 Henry Lynch began the first studies on inher- 1994 Yoshio Miki et al. announce the cloning of
ited cancers. BRCA1 on chromosome 17.
1970 The first cancer-causing gene (oncogene) 1995 Richard Wooster et al. announce the dis-
was reported in chickens by Peter Vogt. covery and cloning of BRCA2 on chromo-
some 13.
1976 J. Michael Bishop and Harold Varmus re-
ported the discovery of oncogenes in the 1996 Prasanna Athma et al. report that heterozy-
DNA of normal chromosomes. gotes for the recessive allele ATM are more
susceptible to breast cancer.
1978 M. H. Bronstein et al. see a link between
Cowden disease, an inherited tumorogenic 1997 Danny Liaw et al. find that germ-line muta-
syndrome, and breast cancer. tions in the PTEN gene lead to Cowden dis-
ease and associated breast cancer.
1979 Arnold Levine and David Baltimore discover
p53, a gene mutated in approximately half of 1998 Dennis Slamon tests Herceptin, a mono-
all known cancers, including breast cancer. clonal antibody that targets the product of
HER-2/neu, against aggressive breast cancers.
1985 The mutant p53 gene is cloned by Arnold
Levine. 1999 Franois Ugolini et al. implicate FGFR1
(fibroblast growth factor receptor gene 1) in
1987 Michael Swift et al. report a hereditary link
some breast cancers.
between ataxia telangiectasia mutated (ATM)
and many cancers, including breast cancer. 2000 Tommi Kainu et al. propose a BRCA3 gene to
explain non-BRCA1/BRCA2 hereditary breast
1988 Dennis Slamon reports that the HER-2/neu
cancers in several families.
growth factor gene is overexpressed in 30
percent of the most aggressive breast cancers. 2001 Paul Yaswen reports that multiple copies of
the gene ZNF217 are seen in 40 percent of
1990 Mary Claire King and coworkers report the
breast cancers.
discovery of BRCA1 in Ashkenazi Jewish
women and locate it on chromosome 17. 2001 Minna Allinen et al. find a mutation in
CHEK2 gene that leads to hereditary breast
1990 David Malkin et al. report a link between the
cancers. This is proposed as BRCA3.
p53 gene product and breast cancer.
2002 Alan DAndrea et al. report that the same in-
1991 Elizabeth Claus et al. do a statistical analysis
herited mutations in the six genes that cause
of familial breast cancer and predict a domi-
Fanconi anemia also increase the susceptibil-
nant breast cancer gene will be found.
ity to breast cancer.
1993 Theodore Krontiris et al. report an associa-
tion between HRAS1 (Harvey rat sarcoma on- Richard W. Cheney, Jr.
cogene 1) and breast cancer.
Possible Functions of Breast Cancer Genes cer. The BRCA2 gene is on chromosome 13q12-
The BRCA1 gene is on chromosome 17 and 13 and encodes a protein of 3,418 amino acids.
encodes a protein that is 1,863 amino acids Germ-line mutations of BRCA2 are thought to
long. Germ-line mutations of BRCA1 are associ- account for approximately 35 percent of fami-
ated with 50 percent of hereditary breast can- lies with multiple-case, early-onset female breast
cers and with an increased risk of ovarian can- cancer. Mutations of BRCA2 are also associated
104 Breast Cancer
with an increased risk of male breast cancer, normally function to control cell growth. The
ovarian cancer, prostate cancer, and pancreatic 1997 work suggests that the breast cancer gene
cancer. mutations act indirectly to disrupt DNA repair
Although BRCA1 was cloned in 1994 and and allow cells to accumulate mutations, includ-
BRCA2 in 1995, the function of these genes has ing mutations that allow cancer development.
been difficult to identify. Part of the difficulty In 2002 the detailed structure of the BRCA2
has been that the proteins coded by these genes protein was determined. It has structural mo-
do not resemble any proteins of known func- tifs that show it to be capable of binding to
tion. In 1997, David Livingston and coworkers DNA. Although the specific role of the BRCA2
of the Dana-Farber Cancer Institute found that protein is uncertain, it is now clear that it does
the BRCA1 gene product associates with repair play a role in repairing double-stranded breaks
protein RAD51. A few months later, Allan Brad- in DNA. The understanding of the function of
ley of Baylor College of Medicine and Paul BRCA1 and BRCA2 is incomplete, but what is
Hasty of Lexicon Genetics reported that the known will encourage additional studies.
BRCA2 protein binds to the RAD51 repair pro-
tein. This work suggests that both genes may be Social Implications of Genetic Screening
in the same DNA-repair pathway. Bradley and With the cloning of the BRCA1 and BRCA2
Hasty also showed that embryonic mouse cells genes, it became possible to test them for muta-
with inactivated mouse BRCA2 genes are un- tions. Such testing has been controversial, rais-
able to survive radiation damage, again suggest- ing a number of social and psychological issues.
ing that the BRCA genes are DNA-repair genes. There is a concern that the technical ability to
Initially, it was thought that the breast cancer test for genetic conditions is ahead of the abil-
genes were typical tumor-suppressor genes that ity to predict outcomes or risks, prescribe the
Myriad Genetic Laboratories president Gregory Critchfield in 2002, posing in front of walls lined with the DNA data on BRCA1
and BRCA2 genes from just one woman. A mutation on either of these genes increases the risk of developing breast cancer signifi-
cantly, but the ability to identify the mutation in individuals may also dramatically increase the chances for early detection and sur-
vival. (AP/Wide World Photos)
Breast Cancer 105
most effective treatment, or counsel individu- Genes, Oncogenes, and Hormones: Advances in
als. Part of the dilemma about testing is the un- Cellular and Molecular Biology of Breast Cancer.
certainty about the meaning of the test results. Boston: Kluwer Academic, 1992. Contains
If a test confirms the presence of a mutation in papers on the genetics and molecular biol-
a breast cancer gene in a woman with a family ogy of breast cancer, including the role of
history of breast cancer, there is a high risk, but suppressor genes, the role of the retinoblas-
not a certainty, that the woman will develop toma gene, oncogenes and stimulatory
breast cancer. Even if a test is negative, it does growth factors, and much more. Index.
not mean the woman is not at risk for breast Kemeny, Mary Margaret, and Paula Dranov.
cancer, because the large majority of breast Beating the Odds Against Breast and Ovarian
cancers are not inherited. If a test is positive, it Cancer: Reducing Your Hereditary Risk. Read-
is not clear what the best course for the woman ing, Mass.: Addison-Wesley, 1992. Designed
would be. Increased monitoring with mam- for women with a family history of breast or
mography and even removal of both breasts ovarian cancer who are motivated to evalu-
as a preventive measure should reduce the ate risk factors, nutrition, warning signs, and
chances of developing cancer but do not guar- options for treatment.
antee a cancer-free life. Even if a woman does Love, Susan M., with Karen Lindsey. Dr. Susan
not yet have cancer, she may feel the additional Loves Breast Book. Illustrations by Marcia Wil-
psychological stress of knowing she has a high liams. 3d ed. New York: Perseus, 2000. Per-
risk of developing cancer. haps the most comprehensive book on breast
There is also concern that test results may be health, including breast cancer. One chapter
misused by employers or insurers. A number of discusses the genetic risks for breast cancer.
states have passed laws that prevent health in- Lynch, Henry T. Genetics and Breast Cancer. New
surance companies from using genetic test re- York: Van Nostrand Reinhold, 1981. One of
sults to discriminate against patients. In 1996, the seminal works on genetic breast cancer,
the National Cancer Institute established the by a pioneer in the investigation of heredi-
Cancer Genetics Network as a means for indi- tary breast-ovarian cancer syndrome.
viduals with a family history of cancer to enroll National Cancer Institute. Genetic Testing for
in research studies and learn of their genetic Breast Cancer: Its Your Choice. Bethesda, Md.:
status while receiving counseling. Author, 1997. One of the National Cancer
Susan J. Karcher, updated by Bryan Ness Institutes large number of pamphlets and
See also: Aging; Cancer; Cell Cycle, The; monographs on various cancers, including
DNA Repair; Genetic Counseling; Genetic genetic risks for cancer, designed to provide
Screening; Genetic Testing; Genetic Testing: responsible and detailed information to the
Ethical and Economic Issues; Hereditary Dis- public.
eases; Human Genome Project; Model Organ- Yang, Haijuan, et al. BRCA2 Function in DNA
ism: Mus musculus; Mutation and Mutagenesis; Binding and Recombination from a BRCA2-
Oncogenes; Tumor-Suppressor Genes. DSS1-ssDNA Structure. Science 297 (Sep-
tember 13, 2002): 1837-1848. This study pre-
Further Reading sents evidence that the failure of BRCA2 in
Bowcock, Anne M., ed. Breast Cancer: Molecular DNA repair through homologous recombi-
Genetics, Pathogenesis, and Therapeutics. nation may account for unsuppressed tumor
Totowa, N.J.: Humana Press, 1999. Detailed growth.
information geared toward researchers and
health professionals. The chapter Heredi- Web Sites of Interest
tary Breast Cancer Genes discusses BRCA1 American Cancer Society, All About Breast
and BRCA2 mutations among Ashkenazi Cancer. http://www.cancer.org. Searchable
women. Also addresses surgery, chemother- information on breast cancer, including an
apy, drug resistance, and the MDR gene. overview, a detailed guide, and practical re-
Dickson, Robert B., and Marc E. Lipman, eds. sources.
106 Burkitts Lymphoma
National Cancer Institute, National Institutes particularly common in cases associated with
of Health. http://www.nci.nih.gov/breast. acquired immunodeficiency syndrome (AIDS).
Provides information on the genetics of Burkitts lymphoma grows very rapidly, with a
breast cancer and useful links. doubling time of approximately twenty-four
National Institutes of Health, National Library hours, and thus prompt diagnosis is essential. A
of Medicine. Genetics Home Reference. healthy child may become critically ill in about
http://www.nlm.nih.gov. This site includes four to six weeks. These children often exhibit
information on breast cancer genetics. a head or neck mass or a large abdominal mass
with fluid (ascites) accumulation. Other symp-
toms include vomiting, pain, anemia, and in-
creased bleeding.
fects people worldwide without producing and reunite, resulting in a reciprocal transloca-
symptoms. EBV is also the causative agent of in- tion. The rearrangement of genes in this kind
fectious mononucleosis, a common disease in of translocation causes the c-myc gene to be-
which B cells are infected. come an oncogene by forming an abnormal fu-
At least two EBV subtypes have been identi- sion protein that triggers the onset of cancer.
fied in human populations: EBV-1 is detected More than sixty human proto-oncogenes have
more commonly in Western societies, whereas now been localized to a specific chromosome
EBV-1 and EBV-2 subtypes seem to be equally or chromosome region. The new location of
distributed in Africa. Although EBV is identi- the c-myc gene results in deregulation and sub-
fied as a possible causative agent of African Bur- sequent overexpression. A normal-acting proto-
kitts lymphoma, it appears that non-African oncogene is transformed into an abnormally
Burkitts lymphoma EBV may be just one factor active oncogene.
in a multistep process of development. Bur- Ninety percent of Burkitts tumors are asso-
kitts lymphoma is a monoclonal proliferation ciated with a reciprocal translocation involving
of B lymphocytes. The lymphocytes have mem-
brane receptors for EBV. African children who
develop Burkitts lymphoma are thought to be
unable to mount an appropriate immune re- The Lymphatic System
sponse to primary EBV infection, possibly be- and Lymphoma
cause of coexistent malaria, which is immuno-
suppressive. As time passes, excessive B-cell pro-
liferation occurs. The precise role of EBV in the
development of Burkitts lymphoma remains
unclear, but much research in this area contin-
ues to be done.
chromosomes 8 and 14. As additional tumors Heim, S., and Felix Mitelman. Cancer Cytogenet-
have been examined, two other related trans- ics. 2d ed. New York: J. Wiley, 1995. Provides
locations involving chromosome 8 have been excellent correlation of molecular and chro-
observed. The variant translocations involved mosomal findings in Burkitts lymphoma.
chromosomes 2 or 22. However, no unified the- Lenoir, G. M., G. T. OConor, and C. L. M.
ory exists to explain the role of chromosome Olweny, eds. Burkitts Lymphoma: A Human
abnormalities in the activation of oncogenes. Cancer Model. New York: Oxford University
The Epstein-Barr virus has been implicated in Press, 1985. Proceedings of a symposium or-
Burkitts lymphoma and is known to be a B-cell ganized by the International Agency for Re-
mitogen (a substance that stimulates cell divi- search on Cancer and co-sponsored by the
sion). As a mitogen, it stimulates inactive cells WHO Regional Office for Africa, the Gen-
to transform into actively dividing cells. Per- eral Motors Cancer Research Foundation,
haps EBV plays a role in the origin of 8/14 and the Association Pour le Dveloppement
translocation abnormalities simply by increas- de la Recherche sur le Cancer.
ing the number of B cells undergoing DNA rep- Weinberg, R. A. How Cancer Arises. Scientific
lication. This could increase the chances for American (September, 1996). A general dis-
developing a chromosome abnormality with cussion for the layperson, which applies to
the potential to become cancerous. Burkitts as well as other cancers. Provides
Phillip A. Farber excellent illustrations, tables, and discussions
See also: Cancer; Oncogenes; Tumor-Sup- of important research.
pressor Genes.
Web Sites of Interest
Further Reading American Cancer Society. http://www.cancer
Burkitt, Denis Parsons, and D. H. Wright. Bur- .org. Comprehensive and searchable site cov-
kitts Lymphoma. Foreword by Sir Harold ering all aspects of cancer.
Himsworth. Edinburgh: Livingstone, 1970. Lymphoma Research Foundation, Getting the
The classic description by the discoverer of Facts on Non-Hodgkins Lymphoma. http://
this type of sarcoma. Illustrations (some www.lymphoma.org. Site has searchable in-
color), maps. formation on Burkitts lymphoma (non-
Cotran, R. S., et al. Robbins Pathologic Basis of Dis- Hodgkins lymphoma), including online
ease. 6th ed. Philadelphia: Saunders, 1999. A guides and information on obtaining guides
leading textbook that presents comprehen- by mail.
sive information accompanied by more than The Leukemia and Lymphoma Society. http://
170 newly created computer-generated dia- www.leukemia-lymphoma.org. Searchable
grams, including schematics, flow charts, site that includes a free, sixty-four-page down-
and diagrammatic representations of the loadable guide on all types of lymphomas, in-
disease. cluding Burkitts.
Cancer mor is called the primary site. Most types of
Field of study: Diseases and syndromes cancer begin in one place (the breast, lung, or
Significance: At its root cancer is a genetic disease. bowel, for example) from which the cells in-
It is characterized by unrestrained growth and re- vade neighboring areas and form secondary tu-
production of cells, loss of contact inhibition, and, mors. To make matters more complicated, some
eventually, metastasis (the wandering of cancer types of cancer, such as leukemia, lymphoma,
cells from a primary tumor to other parts of the and myeloma, begin in several places at the
body). All of these changes represent underlying same time, usually in the bone marrow or lym-
mutations or inappropriate expression of genes in- ph nodes. Primary tumors begin with one ab-
volved in the control of the cell cycle and related normal cell. This cell, as is true of all cells, is
processes. extremely small, no more than 0.002 or 0.003
millimeter across (about one-twentieth the
Key terms width of a human hair). Therefore early cancer
carcinogen: a substance or other environmen- is very difficult to locate. Even if there are more
tal factor that produces or encourages cancer than 100,000 cancer cells in a tumor, it is barely
oncogenes: genes that cause cancer but that, in visible except under a microscope.
their normal form, called proto-oncogenes, Cancer cells divide and reproduce about ev-
are important in controlling the cell cycle ery two to six weeks. If they divide on the aver-
and related processes age of once per month, a single cell will multi-
tumor: a mass formed by the uncontrolled ply into approximately four thousand cells by
growth of cells, which may be malignant the end of a year. After twenty months, there
(considered cancerous) or benign (nonma- will be one million cells, which would form a tu-
lignant) mor about the size of a pinhead and would still
tumor-suppressor genes: genes involved in be undetectable. A tumor can be discovered
regulating the cell cycle and preventing cell only when a lump of approximately one billion
division until an appropriate time; when mu- cells is present. This would be about the size of
tated, these genes can cause cancer a small grape. It would take about two and one-
half years for a single cancer cell to reach this
The Problem of Cancer size. Within seven months, the one billion cells
Cancer is characterized by abnormal cell would grow to more than 100 billion cells, and
growth that leads to the invasion and destruc- the tumor would weigh about four ounces. By
tion of healthy tissue by cells that meet certain the fortieth month of growth, the lump of can-
criteria. Normal cells in the human body are cer cells would weigh about two pounds. By the
continuously growing but are under normal time a tumor has reached this size, death often
cell control mechanisms. Cancer cells begin as occurs. Death normally occurs about three and
normal cells that, due to genetic mutations, one-half years after the first cancer cell begins
start to grow uncontrollably, escaping from the to grow. It takes about forty-two cell doublings
normal rules regulating cell growth and behav- to reach the lethal stage. The problem is that,
ior. Contact inhibition, in which cells contact- in most cases, tumors are detectable only after
ing other cells prevent unrestrained growth, is thirty doublings. By this time, cancer cells may
lost in cancer cells. Normal cells also remain in have invaded many other areas of the body be-
one location, or at least in the same tissue, but yond the primary site.
malignant tumors, in their later stages, metas-
tasize, allowing their cells to wander freely in How Cancer Cells Grow and Invade
the body, leading to the development of tu- Cancer cells are able to break down the bar-
mors in other organs. A final common feature riers that normally keep cells from invading
is that cancer cells lose their normal cell shape. other groups of cells. With the aid of a micro-
The area where cancer begins to form a tu- scope, cancer cells can be observed breaking
110 Cancer
through the boundary between cells, called the have invaded, forming numerous secondary
basement membrane. Cancer cells can make tumors along the way. Because cancer cells are
substances that break down the intercellular not considered foreign substances, such as bac-
matrix, the glue that holds cells together. The teria or viruses, they are able to evade the
intercellular matrix is a complex mixture of bodys immune system. Because of their overall
substances, including collagen, a strong, fi- resemblance to normal cells, cancer cells fool
brous protein that gives strength to tissues. the body into thinking they are normal and
Cancer cells produce collagenase, an enzyme therefore not dangerous.
that breaks down collagen. Cancer cells also Cancer cells eventually enter narrow blood
produce hyaluronidase, which further breaks vessels called capillaries and stay there for a brief
down the intercellular matrix. This causes can- period before they enter tissues such as lungs,
cer cells to lose their normal shape and allows bones, skin, and muscle. The secondary tumors
them to push through normal boundaries and then capture their own territory. As a tumor es-
establish themselves in surrounding tissues. tablishes itself, its cells often secrete signal pro-
Cancer cells have jagged edges, are irregular in teins that stimulate new blood vessels to form (a
shape, and have hard-to-detect borders, mak- process called angiogenesis) to increase blood
ing them relatively easy to identify microscopi- supply to the growing tumor. The body thus not
cally. Normal cells, on the other hand, have a only fails to destroy developing tumors, but un-
regular, smooth edge and shape. wittingly helps establish them as well.
There are many steps involved in the process
of metastasizing, not all of which are under- The Genetics of Cancer
stood by researchers. First is the entry into a Cancer has been known since antiquity, but
blood vessel or lymph channel. Lymph chan- it was not until the twentieth century that the
nels, or lymphatics, comprise a network of ves- underlying causes of cancer began to be ex-
sels that carry lymph from the tissues to the plored. In 1910, Peyton Rous discovered a type
bloodstream. Lymph is a colorless liquid that of cancer in chickens called a sarcoma (a can-
drains from spaces between cells. It consists cer of connective tissue) that could be passed
mainly of water, salts, and proteins and eventu- on to other chickens. He demonstrated this by
ally enters the bloodstream near the heart. The removing tumors from affected chickens, grind-
function of lymph is to filter out bacteria and ing the tumors up, filtering the grindate, and
other foreign particles that might enter the then injecting the filtrate into healthy chickens.
blood and cause infections. A mass of lymph Injected chickens invariably developed sarcoma
vessels is called a lymph node. In the human tumors, suggesting that something smaller than
body, lymph nodes are found in the neck, un- the tumor cells was being passed on and was
der the arms, and in several other places. Every stimulating cancer development in otherwise
body tissue has a network of lymph and blood normal cells. It is now known that the filtrate
vessels running through it. contained a cancer-causing virus, now called
Once a malignant tumor develops and metas- the Rous sarcoma virus. Similar types of viruses
tasizes, the cells often travel through the body were discovered to be responsible for cancers
using the lymphatic system, a network of ves- in a variety of animals, but none was discovered
sels that filter pathogens and transport lymph, in humans initially.
a fluid similar to blood plasma. Cancer cells As the genetic material of some of the tumor
may gain entry into a nearby lymph vessel by viruses was later analyzed, all of them were dis-
breaking down defensive enzymes. Once in the covered to contain genes called oncogenes,
lymph system, they can travel to nodes (gland- because they promoted oncogenesis (tumor
like masses of cells that produce white blood development). Even more surprising was the
cells) and eventually into the bloodstream. discovery that humans have genes in their ge-
Whatever route they take, groups of cancer nome that are homologous (having a high de-
cells can break away from the primary site of gree of similarity) to viral oncogenes. The hu-
the tumor and float along whatever vessel they man genes did not seem to cause cancer under
Cancer 111
normal circumstances and were called proto- checked. Retinoblastoma occurs in children
oncogenes. In cancer cells, some of these proto- when they inherit one faulty copy from a par-
oncogenes were discovered to have mutations ent. If the other copy experiences a mutation,
or, in some cases, were simply overexpressed. which frequently occurs, then retinoblastoma
In recognition of their abnormal state, these develops.
genes were called cellular oncogenes, to distin-
guish them from viral oncogenes. It is now How Cancer Develops
known that proto-oncogenes are important in The development of cancer is typically more
controlling the cell cycle by stimulating cell di- complicated than implied above. It generally
vision only at the appropriate time. When they requires mutations in more than a single proto-
are transformed into oncogenes, uncontrolled oncogene or tumor-suppressor gene. Any fac-
cell growth and division occurs, two of the hall- tors that increase mutation rates or decrease a
marks of cancer. cells ability to repair mutations will increase
A second type of cancer-causing gene, called the likelihood that cancer will develop. Inheri-
a tumor-suppressor gene, was discovered to be tance of already mutated genes can also greatly
the cause of retinoblastoma, a cancer of the ret- increase a persons chance of developing can-
ina, most often occurring in children. Tumor- cer, which accounts for the above-normal oc-
suppressor genes have an effect opposite to currence of cancer in some families.
that of proto-oncogenes; they suppress cell divi- One of the best-studied cases of oncogenesis
sion and thus prevent unrestrained cell prolif- involves colorectal cancer, which takes years to
eration. If both alleles of a tumor-suppressor develop from a small cluster of abnormal cells
gene have a mutation that makes them non- into life-threatening cancer. It involves the loss
functional, then cell division can occur un- or mutation of three tumor-suppressor genes
Leland H. Hartwell, co-winner of the 2001 Nobel Prize in Physiology or Medicine with R. Timothy Hunt and Paul M. Nurse, at the
Fred Hutchinson Cancer Research Center in Seattle, Washington, shortly after the Nobel Foundations announcement. The three
men won for their work on cell division and its implications for cancer research. (AP/Wide World Photos)
112 Cancer
so chemotherapy also kills some normal cells. Angiogenesis inhibitors are also at the ex-
Cancer patients often feel very ill during che- perimental stage. As noted above, many cancer
motherapy because of this. cells secrete agents that encourage angiogenesis
Radiation therapy works similarly, being (the formation of blood vessels) in the region
more damaging to dividing cells. An added ad- of the tumor to increase blood supply to the
vantage of radiation therapy, if the tumor has rapidly dividing cells. It is hoped that angio-
not yet metastasized, is that it can be focused genesis inhibitors might counteract this activity
more intensely in the vicinity of the tumor, pre- and essentially starve the cancer cells. Shrink-
venting damage to other tissues. If the tumor age of tumors in laboratory animals has been
has metastasized, then more widespread expo- observed using this approach.
sure to radiation may be used, with the obvious Photodynamic therapy also shows promise.
drawback that many other normal cells will also It is based on the observation that certain chem-
be damaged. Radiation therapy is often used to icals, when ingested by single-celled organisms,
treat leukemia. Radiation is used to kill the pa- release damaging oxygen radicals when exposed
tients bone marrow, and then new bone mar- to light, thus killing the organisms. It has been
row is transplanted from a compatible donor. observed that cancer cells retain these chemi-
The new bone marrow can then restore normal cals longer than normal cells. Treatment in-
function to production of blood cells. volves administering the chemical by injection,
Genetics has played a part in improving che- then waiting for a specified period for it to be
motherapy. It has long been known that some retained by cancer cells and flushed out of nor-
people will respond better than others to cer- mal cells. Then the tissue in which the cancer
tain chemotherapeutic drugs. It is now known cells are located is exposed to laser light. This
that some of these differences are genetic, and method works on any tissues that can be ex-
the underlying genetic differences have been posed to laser light, which includes any part of
uncovered in some cases. Therefore, as part of the body accessible to endoscopy.
cancer treatment for some kinds of cancer, a The ultimate treatment for cancer would be
person may be tested genetically to make more replacement or repair of the mutated genes re-
intelligent choices about which drugs to use. sponsible. Currently such treatment is not pos-
As more genetic data become available, it is an- sible. There are many hurdles to overcome, in-
ticipated that more effective and personalized cluding designing safe methods for inserting
treatments will be developed. corrected gene copies. There is danger that im-
proper gene therapy methods could actually
Innovations and Future Treatments make things worse, causing additional tumors
Although the immune system cannot nor- or other diseases. A much better understand-
mally identify cancer cells accurately, there has ing of the genetics of cancer and future im-
been some success in immunological ap- provements in gene therapy techniques hold
proaches. A recent new treatment involves Her- promise of someday being able to cure or pre-
ceptin, a specially designed monoclonal an- vent most kinds of cancer.
tibody that attacks cells that overproduce a Leslie V. Tischauser, updated by Bryan Ness
protein called HER-2. It has shown some prom- See also: Aging; Breast Cancer; Burkitts
ise in treating breast cancer and is being stud- Lymphoma; Cell Culture: Animal Cells; Cell
ied as an agent for treating other forms of can- Cycle, The; Cell Division; Chemical Mutagens;
cer. Unfortunately, some of the possible side Chromosome Mutation; Developmental Genet-
effects include damage to the heart and lungs ics; DNA Repair; Gene Therapy; Genetic Engi-
and serious allergic reactions. Careful moni- neering: Medical Applications; Genetic Test-
toring is required to prevent life-threatening ing: Ethical and Economic Issues; Hereditary
damage. Research is also progressing on devel- Diseases; Homeotic Genes; Human Genome
opment of vaccines against cancer, but so far Project; Huntingtons Disease; Hybridomas and
this approach is still in its early experimental Monoclonal Antibodies; Hypercholesterol-
stages. emia; Insurance; Model Organism: Caenorhab-
114 Cancer
ditis elegans; Model Organism: Mus musculus; search into the genetic causes of breast can-
Mutation and Mutagenesis; Nondisjunction cer and other types of cancer.
and Aneuploidy; Oncogenes; Proteomics; Re- Ehrlich, Melanie, ed. DNA Alterations in Cancer:
verse Transcriptase; RNA Transcription and Genetic and Epigenetic Changes. Natick, Mass.:
mRNA Processing; Signal Transduction; Stem Eaton, 2000. A comprehensive overview of
Cells; Steroid Hormones; Telomeres; Tumor- the numerous and varied genetic alterations
Suppressor Genes. leading to the development and progression
of cancer. Topics include oncogenes, tumor-
Further Reading suppressor genes, cancer predisposition,
Bowcock, Anne M., ed. Breast Cancer: Molecular DNA repair, and epigenetic alteration such
Genetics, Pathogenesis, and Therapeutics. as methylation.
Totowa, N.J.: Humana Press, 1999. Detailed Fitzgerald, Patrick J. From Demons and Evil Spirits
information geared toward researchers and to Cancer Genes: The Development of Concepts
health professionals. The chapter Heredi- Concerning the Causes of Cancer and Carcino-
tary Breast Cancer Genes discusses BRCA1 genesis. Washington, D.C.: American Regis-
and BRCA2 mutations among Ashkenazi try of Pathology, Armed Forces Institute of
women. Also addresses surgery, chemother- Pathology, 2000. Traces the history, epide-
apy, drug resistance, and the MDR gene. miology, and genetics of neoplasms, cancer,
Bradlow, H. Leon, Jack Fishman, and Michael and medical oncology.
P. Osborne, eds. Cancer Prevention: Novel Nu- Greaves, Mel F. Cancer: The Evolutionary Legacy.
trient and Pharmaceutical Developments. New New York: Oxford University Press, 2000.
York: New York Academy of Sciences, 1999. Presents a Darwinian explanation for cancer
Examines several classes of nutrients and that includes historical anecdotes and scien-
pharmaceutical agents believed to be im- tific findings.
portant for tumor inhibition. Reviews novel Habib, Nagy A., ed. Cancer Gene Therapy: Past
preclinical models that facilitate analysis of Achievements and Future Challenges. New York:
chemopreventive agent efficacy and mecha- Kluwer Academic/Plenum, 2000. Reviews
nisms of gene-nutrient interaction and pro- forty-one preclinical and clinical studies in
vides information on clinical trials studying cancer gene therapy, organized into sections
chemopreventive regimens. on the vectors available to carry genes into
Coleman, William B., and Gregory J. Tsongalis, tumors, cell cycle control, apoptosis, tumor-
eds. The Molecular Basis of Human Cancer. suppressor genes, antisense and ribozymes,
Totowa, N.J.: Humana Press, 2002. Surveys immuno-modulation, suicidal genes, an-
the known molecular mechanisms govern- giogenesis control, and matrix metallo pro-
ing neoplastic transformation in the breast, teinase.
prostate, lung, liver, colon, skin, leukemias, Hanski, C., H. Scherbl, and B. Mann, eds.
and lymphomas. Illuminates both recent de- Colorectal Cancer: New Aspects of Molecular Biol-
velopments and established concepts in epi- ogy and Immunology and Their Clinical Applica-
demiology, molecular techniques, oncogen- tions. New York: New York Academy of Sci-
esis, and mutation mechanisms. ences, 2000. Explores the immunological
Cowell, J. K., ed. Molecular Genetics of Cancer. 2d and molecular aspects of colon and rectal
ed. San Diego: Academic Press, 2001. Fo- cancer.
cuses on tumors of tissues such as liver, lung, Hodgson, Shirley V., and Eamonn R. Maher. A
bladder, and brain and surveys research in Practical Guide to Human Cancer Genetics. 2d
the cloning and analysis of genes central to ed. New York: Cambridge University Press,
the development and progression of human 1999. Gives a general overview of the underly-
cancers. ing molecular genetic basis of cancer, the ge-
Davies, Kevin, and Michael White. Breakthrough: netics of human cancers by site of origin, and
The Race to Find the Breast Cancer Gene. New a review of inherited cancer-predisposing
York: John Wiley, 1996. A history of the re- syndromes.
cDNA Libraries 115
Liotta, L. A. Cancer Cell Invasion and Metasta- National Cancer Institute. http://www.cancer
sis. Scientific American (1992). Provides a ba- .gov. Site links to comprehensive information
sic description of cancer genetics. on genetics and cancer, including a cancer-
Maruta, Hiroshi, ed. Tumor-Suppressing Viruses, basics tutorial.
Genes, and Drugs: Innovative Cancer Therapy
Approaches. San Diego, Calif.: Academic,
2002. An international field of experts ad-
dress a number of innovative approaches to cDNA Libraries
treating cancer, such as viral therapy using
specific viral mutants, gene therapy using a Fields of study: Bioinformatics; Techniques
variety of tumor-suppressor genes, and drug and methodologies
therapy targeted to block oncogenic signal Significance: A cDNA library is a set of cloned
pathways. DNA copies of the RNAs found in a specific cell
Mendelsohn, John, et al. The Molecular Basis of type at a specific time. This library can be used to
Cancer. 2d ed. Philadelphia: Saunders, 2001. construct probes for mapping these genes, to study
Surveys the principles that constitute the sci- the changing expression of genes over time (during
entific basis for understanding the patho- development, for example), or to clone genes into
genesis of cancer and emphasizes clinical organisms for further study or production of pro-
implications for treatment. Covers recent teins.
advances and current research, with descrip-
tions of the basic mechanisms of malignant Key terms
cells and molecular abnormalities, as well as complementary DNA (cDNA): also known as
new approaches to therapy. copy DNA, a form of DNA synthesized by re-
Schneider, Katherine A. Counseling About Can- verse transcribing RNAs (usually messenger
cer: Strategies for Genetic Counseling. 2d ed. RNAs) into DNA
New York: Wiley-Liss, 2002. A reference DNA library: a collection of DNA fragments
guide to assist genetic counselors and other cloned from a single source, such as a ge-
health care providers help patients and fam- nome, chromosome, or set of mRNAs
ilies through the emotional difficulties of in situ hybridization: a technique that uses a
managing hereditary cancer. molecular probe to determine the chromo-
Vogelstein, Bert, and Kenneth W. Kinzler, eds. somal location of a gene
The Genetic Basis of Human Cancer. 2d ed. introns: noncoding segments of DNA within a
New York: McGraw-Hill, 2002. Introduces gene that are removed from mRNA copies of
the fundamentals of genetics and human the gene before polypeptide translation
phenotypes, gene mutation, the Human Ge- reverse transcriptase: an enzyme, isolated
nome Project, and gene imprinting and cov- from retroviruses, that synthesizes a DNA
ers advances in the field. strand from an RNA template
Wilson, Samuel, et al. Cancer and the Environ-
ment: Gene-Environment Interaction. Washing- Gene Cloning and DNA Libraries
ton, D.C.: National Academy Press, 2002. In- In order to study and map genes, research-
cludes The Links Between Environmental ers need to take potentially very large sections
Factors, Genetics, and the Development of of DNA (such as a chromosome or whole ge-
Cancer, Gene-Environment Interaction in nome), break them into smaller, manageable
Special Populations, and Gene-Environ- fragments, and clone these fragments to con-
ment Interaction in Site-Specific Cancers. struct a DNA library. A genomic or chromo-
some library may contain many thousands of
Web Sites of Interest cloned fragments, many of which will represent
American Cancer Society. http://www.cancer stretches of noncoding DNA between genes.
.org. Comprehensive and searchable site cov- If the researcher is interested is studying the
ering all aspects of cancer. protein-coding regions, or genes, of the DNA,
116 cDNA Libraries
it is better to start with the messenger RNAs search, because the developmental pattern of
(mRNAs) of the cell, which represent the genes an organism can be correlated with the activity
being actively transcribed in the cell at that of specific genes.
time. By constructing and cloning complemen- Cloned cDNAs can also be used to find the
tary DNA (cDNA) copies of these mRNAs, re- chromosomal location of an expressed gene.
searchers can create a library that contains cop- One strand of the cDNA clone is labeled with a
ies of only the active genes. fluorescent tag and used as a molecular probe.
In the technique of in situ hybridization, the
cDNA Library Construction probe will base pair, or hybridize, to the com-
DNA copies of mRNAs are synthesized using plementary sequence in a preparation of par-
the enzyme reverse transcriptase. This enzyme tially denatured chromosomes, and the chro-
was independently discovered by Howard mosomal location of the original gene will be
Temin and David Baltimore in 1970 in retrovi- visible because of the fluorescent label. Such a
ruses, which reverse transcribe their RNA ge- probe can also be used to screen a chromo-
nomes into DNA after infecting their host cells. some or genomic library for the cloned frag-
In the late 1970s, researchers began using the ment containing the target gene. Using the
enzyme to make DNA copies of mRNAs, and entire cDNA library to probe a genome will
later to construct cDNA libraries. generate a cDNA map that suggests the most bi-
To create a cDNA library from a sample of ologically and medically important parts of the
cells, mRNAs from the cells are isolated and pu- genome, aiding researchers in the search for
rified. Reverse transcriptase is used to synthe- disease genes.
size a complementary DNA strand using each Genes of eukaryotes (nonbacterial organ-
mRNA strand as a template, resulting in a col- isms) usually contain introns, noncoding seg-
lection of double-stranded RNA-DNA hybrids. ments that are transcribed but removed from
To obtain double-stranded cDNAs suitable for mRNAs before translation, but bacterial genes
cloning, the enzyme RNase H is used to digest do not. Often, a eukaryotic gene put into a bac-
the RNA strand, and DNA polymerase I is used terial cell will not produce a functional poly-
to synthesize the second DNA strand using the peptide because the cell does not have the bio-
first as a template. If desired, sticky ends can chemical machinery for removing introns. If
be added to the cDNAs for cloning into a vec- the goal of the research is to have a bacterium
tor. The set of recombinant vectors are inserted make the protein product of a gene, it may be
into bacterial cells in the process of transforma- necessary to clone a cDNA version of the gene,
tion, resulting in a cloned cDNA library. The li- which lacks introns, using a special expression
brary is maintained as a collection of bacterial vector that allows the cell to transcribe the in-
colonies, each colony containing a different serted gene and translate it to the proper poly-
cloned DNA fragment. peptide.
cDNA copies of genes are not identical to the micropropagation: removal of small pieces of
original sequences of the genes and also lack plant tissue for growth in culture
the promoter region necessary for proper tran- primary cells: explants removed from an ani-
scription of the gene. However, using cDNA as mal
a molecular probe can lead to the identifica- transformation: any physical change to a
tion of the original gene. cell, but generally the change of a normal
Stephen T. Kilpatrick cell into a cancer cell
See also: Bioinformatics; DNA Finger-
printing; DNA Sequencing Technology; For- Early History
ensic Genetics; Genetic Testing: Ethical and Methodology for maintaining tissues in vitro
Economic Issues; Genetics, Historical Develop- (in laboratory vessels) began in 1907 with Ross
ment of; Genomic Libraries; Genomics; Human Harrison at Yale College. Harrison placed tis-
Genome Project; Icelandic Genetic Database; sue extracts from frog embryos on microscope
Linkage Maps; Proteomics; Reverse Transcrip- slides in physiological fluids such as clotted
tase. frog lymph. The material was sealed with paraf-
fin and observed; specimens could be main-
Further Reading tained for several weeks. In 1912, Alexis Carrel
Sambrook, Joseph, and David Russell. Molecu- began the maintenance of cardiac tissues from
lar Cloning: A Laboratory Manual. 3d ed. Cold a warm-blooded organism, a chicken, in a simi-
Spring Harbor, N.Y.: Cold Spring Harbor lar manner. The term tissue culture was origi-
Laboratory Press, 2001. Contains detailed nally applied to the cells maintained in the lab-
protocols for mRNA isolation, cDNA synthe- oratory in this manner, reflecting the origin of
sis, and library construction. the technique. More appropriate to modern
Watson, James D., John Tooze, and David T. techniques, the proper terminology is cell cul-
Kurtz. Recombinant DNA: A Short Course. New ture, since it is actually individual cells which
York: W. H. Freeman, 1983. An introduction are grown, developing as explants from tissue.
to techniques for cloning genes, including Nevertheless, the terms tend to be used inter-
construction of cDNA libraries. changeably for convenience.
Endoplasmic
reticulum Nucleolus
Nucleus
Centriole Lysosome
Endosome Cytoplasm
Golgi apparatus
Secretion granule
Cytoskeleton
Cell membrane
Nuclear envelope
Mitochondrion Ribosomes
Peroxisome
All animal cells are eukaryotic cells, which differ from more primitive prokaryotic cells in having a nucleus that houses the primary
genetic material. This drawing depicts the basic features of a eukaryotic animal cell. (Electronic Illustrators Group)
Cell Culture: Animal Cells 119
is of utmost importance since some organisms During the same period, Howard Temin at
are unaffected by these antibiotics. Depending the University of Wisconsin, while studying the
upon the type of cell, the particular pH, or acid growth of RNA tumor viruses in cultured cells,
content, of the culture may be variable. Most reported the apparent requirement for DNA
mammalian cells grow best at a pH of 7-7.2. For production by these viruses in transforming
this reason, cells are generally grown in special normal cells into cancer cells. Temins and
incubators which utilize a relatively high CO2 Hayflicks investigations contributed signifi-
atmosphere. cantly to the question of how cancer cells differ
Replication of animal cells requires the pres- from normal cells, and the understanding of
ence of certain growth factors to be present in genes involved in such changes. Eventually, this
the medium. Historically, the source of such led to the discovery of oncogenes.
factors has been serum, usually obtained from The term oncogene is somewhat mislead-
fetal bovines. Genetic engineering techniques ing. Its definition was originally based on the
have resulted in production of commercially fact that mutations in such genes may contrib-
available growth factors, eliminating the re- ute to transformation of cells from normal to
quirement for expensive serum for growth of cancerous. The study of these genes in cultured
some forms of cells in culture. cells clarified their role: Most oncogene prod-
ucts can be classified as growth factors, which
Genetics of Cells in Culture stimulate cell growth; receptors, which respond
Study of cultured animal cells has resulted to such stimulation; or intracellular molecules,
in significant advancement in understanding which transfer such signals to the cell DNA. In
many areas of cell regulation. For example, the other words, the normal function of the onco-
role played by cell receptors in response to the gene is to regulate replication of normal cells;
presence of extracellular ligands such as hor- only when these proteins are inappropriately
mones and other metabolites was clarified by expressed do they result in transformation of
studying the response of cells to such stimula- the cell.
tion. Intracellular events, including the role of
enzymes in cell activities, was clarified and re- Application of Cell Culture to Virology
mains a primary area of research. The use of mammalian cells for the study of
The ability to transform mammalian cells us- viruses represented among the earliest, and ar-
ing isolated DNA has allowed for significant ap- guably among the most important, applica-
plications in genome analysis. Such genetic ma- tions of the technique of cell culture. Prior to
nipulation has led to a greater understanding the 1940s, study of most animal viruses, includ-
in the role specific genes play in cell regulation. ing those that cause disease in humans, was
In particular, use of cultured cells was instru- confined to in vivo studies in animals. For ex-
mental in clarifying the role played by specific ample, the study of poliovirus required inocu-
gene products in intracellular trafficking, the lation of the virus directly into the brains of
movement of molecules to specific sites within suitable monkeys.
the cell. Similar techniques continue to be used In 1949, John Enders and his co-workers
to further understand the regulatory process. demonstrated the growth of poliovirus in hu-
man embryonic cells, eliminating the require-
Mammalian Cells and Oncogenesis ment for monkeys. Their work played a critical
During the 1960s, Leonard Hayflick at the role in the later development of poliovirus vac-
Wistar Institute in Philadelphia, Pennsylvania, cines by Jonas Salk and Albert Sabin. The abil-
observed that primary cells in culture exhibit a ity to grow viruses in cells maintained in the
finite life span; normal cells generally divide no laboratory opened the field to nearly all virolo-
more than approximately fifty times (a phe- gists and biochemists, rather than restricting
nomenon now called the Hayflick limit). Any such studies to those with access to animal facil-
cells that survive generally take on the charac- ities.
teristics of cancer cells. Richard Adler
120 Cell Culture: Plant Cells
See also: Cancer; Cell Culture: Plant Cells; plant growth regulators: hormonelike sub-
Cell Cycle, The; Cell Division; Gene Regulation: stances that profoundly affect plant growth
Eukaryotes; Gene Regulation: Viruses; Mitosis and development
and Meiosis; Oncogenes; Stem Cells; Totipo- somatic embryos: asexual embryoid structures
tency; Tumor-Suppressor Genes; Viral Genetics. derived from somatic cells
totipotency: the ability of a plant cell or part
Further Reading to regenerate into a whole plant
Freshney, R. Ian. Culture of Animal Cells. New
York: Wiley-Liss, 2000. Basically a how-to text Culturing Plant Cells
on the science and art of tissue culture. Use- Plant cell cultures are typically initiated by
ful as a source of recipes and techniques, as taking explantssuch as root, stem, leaf, or
well as an extensive bibliography. flower tissuefrom an intact plant. These
Gold, Michael. A Conspiracy of Cells. Albany: explants are surface-sterilized and then placed
State University of New York Press, 1986. A in vitro on a formulated, artificial growth me-
full account of the history behind develop- dium containing various inorganic salts, a car-
ment of the HeLa cell line. Much of the ac- bon source (such as sucrose), vitamins, and var-
count deals with the (literal) spread of these ious plant growth regulators, depending on the
cells throughout the field of cell culture. desired outcome. There are many commer-
Hayflick, L., and P. Moorhead. The Serial Cul- cially available media formulations; the two
tivation of Human Diploid Cell Strains. Ex- most common include MS (murashige and
perimental Cell Research 25 (1961): 585-621. skoog) and WPM (woody plant media). Alter-
The classic work that first reported the lim- natively, customized formulations may be nec-
ited life span of human cells in culture. essary for culturing certain plant species. One
Pollack, Robert, ed. Readings in Mammalian Cell of the most important uses of plant tissue cul-
Culture. 2d ed. Cold Spring Harbor, N.Y.: ture has been for the mass propagation of eco-
Cold Spring Harbor Press, 1981. A collec- nomically important agricultural and horticul-
tion of reprints consisting of nearly all classi- tural crops. Since the 1980s, however, plant
cal papers in the field of cell culture. cell culture has become an important tool al-
lowing for direct genetic manipulations of sev-
eral important agricultural crops, including
corn, soybeans, potatoes, cotton, and canola,
Cell Culture: Plant Cells to name only a few.
Endoplasmic Nucleolus
reticulum Golgi apparatus
Cell membrane
Nucleus
Cell wall
Vacuole
Nuclear envelope
Mitochondrion
Cytoplasm
Ribosomes
Chloroplast
All plant cells, like animal cells, are eukaryotic cells. However, plant cells contain chloroplasts, the factories that produce chloro-
phyll during photosynthesis.This drawing depicts the basic features of a eukaryotic plant cell. (Electronic Illustrators Group)
structures that can then develop into plantlets. exert hormonelike activity in plant cell cul-
The totipotency of plant cells thus allows for a tures. While each class has a demonstrative and
single cell, such as a plant protoplast, to be able unique effect on overall whole plant growth
to regenerate into a complete, whole plant. An and development, auxins and cytokinins con-
analogous comparison of the totipotency of tinue to be the most widely used in manipulat-
plant cells would be that of stem cells in ani- ing plant growth in vitro. Auxins (such as IAA,
mals. Genetic manipulation of individual plant NAA, and 2,4-D) and cytokinins (such as zeatin,
cells coupled with their totipotency makes plant kinetin, and BAP) are frequently used in com-
cell culture a powerful tool for the plant geneti- bination in plant tissue culture. Generally, a
cist. high auxin-to-cytokinin ratio results in the in-
duction of root tissue from callus, while a high
Role of Plant Growth Regulators cytokinin-to-auxin ratio results in the induc-
Hormones or plant growth regulators tion of shoot formation. For many plant spe-
(PGRs) are naturally occurring or synthetic cies, an intermediate ratio of auxin to cytokinin
compounds that, in small concentrations, have results in continued callus formation.
tremendous regulatory influence on the physi- There are also specific uses of certain PGRs
ological and morphological growth and devel- in plant cell culture. For example, 2,4-D is typi-
opment of plants. There are several established cally used to induce somatic embroygenesis
classes of PGRs, including auxins, cytokinins, in cultures but then must be removed for sub-
gibberellins, abscisic acid (ABA), and ethylene. sequent embryoid development. Gibberellins,
Additionally, several other compounds, such such as GA4 and GA7, can be inhibitory to mor-
as polyamines, oligosaccharides, and sterols, phogenesis. Some PGRs may even elicit oppo-
122 The Cell Cycle
site morphogenic effects in two different plant ricultural Applications; Genetically Modified
species. Nevertheless, the use of PGRs remains (GM) Foods; High-Yield Crops; Mitosis and
essential in plant cell culture to direct morpho- Meiosis; Oncogenes; Shotgun Cloning; Stem
logical development. Cells; Totipotency.
MPF (maturation promoting factor) was puri- Yeast MPF made by joining late G2 cyclin and
fied from the older oocytes. MPF was later cdk is not active until it is itself phosphorylated.
found in developing frog embryos, where its MPF first receives two phosphates. Then the ad-
levels fluctuated, peaking just before the em- dition of a third phosphate causes the first two
bryonic cells began mitosis. Thus, MPF also to come off in a peculiar MPF activation path-
controls mitosis as well as meiosis and is often way. In fact, MPF remains unphosphorylated
called mitosis-promoting factor. MPF consists and inactive in cells experimentally prevented
of cyclin and cyclin-dependent protein kinase from replicating. In normal cells, blocking pre-
(cdk). Cyclin-bound cdk catalyzes phosphory- mature activation of MPF could prevent con-
lation of other cellular proteins. Levels of cdk densing chromosomes from damaging DNA
were shown to be constant in the cell, while cy- that is still replicating. When properly acti-
clin levels rose and peaked late in G2, explain- vated, MPF phosphorylates (a) proteins that
ing why MPF activity is highest during mitosis break down the nuclear membrane, (b) his-
and why mitotic cells induce nuclear break- tones and other chromatin proteins thought
down and chromosome condensation when to start chromosome condensation, and (c)
fused to nonmitotic cells. microtubule-associated proteins associated with
To study cell cycle regulation further, re- mitotic spindle formation.
searchers turned to yeast, a model single-cell G1 cyclin and cdk production occur when
eukaryote easily subject to genetic manipu- cells reach a suitable size during G1 and when
lation. Mutagenized yeast was screened for they are stimulated by a growth factors. For ex-
temperature-sensitive mutations that repro- ample, EGF (epidermal growth factor) stimu-
duced at lower temperatures but were blocked lates embryonic cell growth by binding to cell
at one or another point in the cell cycle when membrane receptors. EGF-receptor binding
grown at higher temperatures. One such tem- converts the intracellular domain of the recep-
perature-sensitive mutant was arrested in G2 at tor into an active protein kinase that catalyzes
the higher temperature. These cells had a de- self-phosphorylation. The auto-phosphorylated
fective cell-division-cycle-2 (cdc2) gene encod- receptor activates a G-protein encoded by the
ing a yeast version of the frog cdk in MPF. Cellu- ras gene, which binds GTP. Then, ras-GTP acti-
lar cdc2 levels are stable, but its kinase activity vates the first in a series of protein kinases, set-
depends on a yeast cyclin whose levels peak at ting off an intracellular kinase cascade. Sequen-
the end of G2. The active yeast MPF triggers pas- tial phosphorylations finally stimulate synthesis
sage through the G2 checkpoint, committing of G1 cyclin and G1 cdk. Active cyclin-bound
the cell to mitosis. Other mutants were found G1 cdk then phosphorylates the Rb protein,
encoding separate G1 cyclin and G1 cdk pro- causing it to detach from protein EF2, which
teins that together form an active kinase that becomes an active transcription factor that stim-
triggers passage through a G1 checkpoint into ulates synthesis of proteins needed for replica-
the S phase of the cell cycle. Among higher eu- tion in the S phase.
karyotes, different combinations of cyclins and To summarize, MPF is activated by a phos-
cdks act at still other checkpoints in the cell cy- phorylation pathway in which the kinase itself
cle. becomes phosphorylated, while G1 cdk is made
in response to growth factors like EGF that initi-
ate phosphorylation cascades, resulting in the
How MPF and G1 cdks Work eventual synthesis of cyclin and cdk. MPF phos-
The proteins phosphorylated by yeast MPF phorylates other proteins, permitting transi-
and G1 cyclin-cdk catalysis function in pathways tion across the G2 checkpoint, while the G1 cdk
that promote mitosis and cytokinesis, on one allows progress through the G1 checkpoint.
hand, and DNA replication, on the other. How
are cdks activated, what proteins do they phos- The Cell Cycle and Cancer
phorylate, and what do these phosphorylated With the discovery of the first MPF, scientists
proteins do? had already begun to suspect that mutations in
Cell Division 125
genes encoding proteins involved in cell cy- Mitosis and Meiosis; Mutation and Mutagene-
cling might cause the uncontrollable cell divi- sis; Oncogenes; Stem Cells; Telomeres; Totipo-
sions associated with cancer. Many cancers are tency; Tumor-Suppressor Genes.
associated with oncogenes (called proto-onco-
genes when they function and are expressed Further Reading
correctly) encoding proteins involved in cell Becker, W. M., L. J. Kleinsmith, and J. Hardin.
cycle control. Some oncogenes are carried by The World of the Cell. 5th ed. San Fransisco, Ca-
viruses, but most arise by mutation of their nor- lif.: Benjamin Cummings, 2003. Provides an
mal counterparts, resulting in inappropriate excellent overview of cell components regu-
activity of the protein encoded by the gene. lating the cell cycle and how their dysfunc-
Representative human oncogenes include neu tion can cause cancer.
(a growth-factor-receptor oncogene associated Campbell, N., and J. B. Reece. Biology. 6th ed.
with breast and ovarian cancers), trk (a recep- San Fransisco, Calif.: Benjamin Cummings,
tor oncogene associated with colon cancer), ras 2002. A standard, periodically updated in-
(a G-protein oncogene), L-myc (a transcription- troductory biology textbook for undergrad-
factor oncogene causing small-cell lung can- uate majors that includes a detailed account
cer), cdk-4 (a cyclin-dependent kinase onco- of meiosis.
gene causing a muscle sarcoma), and CYCD1 (a McCormick, F. Signaling Networks That Cause
cyclin oncogene associated with lymphoma). Cancer. Trends in Cell Biology 9 (1999): M53-
Each of these oncogenes produces proteins M56. A review of signaling pathway compo-
that promote unrestricted passage through the nents whose inappropriate activity causes
cell cycle. In contrast, retinoblastoma is a rare cancer.
eye cancer in which the Rb oncogene product Murray, A. W., and Tim Hunt. The Cell Cycle: An
is not made, so that EF2 transcription factor is Introduction. New York: W. H. Freeman, 1993.
always active and genes involved in replica- An informative overview for both students
tion are continuously on. Because Rb restrains and general readers, without too much sci-
unwanted cell divisions, it is called a tumor- entific jargon. Bibliographical references,
supressor gene. Unfortunately, the Rb onco- index.
gene is also associated with more common hu- Orr-Weaver, T. L., and R. A. Weinberg. A
man adult lung, breast, and bladder cancers. Checkpoint on the Road to Cancer. Nature
Another tumor-suppressor gene, p53, is also 392 (1998): 223-224. Describes a mutation in
implicated in several human cancers; a defec- a gene regulating the cell cycle in cancer
tive p53 gene allows cells with damaged DNA to cells.
replicate, increasing the chances of cancer de-
velopment.
In the brief history of cell cycle studies, the
discovery of an oncogene identifies the cause Cell Division
of a cancer while the newfound actor in a phos-
phorylation cascade is a candidate for an onco- Field of study: Cellular biology
gene. The study of the cell cycle is an excellent Significance: Eukaryotic cell division (mitosis and
example of the synergy between basic and ap- cytokinesis) are a short part of the cell cycle. In the
plied science: The fundamental drive to know longer time between successive cell divisions cells
how cells grow and divide has merged with a grow and replicate their DNA. Molecular signals
fervent desire to conquer a group of human tell cells when to enter each stage of the cycle.
diseases increasingly prevalent in our aging
population. Key terms
Gerald K. Bergtrom asexual reproduction: a form of reproduc-
See also: Cancer; Cell Division; Chemical tion wherein an organisms cell DNA dou-
Mutagens; Chromosome Mutation; Cytokine- bles and is distributed equally to progeny
sis; DNA Repair; Gene Regulation: Eukaryotes; cells
126 Cell Division
prophase (the initial phase of mitosis), nuclei between mitoses, but it was only in the middle of
seem to disintegrate in a matter of minutes at the twentieth century that the cell cycle was fully
the same time that chromosomes take shape characterized, showing interphase to be a long
from nondescript nuclear substance. Spindle and very productive time in the life of a cell.
fibers form at opposite poles and grow toward In an elegant experiment, cultured cells
the center of the cell. After about thirty min- were exposed to radioactive thymidine, a DNA
utes, cells are in metaphase. The spindle fibers precursor. After a few minutes, radioactive
extend across the cell, attaching to fully formed DNA was detected in the nuclei of some cells.
chromosomes lined up at the metaphase plate However, no cells actually in mitosis were radio-
in the middle of the cell. Each chromosome is active. This meant that DNA is not synthesized
actually composed of two attached strands, or during mitosis. Radioactive condensed mitotic
chromatids. chromosomes were detected only four to five
During anaphase the chromatids of each hours after cells had been exposed to the radio-
chromosome pull apart and move toward op- active DNA precursor, suggesting that replica-
posite poles of the cell. Telophase is character- tion had ended four to five hours before the be-
ized by the re-formation of nuclei around the ginning of mitosis. Studies like this eventually
chromosomes and the de-condensation of the revealed the five major intervals of the cell cy-
chromosomes back to the shapeless substance cle: mitosis, cytokinesis, gap 1 (the G1 phase, a
now called chromatin. time of cell growth), DNA synthesis (the S
Cytokinesis, meaning cell movement, be- phase of DNA synthesis), and gap 2 (the G2
gins during telophase, lasts about thirty min- phase, during which a cell continues growing
utes, and is the actual division of the parent cell and prepares for the next mitosis).
into two cells, each of which gets one of the The overall length of the cell cycle differs for
newly forming nuclei. The processes of mitosis different cell types. Human neurons stopped
and cytokinesis, which together typically last dividing shortly after birth, never to be re-
about 1.5 hours, ensures that duplicated pairs placed. Many other differentiated cells do not
of chromosomes are partitioned correctly into divide but are replaced periodically by stem
progeny cells. cells that have the capacity to continue to di-
Meiosis actually consists of two cell divisions, vide and differentiate. Clearly, human genes
each progressing through prophase, meta- must issue instructions telling cells when and
phase, anaphase, and telophase. In the first di- when not to reproduce.
vision, homologous chromosomes with their
chromatids are separated into progeny cells; in Controlling the Cell Cycle
the second, chromatids are pulled apart into Sometimes cells receive faulty instructions
the cells that will become gametes. The result is (for example, from environmental carcino-
to produce haploid eggs or sperm, rather than gens) or respond inappropriately to otherwise
the diploid progeny with paired homologous normal commands from other cells. Cancer is a
chromosomes that result from mitosis. group of diseases in which normal regulation
of the cell cycle has been lost and cells divide
The Cell Cycle out of control. In research published in the
Early histologists studying mitosis noted that 1970s, cells synchronized in mitosis were mixed
it often took cells about twenty hours to double, with others synchronized in other phases of the
implying a long period between successive cell cell cycle in the presence of polyethylene glycol
divisions. This period was called interphase, (the main ingredient in automobile antifreeze).
meaning simply between the mitotic phases. The antifreeze caused cells to fuse. Right after
An interphase also separates the first meiotic mixing, chromosomes and a mitotic spindle
division from a prior mitosis, though there is could be seen alongside an intact nucleus in
not always an interphase between the first and the fused cells. Later, the intact nucleus broke
second meiotic divisions. One might have sus- down and chromosomes condensed. The con-
pected that cells were not just biding their time clusion from studies like this is that mitosing
128 Central Dogma of Molecular Biology
cells contain a substance that causes nuclear changes in cyclin concentrations regulate
breakdown and chromosome condensation in the cell cycle.
nonmitosing cells. Similar results were seen Campbell, N., and J. B. Reece. Biology. 6th ed.
when cells in meiosis were fused with non- San Fransisco, Calif.: Benjamin Cummings,
meiotic cells. When purified, the substances 2002. Includes a detailed account of meiosis
from meiotic and mitotic cells could be injected (pp. 239-243) in a standard, periodically up-
into nonmitosing cells, where they caused nu- dated textbook for undergraduate majors.
clear breakdown and the appearance of chro- Karp, Gerald. Cell and Molecular Biology. 3d
mosomes from chromatin. The substance was ed. Hoboken, N.J.: John Wiley & Sons, 2002.
called maturation (or mitosis) promoting fac- Detailed accounts of mitosis and events and
tor (MPF). MPF contains one polypetide called regulation of the cell by cyclins and kinases
cyclin and another called cyclin-dependent pro- (pp. 580-608) in a standard, periodically up-
tein kinase (cdk). The kinase enzyme catalyzes dated textbook for professionals and under-
transfer of a phosphate to other proteins; it is graduate majors.
active only when bound to cyclinhence the Murray, A. W., and Tim Hunt. The Cell Cycle:
name. The kinase is always present in cells, An Introduction. New York: W. H. Freeman,
while cyclin concentrations peak at mitosis and 1993. An informative overview for both stu-
then fall. This explains why MPF activity is high- dents and general readers, without too much
est during mitosis and why mitotic cells fused to scientific jargon. Bibliographical references,
G1 cells, for example, can cause the G1 cell nu- index.
cleus to disappear and chromosomes to emerge Orr-Weaver, T. L., and R. A. Weinberg. A
from chromatin. Checkpoint on the Road to Cancer. Nature,
Since the initial discovery of MPF, studies of March 9, 1998. Describes a mutation in a
eukaryotic cells, from yeast cells to human cells, gene regulating the cell cycle in cancer cells.
have revealed many different cyclin-dependent
kinases and other regulatory proteins that ex-
ert control at different checkpoints on the cell
cycle, determining whether or not cells prog- Central Dogma of Molecular
ress from one stage to another. Scientists re- Biology
main ignorant of the exact causes of most can-
cers, but because of the compelling need to Field of study: Molecular genetics
know, researchers are beginning to understand Significance: The central dogma states precisely
the normal controls on cellular reproduction. how DNA is processed to produce proteins. Ori-
A final word on the cyclin-dependent pro- ginally thought to be a unidirectional process pro-
tein kinase: This enzyme is one of a large num- ceeding from DNA to RNA and then to protein, it
ber of kinases that participate in regulating cell is now known to include reverse transcription and
chemistry and behavior in response to many the enzymatic activity of certain RNA molecules.
extracellular signals (such as hormones). The The central dogma lies at the core of molecular ge-
phosphor ylation of cellular proteins has netics, and understanding it, and particularly re-
emerged as a major theme in the regulation of verse transcription, is key to comprehending both
many cellular activities, including cell division. the way viruses cause disease and methods that
Gerald K. Bergtrom have revolutionized biology.
See also: Cell Culture: Animal Cells; Cell
Culture: Plant Cells; Cell Cycle, The; Cytokine- Key terms
sis; Gene Regulation: Eukaryotes; Mitosis and codon: three nucleotides in DNA or RNA that
Meiosis; Polyploidy; Totipotency. correspond with a particular amino acid or
stop signal
Further Reading colinearity: the exact correspondence be-
Baringa, M. A New Twist to the Cell Cycle. Sci- tween DNA or RNA codons and a protein
ence, August 4, 1995. Addresses how periodic amino acid sequence
Central Dogma of Molecular Biology 129
ficiency virus (HIV). Howard Temin reported cessing has taken place. Therefore, the corre-
that viruses of this group contained an enzyme spondence of the codons in the original DNA
called reverse transcriptase, which was capable sequence containing the introns does not cor-
of converting RNA to DNA and thus challeng- respond to the order of amino acids in the pro-
ing the whole basis of molecular reactions and tein product.
the central dogma. Temin and David Baltimore Numerous examples also exist of DNA rear-
were subsequently awarded Nobel Prizes for rangements occurring before final gene expres-
their work describing this new enzyme. They sion takes place. Examples include the forma-
were able to show that it synthesizes a DNA tion of antibodies, the expression of different
strand complementary to the RNA template, mating types in yeast, and the expression of dif-
and then the DNA-RNA hybrid is converted to ferent surface antigens in parasites, such as the
a DNA-DNA molecule, which inserts into the trypanosome protozoan parasite, which causes
host chromosome. Only then can transcription sleeping sickness. All of these gene products
and translation take place. are produced as a result of gene rearrange-
The second significant change was finding ments, and the original DNA sequences are not
that RNA can act as a template for its own syn- colinear with the amino acid sequences in the
thesis. This situation occurs in RNA bacterio- protein.
phages such as MS2 and QB. These phages are
very simple, with genomes specifying only three
proteins, a coat and attachment proteins and Importance and Applications
an RNA replicase subunit. This subunit com- The theoretical importance of the central
bines with three host proteins to form the ma- dogma is unquestioned. For example, one
ture RNA replicase that catalyzes the replication modern-day scourge, the human immunodefi-
of the single-stranded RNA. Thus translation to ciency virus (HIV), replicates its genetic mate-
form the protein subunit of RNA replicase oc- rial by reverse transcription (central dogma
curs using the RNA genome as mRNA upon vi- modification), and one of the drugs shown to
ral infection without transcription taking place. contain this virus, azidothymidine (AZT), tar-
Only then is the RNA template successfully rep- gets the reverse transcriptase enzyme. Perhaps
licated. even more important is the use of the reverse
The third natural modification of the origi- transcription polymerase chain reaction (RT-
nal dogma also concerned the properties of PCR), one application of the polymerase chain
RNA. Thomas Cech in 1982 discovered that in- reaction originally devised in 1983 by Kary B.
trons could be spliced out of eukaryotic genes Mullis, formerly of Cetus Corporation. RT-PCR
without proteins catalyzing the process. For the employs reverse transcriptase to form a double-
discovery and characterization of catalytic RNA, stranded molecule from RNA, resulting in a
Cech and Sidney Altman were awarded Nobel revolutionary technique that can generate us-
Prizes for their work in 1989. Their experi- able amounts of DNA from extremely small
ments demonstrated that RNA introns, also quantities of DNA or from poor-quality DNA.
called ribozymes, had enzymatic activity that Also of practical importance is the laboratory
could produce a functional mRNA. This pro- modification of hammerhead ribozymes (cen-
cess occurred by excising the introns and com- tral dogma modification), found naturally in
bining the exons, thus restoring colinearity of plant pathogens, for clinical uses, such as to tar-
DNA and amino acid sequence. RNA process- get RNA viruses infecting patients, including
ing thus demonstrates another needed modifi- HIV and papillomavirus.
cation of the central dogma: The colinearity of Steven A. Kuhl
gene and protein in prokaryotes predicts that See also: DNA Structure and Function;
gene expression results directly from the se- Gene Regulation: Viruses; Genetic Code; Ge-
quence of bases in its DNA. In the case of eu- netic Code, Cracking of; Molecular Genetics;
karyotic genes with multiple introns, however, Protein Synthesis; Reverse Transcriptase; RNA
colinearity does not result until the RNA pro- Structure and Function; RNA World.
Chemical Mutagens 131
formed by digestion of nitrite preservatives amines are relatively inactive on DNA until they
found in some foods. Nitrous acid removes an react with certain cellular enzymes, after which
amino (NH3) group from the bases cytosine they react readily with guanine. Mutagens of
and adenine. When cytosine is deaminated, it this type and all others with indirect action
becomes the base uracil, which is not a normal work by triggering cells to induce mutagenic
component of DNA but is found in RNA. It is DNA repair pathways, which results in a loss of
able to pair with adenine. Therefore, the action accuracy in DNA replication.
of nitrous acid on DNA will convert what was a One of the oldest known environmental car-
cytosine-guanine base pair to uracil-guanine, cinogens is the chemical benzo()pyrene, a hy-
which, if replicated, will give rise to a thymine- drocarbon found in coal tar, cigarette smoke,
adenine pair. This is also a transition type of and automobile exhaust. An English surgeon,
mutation. Percivall Pott, observed that chimney sweeps
Alkylating agents are a large class of chemi- had a high incidence of cancer of the scrotum.
cal mutagens that act by causing an alkyl group The reason for this was later found to be their
(which may be methyl, ethyl, or a larger hydro- exposure to benzo()pyrene in the coal tar
carbon group) to be added to the bases of and soot of the chimneys. Like the aromatic
DNA. Some types of alkylation cause the base to amines, benzo()pyrene is activated by cellular
become unstable, resulting in a single-strand enzymes and causes mutations indirectly.
break in the DNA; this type of event can cause a Another important class of chemical muta-
mutation if the DNA is replicated with no base gens with indirect action are agents causing
present or can lead to more serious breaks in cross-links between the strands of DNA. Such
the DNA strand. Other alkylation products will cross-links prevent DNA from being separated
change the pairing specificity of the base and into individual strands as is needed during
create mutations when the DNA is replicated. DNA replication and transcription. Examples
Intercalating agents such as acridine orange, of cross-linking agents are psoralens (com-
proflavin, and ethidium bromide (which are pounds found in some vegetables and used in
used in labs as dyes and mutagens) have a treatments of skin conditions such as psoriasis)
unique mode of action. These are flat, multiple- and cis-platinum (a chemotherapeutic agent
ring molecules that interact with bases of DNA used to fight cancer).
and insert themselves between them. This in- Another important class of chemical muta-
sertion causes a stretching of the DNA du- gens are those that result in the formation of
plex, and the DNA polymerase is fooled into active species of oxygen (oxidizing agents).
inserting an extra base opposite an interca- Some of these are actually created in the body
lated molecule. The result is that intercalating by oxidative respiration (endogenous muta-
agents cause frame-shift mutations in which gens), while others are the result of the action
the sense of the DNA message is lost, just as if of chemicals such as peroxides and radiation.
an extra letter were inserted into the phrase Reactive oxygen species cause a wide variety
the fat cat ate the hat to make it the ffa tca tat of damage to the bases and the backbone of
eth eha t. This occurs because genes are read DNA and may have both direct and indirect ef-
in groups of three bases during the process of fects.
translation. This type of mutation always results
in production of a nonfunctional protein. Detection of Chemical Mutagens
The Ames test, developed by biochemistry
Chemical Mutagens with Indirect Action professor Bruce Ames and his colleagues, is
Aromatic amines are large molecules that one of the most widely used screening methods
bind to bases in DNA and cause them to be for chemical mutagens. It employs particular
unrecognizable to DNA polymerase or RNA strains of the bacterium Salmonella typhimurium
polymerase. An example is N-2-acetyl-2-amino- that require the amino acid histidine because
fluorine (AAF), which was originally used as an of mutations in one of the genes controlling
insecticide. This compound and other aromatic histidine production. The bacteria are exposed
Chloroplast Genes 133
to the potential mutagen and then spread on Hollaender, Alexander, and Frederick J. De
an agar medium lacking histidine. The strains Serres, eds. Chemical Mutagens: Principles and
can grow only if they develop a mutation restor- Methods for Their Detection. 10 vols. New York:
ing function to the mutated gene required for Kluwer Academic, 1971-1986. This illus-
histidine synthesis. The degree of growth indi- trated, multivolume work is the most com-
cates the strength of the mutagen; mutagens of prehensive set of volumes on chemical muta-
different types are detected by using bacterial genesis.
strains with different mutations. Mutagens re- Kuroda, Yukioki, et al., eds. Antimutagenesis and
quiring metabolic activation are detected by Anticarcinogenesis Mechanisms II. New York:
adding extracts of rat liver cells (capable of mu- Plenum Press, 1990. Part of the proceedings
tagen activation) to the tested substance prior of the Second International Conference on
to exposure of the bacteria. The Ames test and Mechanisms of Antimutagenesis and Anticar-
others like it involving microorganisms are cinogenesis, held December, 1988, in Ohito,
rapid, safe, and relatively inexpensive ways to Japan. Addresses topics such as antimutagens
detect mutagenic chemicals, but it is not always in food, environmental toxicology, free radi-
clear how the results of the Ames test should be cals, aspects of mammalian and human ge-
interpreted when determining the degree of netics, and molecular aspects of mutagene-
mutagenicity predicted in humans. sis and antimutageneis.
Neumann, David, et al. Human Variability in Re-
Impact and Applications sponse to Chemical Exposures: Measures, Model-
Mutations can have serious consequences ing, and Risk Assessment. Boca Raton, Fla.:
for cells of all types. If they occur in gametes, CRC Press, 1998. Addresses genetic evidence
they can cause genetic diseases or birth defects. for variability in the human response to
If they occur in somatic (body) cells of multi- chemicals associated with reproductive and
cellular organisms, they may alter a growth- developmental effects, the nervous system
controlling gene in such a way that the mutated and lungs, and cancer.
cell begins to grow out of control and forms a
cancer. DNA is subject to a variety of types of
damage by interaction with a wide array of
chemical agents, some of which are ubiquitous Chloroplast Genes
in the environment, while others are the result
of human intervention. Methods of detection Field of study: Molecular genetics
of chemicals with mutagenic ability have made Significance: Plants are unique among higher
it possible to reduce the exposure of humans to organisms in that they meet their energy needs
some of these mutagenic and potentially carci- through photosynthesis. The specific location for
nogenic chemicals. photosynthesis in plant cells is the chloroplast,
Beth A. Montelone which also contains a single, circular chromosome
See also: Biochemical Mutations; Cancer; composed of DNA. Chloroplast DNA (cpDNA)
DNA Repair; DNA Replication; Mutation and contains many of the genes necessary for proper
Mutagenesis; Oncogenes; Repetitive DNA; chloroplast functioning. A better understanding
Tumor-Suppressor Genes. of the genes in cpDNA has improved the under-
standing of photosynthesis, and analysis of the
Further Reading DNA sequence of these genes has also been useful
Ahern, Holly. How Bacteria Cope with Oxida- in studying the evolutionary history of plants.
tively Damaged DNA. ASM News (March,
1993). Discusses oxidative damage to DNA. Key terms
Friedberg, Errol C., et al. DNA Repair and Muta- chloroplast: the cell structure in plants re-
genesis. Washington, D.C.: ASM Press, 1995. sponsible for photosynthesis
Provides extensive descriptions of the mech- genome: all of the DNA in the nucleus or in
anisms of chemical mutagenesis. one of the organelles such as a chloroplast
134 Chloroplast Genes
open reading frames: DNA sequences that tion always resulted in offspring whose leaves
contain all the components found in active resembled those on the branch containing the
genes, but whose functions have not yet been flower that received the pollenthat is, the ma-
identified ternal parent. These results could not be ex-
photosynthesis: the process in which sun- plained by Mendelian genetics.
light is used to take carbon dioxide from the Since Correnss discovery, many other such
air and convert it into sugar traits have been discovered. It is now known
that the reason these traits do not follow Men-
The Discovery of Chloroplast Genes delian inheritance patterns is that their genes
The work of nineteenth century Austrian are not on the chromosomes in the nucleus of
botanist Gregor Mendel showed that the inher- the cell where most genes are located. Instead,
itance of genetic traits follows a predictable pat- the gene for the four-oclock leaf color trait is
tern and that the traits of offspring are deter- located on the single, circular chromosome
mined by the traits of the parents. For example, found in chloroplasts. Because chloroplasts are
if the pollen from a tall pea plant is used to pol- specialized for photosynthesis, many of the
linate the flowers of a short pea plant, all the genes on the single chromosome produce pro-
offspring are tall. If one of these tall offspring is teins or RNA that either directly or indirectly
allowed to self-pollinate, it produces a mixture affect synthesis of chlorophyll, the pigment pri-
of tall and short offspring, three-quarters of marily responsible for trapping energy from
them tall and one-quarter of them short. Simi- light. Because chlorophyll is green and because
lar patterns are observed for large numbers of mutations in many chloroplast genes cause
traits from pea plants to oak trees. Because of chloroplasts to be unable to make chlorophyll,
the widespread application of Mendels work, most mutations result in partially or completely
the study of genetic traits by controlled mating white or yellow leaves.
is often referred to as Mendelian
genetics.
In 1909, German botanist Carl
Erich Correns discovered a trait in
four-oclock plants (Mirabilis ja-
lapa) that appeared to be inconsis-
tent with Mendelian inheritance
patterns. He discovered four-
oclock plants that had a mixture
of leaf colors on the same plant:
Some were all green, many were
partly green and partly white (var-
iegated), and some were all white.
If he took pollen from a flower on
a branch with all-green leaves and
used it to pollinate a flower on a
branch with all-white leaves, all
the resulting seeds developed into
plants with white leaves. Likewise,
if he took pollen from a flower on
a branch with all-white leaves and
used it to pollinate a flower on a
branch with all-green leaves, all
the resulting seeds developed into
plants with green leaves. Repeated Carl Erich Correns, whose experiments with four-oclock plants led to the discov-
pollen transfers in any combina- ery of chloroplast genes. (National Library of Medicine)
Chloroplast Genes 135
Chloroplasts
Mitochondrion
Nucleus
Cytoplasmic strands
Nucleolus
Cytosol
Peroxisome
for the biochemical reactions of photosynthe- did they transfer some of their genes into the
sis. What is unusual about these genes is that nuclei of the cells in which they are now found?
their products represent only a portion of the Of greater importance has been the discov-
polypeptides required for photosynthesis. For ery that the DNA sequences of many chloro-
example, the very important enzyme ATPase plast genes are highly conservedthat is, they
the enzyme that uses proton gradient energy to have changed very little during their evolution-
produce the important energy molecule ade- ary history. This fact has led to the use of chlo-
nosine triphosphate (ATP)comprises nine roplast gene DNA sequences for reconstruct-
different polypeptides. Six of these polypep- ing the evolutionary history of various groups
tides are products of chloroplast genes, but the of plants. Traditionally, plant systematists (sci-
other three are products of nuclear genes that entists who study the classification and evolu-
must be transported into the chloroplast to tionary history of plants) have used structural
join with the other six polypeptides to make ac- traits of plants such as leaf shape and flower
tive ATPase. Another notable example is the anatomy to try to trace the evolutionary history
enzyme ribulose biphosphate carboxylase of plants. Unfortunately, there are a limited
(RuBP carboxylase, or Rubisco), which is com- number of structural traits, and many of them
posed of two polypeptides. The larger polypep- are uninformative or even misleading when
tide, called rbcL, is a product of a chloroplast used in evolutionary studies. These limitations
gene, whereas the smaller polypeptide is the are overcome when gene DNA sequences are
product of a nuclear gene. used.
The last thirty or so genes remain unidenti- A DNA sequence several hundred base pairs
fied. Their presence is inferred because they in length provides the equivalent of several
have DNA sequences that contain all the com- hundred traits, many more than the limited
ponents found in active genes. These kinds of number of structural traits available (typically
genes are often called open reading frames much fewer than one hundred). One of the
(ORFs) until the functions of their polypeptide most widely used sequences is the rbcL gene. It
products are identified. is one of the most conserved genes in the chlo-
roplast genome, which in evolutionary terms
Impact and Applications means that even distantly related plants will
The discovery that chloroplasts have their have a similar base sequence. Therefore, rbcL
own DNA and the further elucidation of their can be used to retrace the evolutionary history
genes have had some impact on horticulture of groups of plants that are very divergent from
and agriculture. Several unusual, variegated one another. The rbcL gene, along with a few
leaf patterns and certain mysterious genetic other very conservative chloroplast genes, has
diseases of plants are now better understood. already been used in attempts to answer some
The discovery of some of the genes that code basic questions about the origins and evolution
for polypeptides required for photosynthesis of some of the major flowering plant groups.
has helped increase understanding of the bio- Less conservative genes and ORFs show too
chemistry of photosynthesis. The discovery that much evolutionary change to be used at higher
certain key chloroplast proteins such as ATPase classification levels but are extremely useful in
and Rubisco carboxylase are composed of a answering questions about the origins of closely
combination of polypeptides coded by chloro- related species, genera, or even families. As an-
plast and nuclear genes also raises some as yet alytical techniques are improved, chloroplast
unanswered questions. For example, why would genes show promise of providing even better
an important plant structure like the chloro- insights into plant evolution.
plast have only part of the genes it needs to Bryan Ness
function? Moreover, if chloroplasts, as evolu- See also: Cell Culture: Plant Cells; DNA Iso-
tionary theory suggests, were once free-living lation; Extrachromosomal Inheritance; Geno-
bacteria-like cells, which must have had all the mics; Hybridization and Introgression; Model
genes needed for photosynthesis, why and how Organism: Chlamydomonas reinhardtii.
Cholera 137
binds to a cell of the intestinal lining (an intesti- these travels. Unfortunately, the vaccines are
nal mucosa cell) via B subunits. Then the A sub- only effective for about six months.
units cause the mucosal cell to stimulate the se- The basis for the operation of cholera toxin
cretion of water and salts from the blood to is production of a hormone substance called
produce diarrhea. Lesser amounts of the wa- cyclic adenosine monophosphate (cAMP). The
tery mix are vomited and exacerbate dehydra- presence of excess cAMP in intestinal mucosa
tion. cells causes movement of water and other tissue
The use of bacterial genetics to compare vir- components into the intestine and then out of
ulent V. cholerae and strains that did not cause the body. The accumulation of cAMP is caused
the disease helped in the discovery of the na- by the ability of the cholera toxin to modify an
ture of the cholera toxin and enabled produc- enzyme protein, adenyl cyclase, to make it pro-
tion of vaccines against the protein. These vac- duce excess cAMP via modification of a control
cines are useful to those individuals who visit substance called a G-protein. This modification,
areas where cholera is endemic, ensuring that called adenine ribosylation, is a mechanism
they do not become infected with it during similar to that causing diphtheria, another dan-
Outbreaks of cholera can occur in nonendemic ar- to explain the 1991 cholera epidemic in Peru, when
eas when an infected person travels to another coun- the oceanic oscillation known as El Nio caused a
try or when infected water is carried in the ballast of warming of ocean temperature.
ships to another country. These two processes alone, Because of the association of V. cholerae with plank-
however, could not explain all of the outbreaks of ton, scientists believe they may be able to track or
cholera observed worldwide. In the late 1960s, Vibrio identify future epidemics by the use of satellite imag-
cholerae was found in the ocean associated with ma- ery. Increases in phytoplankton turn the ocean color
rine plankton. This association, along with climate from blue to green. Thus, changes in green areas in
change, helps to explain the spread of cholera. the ocean on satellite pictures show where the phyto-
Plankton are the small organisms suspended in plankton and, by association, zooplankton and chol-
the oceans upper layers. Plankton can be divided era bacteria, are relocating or increasing in number.
into two groups, phytoplankton (small plants) and The association of cholera with zooplankton has
zooplankton (small animals). Vibrio cholerae is found also helped reveal a new way to prevent the disease.
associated with the surface and gut of copepods, People get cholera by ingesting several thousand
which are members of the zooplankton group. cholera bacteria at one time. A single copepod can
These small crustaceans act as a reservoir for the harbor ten thousand bacteria; therefore, the inges-
cholera bacteria, allowing them to survive in the tion of one infected copepod can cause disease in a
ocean for long periods of time. Then, a change in person. Researchers have found a simple and inex-
weather that causes the ocean temperature to rise pensive way to reduce this risk from copepods dra-
could also cause currents that stir up nutrients from matically. Filtering water through four layers of fab-
lower layers of the ocean to the upper layers. Num- ric used to make saris, which are commonly worn
bers of phytoplankton, which live in the upper layers in regions plagued by cholera, removes 99 percent
of ocean waters, increase in these periods as a result of copepods from water containing high levels of
of the warmer temperatures and greater availability plankton.
of nutrients. Zooplankton numbers increase as well, Now that the entire genetic sequence of V. cholerae
because of the increase in main food source, the has been determined, scientists are armed with addi-
phytoplankton. Consequently, the number of chol- tional genetic data to elucidate the relationship of
era bacteria increase to a level that can cause the dis- the bacterium with copepods, which may help them
ease. Thus, climate change can result in an outbreak find more ways of controlling the spread of the dis-
of cholera in a region where cholera is endemic, or, if ease.
currents move the plankton to other coastal areas, in Vicki J. Isola
a new, nonendemic region. This scenario is believed
Cholera 139
gerous disease that can be fatal, although in (1998). Describes a promising new approach
diphtheria other tissues and processes are af- to more safely and quickly immunizing peo-
fected. ple against cholera.
Heidelberg, John F., et al. DNA Sequence of
Impact and Applications Both Chromosomes of the Cholera Patho-
Cholera has, for centuries, been a serious gen Vibrio cholerae. Nature 406 (2000). Publi-
threat to humans throughout the world. Dur- cation of the complete genome sequence of
ing the twentieth century, its consequences the bacteria responsible for cholera.
to industrialized nations diminished signifi- Holmgren, John. Action of Cholera Toxin and
cantly with the advent of sound sanitation prac- Prevention and Treatment of Cholera. Na-
tices that almost entirely prevented the entry of ture 292 (1981). Clearly describes both the
V. cholerae into the food and water supply. In composition and bioaction of cholera toxin.
poorer nations with less adequate sanitation, Keusch, Gerald, and Masanobu Kawakami, eds.
the disease flourishes and is still a severe threat. Cytokines, Cholera, and the Gut. Amsterdam:
It must be remembered that handling chol- IOS Press, 1997. Surveys the role of peptide
era occurs at three levels. The isolation and mediators in the intestinal responses to in-
identification of cholera toxin, as well as devel- fectious and inflammatory challenges pre-
opment of current short-term cholera vaccines, sented by diverse disease states, including
were highly dependent on genetic methodol- inflammatory bowel disease and infectious
ogy. Vaccine protects most travelers from the diarrheas and dysenteries, and the epidemi-
disease. However, wherever the disease afflicts ology and pathogenesis of cholera and re-
individuals, its treatment depends solely upon lated diarrheal diseases.
rehydration and use of antibiotics. Finally, mod- Kudlick, Katherine. Cholera in Post-revolutionary
ern cholera prevention focuses solely on ade- Paris: A Cultural History. Berkeley: University
quate sanitation. It is thus essential to produce of California Press, 1996. Explores the dy-
a long-lasting vaccine for treatment of cholera namics of class relations through an investi-
to enable prolonged immunization at least at gation of the responses to two cholera epi-
the ten-year level of tetanus shots. Efforts aimed demics in Paris during 1832 and 1849.
at this goal are ongoing and utilize molecular Pennisi, Elizabeth. Cholera Strengthened by
genetics to define more clearly why long-term Trip Through Gut. Science 296 (2002). Ex-
vaccination has so far been unsuccessful. Par- amines the effect that passing through a
ticularly useful will be fine genetic sequence hosts gut has on cholera bacteria.
analysis and the use of gene amplification fol- Rakel, Robert E., ed. Conns Current Therapy:
lowed by DNA fingerprinting. Latest Approved Methods of Treatment for the
Sanford S. Singer Practicing Physician. Philadelphia: W. B.
See also: Anthrax; Archaea; Bacterial Ge- Saunders, 2003. Provides for general readers
netics and Cell Structure; Bacterial Resistance a succinct overview of cholera and its treat-
and Super Bacteria; Diphtheria; Emerging Dis- ment.
eases; Gene Regulation: Bacteria; Gene Regu- Wachsmuth, Kate, et al., eds. Vibrio Cholerae and
lation: Lac Operon; Transgenic Organisms. Cholera: Molecular to Global Perspectives. Wash-
ington, D.C.: ASM Press, 1994. A compre-
Further Reading hensive guide to the disease and its genetics.
Colwell, Rita R. Global Climate and Infectious
Disease: The Cholera Paradigm. Science 274 Web Site of Interest
(1996). An analysis of the role climate change Food and Drug Administration. http://vm
might have on the spread of cholera. In- .cfsan.fda.gov. The FDAs Bad Bug Book pro-
cludes a good overview of the history of chol- vides information on Vibrio cholerae, the bac-
era as well. terium that causes cholera. Links to the Cen-
Glenn, Gregory M., et al. Skin Immunization ters for Disease Control and Preventions
Made Possible by Cholera Toxin. Nature 391 food illness fact sheet on the disease.
140 Chromatin Packaging
Nonhistones as a class of proteins are much nucleosomes. Each turn of the chromatin fiber
more heterogeneous than the histones. They contains about 1,200 base pairs (six nucleo-
are usually acidic (carrying a net negative somes), and the DNA has now been compacted
charge), so they will most readily attract and by about a factor of fifty. The coiled solenoid
bind with the positively charged histones fiber is organized into large domains of 40,000
rather than the negatively charged DNA. Each to 100,000 base pairs, and these domains are
cell has many different kinds of nonhistone separated by attached nonhistone proteins that
proteins, some of which play a structural role in serve to both organize and to control their
chromosome organization and some of which packaging and unpackaging.
are more directly involved with the regulation
of gene expression. Weight for weight, there is Long DNA Loops and the Chromosome
often as much nonhistone protein present in Scaffold
chromatin as histone protein and DNA com- Physical studies using the techniques of X-ray
bined. crystallography and neutron diffraction have
suggested that solenoid fibers may be further
Nucleosomes and Solenoids organized into giant supercoiled loops. The ex-
The fundamental structural subunit of chro- tent of this additional looping, coiling, and
matin is an association of DNA and histone pro- stacking of solenoid fibers varies, depending
teins called a nucleosome. First discovered in on the cell cycle. The most relaxed and ex-
the 1970s by Ada and Donald Olins and Chris tended chromosomes are found at interphase,
Woodcock, each nucleosome consists of a core the period of time between cell divisions. Inter-
of eight histone proteins: two each
of the histones H2A, H2B, H3, and
H4. Around this histone octamer is
wound 146 base pairs of DNA in
one and three-quarter turns (ap-
proximately eighty base pairs per
turn). The overall shape of each
nucleosome is similar to that of a
lemon or a football. Each nucleo-
some is separated from its adjacent
neighbor by about 55 base pairs of
linker DNA, so that in its most un-
raveled state they appear under the
electron microscope to be like tiny
beads on a string. Portions of each
core histone protein protrude out-
side of the wound DNA and interact
with the DNA that links adjacent
nucleosomes.
The next level of chromatin pack-
aging involves a coiling and stack-
ing of nucleosomes into a ribbon-
like arrangement, which is twisted
to form a chromatin fiber about 30
nanometers (nm) in diameter com- This image, captured through neutron crystallography, shows the molecular
monly called a solenoid. Forma- structure of the fundamental repeating unit of the chromosome, the nucleo-
tion of solenoid fibers requires the some core complex: 146 base pairs of DNA wrapped around a core of eight his-
interaction of histone H1, which tone proteins. (U.S. Department of Energy Genomes to Life Program,
binds to the linker DNA between http://doegenomestolife.org)
142 Chromatin Packaging
phase chromosomes typically have a diameter lenoid fibers, may contain several genes, or the
of about 300 nm. Chromosomes that are getting boundary of a domain can lie within a gene.
ready to divide (metaphase chromosomes) have These domains have the capacity to influence
the most highly condensed chromatin, and gene expression, and this property is mediated
these structures may have a diameter of up to by specific DNA sequences known as locus con-
700 nm. One major study on the structure of trol regions (LCRs). An LCR is like a powerful
metaphase chromosomes has shown that a skel- enhancer that activates transcription, thereby
eton of nonhistone proteins in the shape of the turning on gene expression. The existence of
metaphase chromosome remains even after all such sequences was first recognized from a
of the histone proteins and the DNA have been study of patients with beta-thalassemia and a re-
removed by enzymatic digestion. If the DNA is lated condition known as hereditary persis-
not digested, it remains in long loops (10 to tence of fetal hemoglobin. In these disorders,
90 kilobase pairs) anchored to this nonhistone there is an error in the expression of a cluster of
protein scaffolding. genes, known as the beta-globin genes, that
In the purest preparations of metaphase prevents the appearance of adult type hemo-
chromosomes, only two scaffold proteins are globin. The beta-globin genes are linearly ar-
found. One of these forms the latticework of rayed over a 50-kilobase-pair chromatin do-
the scaffold, while the other has been identi- main, and the LCR is found upstream from this
fied as toposiomerase II, an enzyme that is criti- cluster. Affected patients were found to have
cal in DNA replication. This enzyme cleaves normal beta-globin genes, but there was a dele-
double-stranded DNA and then rapidly reseals tion of the upstream LCR that led to failure to
the cut after some of the supercoiling has been activate the genes appropriately. Further inves-
relaxed, thus relieving torsional stress and pre- tigation led to the conclusion that the variation
venting tangles in the DNA. Apparently this in expression of these genes observed in differ-
same enzyme activity is necessary for the coil- ent patients was caused by differences in the as-
ing and looping of solenoid fibers along the sembly of the genes into higher-order chroma-
chromosome scaffold that occurs during the tin structures. In some cases, gene expression
transition between interphase and metaphase was repressed, while in others it was facilitated.
chromosome structure. In the most highly con- Under normal circumstances, a nonhistone
densed metaphase chromosomes, the DNA has protein complex was found to bind to the LCR,
been further compacted by an additional fac- causing the chromatin domain to unravel and
tor of one hundred. making the DNA more accessible to transcrip-
tion factors, thus enhancing gene expression.
Impact and Applications DNA sequencing studies have demonstrated
Studies of chromatin packaging continue to a common feature in several genes whose al-
reveal the details of the precise chromosomal tered expression leads to severe human genetic
architecture that results from the progressive disease. For example, the gene that causes myo-
coiling of the single DNA molecule into in- tonic dystrophy has a large number of repeat-
creasingly compact structures. Evidence sug- ing nucleotide triplets in the DNA region im-
gests that the regulation of this coiling and mediately adjacent to the protein-encoding
packaging within the chromosome has a signif- segment. Physical studies have shown that this
icant effect on the properties of the genes results in the formation of unusually stable
themselves. In fact, errors in DNA packaging nucleosomes, since these repeated sequences
can lead to inappropriate gene expression and create the strongest naturally occurring sites
developmental abnormalities. In humans, the for association with the core histones. It has
blood disease thalassemia, several neuromus- been suggested that these highly stable nucleo-
cular diseases, and even male sex determina- somes are unusually resistant to the unwinding
tion can all be explained by the altered assem- and denaturation of the DNA that must occur
bly of chromosomal structures. in order for gene expression to begin. RNA
Chromatin domains, composed of coiled so- polymerase is the enzyme that makes an RNA
Chromatin Packaging 143
transcript of the gene, and its movement idence has left no doubt that the packaging
through the protein-coding portion of the gene process is an essential component of regulated
is inhibited if the DNA is unable to dissociate gene expression.
from the nucleosomes. Thus, although the nec- Jeffrey Knight
essary protein product would be normal and See also: Cell Division; Central Dogma of
functional if it could be made, it is a problem Molecular Biology; Chromosome Structure;
with chromatin unpackaging that leads to re- Developmental Genetics; Fragile X Syndrome;
duced gene expression that ultimately leads to Gene Regulation: Eukaryotes; Huntingtons
clinical symptoms of the disease. Both mild and Disease; Mitosis and Meiosis; Molecular Genet-
severe forms of myotonic dystrophy are known, ics.
and an increase in the clinical severity correlates
exactly with an increased number of nucleotide Further Reading
triplet repeats in the gene. Similar triplet re- Becker, Peter B. Chromatin Protocols. Totowa,
peats have been found in the genes responsible N.J.: Humana Press, 1999. Western scientists
for Kennedys disease, Huntingtons disease provide step-by-step instructions for analyz-
(Huntingtons chorea), spinocerebellar ataxia ing the relationship between chromatin
type I, fragile X syndrome, and dentatorubral- structure and function and for elucidating
pallidoluysian atrophy. the molecular mechanisms that control such
Fascinating and unexpected recent research vital cellular functions as transcription, rep-
results have suggested that a central event in lication, recombination, and DNA repair.
the determination of gender in mammals de- Elgin, Sarah C. R., and Jerry L. Workman, eds.
pends on local folding of DNA within the chro- Chromatin Structure and Gene Expression. 2d
mosome. Molecular biologists Peter Good- ed. New York: Oxford University Press, 2000.
fellow and Robin Lovell-Badge successfully Examines numerous facets of chromatin
cloned a human gene from the Y chromosome structure, including its histones, nucleo-
that determines maleness. This SRY gene somes, and fiber elements, its relationship to
(named from the sex-determining region of DNA structure, its replication and assembly,
the Y chromosome) encodes a protein that se- and its initiation of expression.
lectively recognizes a specific DNA sequence Kornberg, Roger, and Anthony Klug. The
and helps assemble a chromatin complex that Nucleosome. Scientific American 244 (1981).
activates other male-specific genes. More spe- Provides a somewhat dated but highly read-
cifically, binding of the SRY protein causes the able summary of the primary association of
DNA to bend at a specific angle and causes con- DNA with histone proteins.
formation that facilitates the assembly of a pro- Lodish, Harvey, et al. Molecular Cell Biology. 4th
tein complex to initiate the cascade of gene ac- ed. New York: W. H. Freeman, 2000. Covers
tivation leading to male development. If the chromatin structure from a cellular and bio-
bend is too tight or too wide, gene expression chemical perspective.
will not occur, and the embryo will develop as a Russell, Peter. Genetics. 5th ed. Menlo Park, Ca-
female. lif.: Benjamin Cummings, 1998. A college-
The unifying lesson to be learned from these level textbook with an excellent discussion
examples of DNA packaging and disease is that of chromatin structure and organization.
DNA sequencing studies and the construction Turner, Bryan. Chromatin and Gene Regulation:
of human genetic maps will not by themselves Mechanisms in Epigenetics. Malden, Mass.:
provide all the answers to questions concerning Blackwell, 2001. Explores the relationship
human variation and genetic disease. An un- between gene expression and DNA packag-
derstanding of human genetics at the molecu- ing by explaining the chromatin-based con-
lar level depends not only on the primary DNA trol mechanisms. An overview of transcrip-
sequence but also on the three-dimensional or- tion in bacteria, refined structures and the
ganization of that DNA within the chromo- control mechanisms, and dosage compensa-
some. Compelling genetic and biochemical ev- tion are covered.
144 Chromosome Mutation
Van Holde, Kensal. Chromatin. New York: in the early years of the twentieth century, ge-
Springer, 1988. Contemporary views on neticists who worked with it were the first to dis-
chromatins functions and structure, ad- cover chromosome mutations. Calvin Bridges
dressing structures of DNA, proteins of proposed deletions in 1917, duplications in
chromatin (both histone and nonhistone), 1919, and translocations in 1923 as explana-
the nucleosome, higher-order structures, tions of phenomena he had observed in ge-
transcription, and replication. Bibliography. netic experiments. Alfred Sturtevant proposed
Wolffe, Alan P. Genetic Effects of DNA Pack- inversions in 1926 to explain experimental
aging. Scientific American, November/De- genetic data. Their proposals were directly con-
cember, 1995: 68-77. Excellent summary for firmed as chromosome mutations when meth-
the general reader of the relationship be- ods for microscopic examination of chromo-
tween gene expression and DNA packaging. somes were developed in the 1920s and 1930s.
Deletions
A deletion results when a chromosomal seg-
Chromosome Mutation ment is lost. A deletion creates an imbalance in
the genetic material because a relatively large
Fields of study: Cellular biology; Molecular segment of it is missing. Most deletions are le-
genetics thal, even when heterozygous. Some small de-
Significance: Unlike gene mutations, which alter letions persist in the heterozygous state but are
individual genes, chromosome mutations delete, usually lethal when homozygous. These small
duplicate, or rearrange chromosome segments. deletions are usually characterized by deleted
Chromosome mutations may create gene muta- portions of only one or two genes and behave
tions if they delete genes or if the breakpoints of re- genetically as recessive alleles when paired with
arranged segments disrupt gene structure or alter a typical recessive allele of the affected gene.
gene expression. Even when they do not create gene
mutations, chromosome mutations may reduce fer- Duplications
tility and are an important cause of inherited in- A duplication arises when a chromosomal
fertility in humans. They also play important roles segment is duplicated and inserted either into
in the evolution of species. the same chromosome, as its parent segment,
or into another chromosome. Duplications are
Key terms present in most genomes. Genome projects
deletion: a missing chromosome segment (including the Human Genome Project) have
duplication: a chromosome segment re- revealed large duplicated segments containing
peated in the same or in a different chromo- multiple genes dispersed throughout the chro-
some mosomes in most species. Some duplications
fission: separation of a single chromosome are repeated in tandem in the same chromo-
into two chromosomes some and are subject to unequal crossing over,
fusion: joining of two chromosomes to be- a process in which duplicated segments mispair
come a single chromosome with one another and a crossover takes place
inversion: a chromosome segment with re- within the mispaired segment. Unequal cross-
versed orientation when compared to the ing over increases the number of tandem dupli-
original chromosome structure cations in one chromosome and decreases that
translocation: a chromosome segment trans- number in the other.
ferred from one chromosome to a nonho-
mologous chromosome Inversions
Two breaks within the same chromosome
Discovery may liberate a chromosome segment. If the
As the fruit fly Drosophila melanogaster be- segment is reinserted into the same chromo-
came a premier organism for genetic research some, but in reverse orientation, an inversion
Chromosome Mutation 145
results. Also, rare crossing over between dupli- location heterozygote, the two chromosomes
cated segments in the same chromosome may with translocated segments pair with two other
produce an inversion. If a breakpoint of the in- chromosomes without translocations. The pair-
version lies within a gene, it disrupts the gene, ing of these four chromosomes forms an X-
causing a gene mutation. Additionally, an in- shaped structure called a quadrivalent, so
version may place a gene in another location in named because it contains four chromosomes
the chromosome, removing the gene from its paired with one another, instead of the usual
regulatory elements and altering its expres- two. Depending on the orientation of the quad-
sion, a phenomenon known as the position ef- rivalent during meiosis, some gametes may re-
fect. ceive a balanced complement of chromosomes
When one chromosome carries an inversion and others an unbalanced complement with
and its homologous partner does not, the indi- large duplications and deletions. Typically,
vidual carrying these two chromosomes is said about half of all gametes in a reciprocal trans-
to be an inversion heterozygote. The two ho- location heterozygote carry an unbalanced
mologous chromosomes in an inversion heter- chromosome complement, a situation that sig-
ozygote cannot pair properly in meiosis; one of nificantly reduces the individuals fertility. How-
them must form a loop in the inverted region. ever, translocation homozygotes suffer no loss
A crossover within the inversion loop results in of fertility, because the chromosomes pair nor-
chromosomes that carry large deletions and mally with no quadrivalent.
duplications. Because of the imbalance of
chromosomal material created by the deletions Fusions
and duplications, progeny resulting from such Very rarely, two chromosomes may fuse with
crossovers usually do not survive. In genetic ex- one another to form a single chromosome.
periments, crossing over appears to be sup- Chromosomes with centromeres at or very
pressed within an inversion, whereas, in reality, near the ends of the chromosomes may un-
crossing over does take place within the inver- dergo breakage at the centromeres and fuse
sion but crossover-type progeny fail to survive. with each other in the centromeric region, re-
For this reason, inversion heterozygotes may sulting in a single chromosome with the long
suffer a reduction in fertility that is propor- arms of the original chromosomes on either
tional to the size of the inversion. An individual side of the fused centromere. Such a chromo-
who is homozygous for an inversion, however, some fusion is called a Robertsonian translo-
suffers no loss of fertility, because the chromo- cation. In other cases, two chromosomes may
somes pair normally. fuse with one another producing a dicentric
chromosome (a chromosome with two centro-
Translocations meres). For the fused chromosome to persist,
A break in a chromosome may liberate a one of the centromeres ceases to function, leav-
chromosome fragment, which if reattached to ing the other centromere as a single, functional
a different chromosome is called a transloca- centromere for the fused chromosome.
tion. Most translocations are reciprocal: Two
chromosome breaks, each in a different chro- Fissions
mosome, liberate two fragments, and each frag- A chromosome break produces two frag-
ment reattaches to the site where the other ments, which may function as individual chro-
fragment was originally attached; in other mosomes if each has telomeres on both ends
words, the two fragments exchange places. If and a functional centromere. Typically, chro-
the breakpoint of a translocation is within a mosome breakage produces one fragment with
gene, a gene mutation may result. Also, a gene a telomere on one end and a centromere, and
at or near the breakpoint may undergo a change another fragment with a telomere on one end
in its expression because of position effect. and no centromere. For both fragments to
Translocations alter chromosome pairing in function as chromosomes, one must acquire a
meiosis. During meiosis in a reciprocal trans- telomere and the other a centromere and a
146 Chromosome Mutation
telomere. These events are highly unlikely, so such a degree that the isolated populations di-
fissions are rarer than fusions. However, com- verge into separate species. Their members can
plex translocations with other chromosomes no longer produce fertile offspring when hy-
may rarely produce functional chromosomes bridized with members of another population
from a fission event, and cases of functional because the chromosomes cannot properly pair
chromosomes arising from fissions have been with one another. Indeed, accumulated chro-
documented. mosome mutations are often evident when ge-
neticists compare the chromosomes of closely
Impact on Human Genetics and Medicine related species. For example, the chromosomes
Chromosome mutations are responsible for of different Drosophila species are differenti-
several human genetic disorders. For example, ated mostly by translocations and fusions. Com-
about 20 percent of hemophilia A cases result parison of human, chimpanzee, gorilla, and
from a gene mutation caused by an inversion orangutan chromosomes reveals numerous in-
with a breakpoint in the F8C gene, which en- versions that distinguish the chromosomes of
codes blood clotting factor VIII. Cri du chat these species. One of the most striking cases of
syndrome, a severe disorder characterized by chromosome evolution is the origin of human
severe mental retardation and distinctive physi- chromosome 2. This chromosome matches two
cal features, is usually caused by deletion of a separate chromosomes in the great apes and
small chromosomal region near the end of apparently arose from a fusion of these two
chromosome 5. A few cases of this syndrome chromosomes after the divergence of the hu-
are associated with deletions that result from a man and chimpanzee lineages. The presence
translocation with a breakpoint near the end of in human chromosome 2 of DNA sequences
chromosome 5 or crossovers within a small in- corresponding to a nonfunctional centromere
version in that chromosome region. Robert- and telomere at sites corresponding to these
sonian translocations that fuse the long arm of structures in the great ape chromosomes is
chromosome 21 with the long arm of another strong evidence of a chromosome fusion dur-
chromosome (usually chromosome 14) are re- ing evolution of the human lineage.
sponsible for some inherited cases of Down syn- Daniel J. Fairbanks
drome. A reciprocal translocation between See also: Cell Cycle, The; Cell Division;
chromosomes 9 and 22, called the Philadel- Central Dogma of Molecular Biology; Chemi-
phia chromosome, causes increased suscepti- cal Mutagens; Chromosome Structure; Chro-
bility to certain types of cancer by altering the mosome Theory of Heredity; Congenital Dis-
expression of a gene located at the breakpoint orders; Cystic Fibrosis; Down Syndrome;
of the translocation. Other translocations are Epistasis; Evolutionary Biology; Hemophilia;
likewise associated with certain cancers. Chro- Hereditary Diseases; Huntingtons Disease; In-
mosome mutations may also cause infertility in born Errors of Metabolism; Infertility; Mitosis
humans. Reciprocal translocations are espe- and Meiosis; Molecular Genetics; Mutation
cially notorious, although certain inversions and Mutagenesis; Punctuated Equilibrium.
are also associated with infertility.
Further Reading
Implications for Evolution Burnham, Charles R. Discussions in Cytogenetics.
Heterozygous carriers of inversions, translo- Minneapolis, Minn.: Burgess, 1962. A classic
cations, fusions, and fissions often suffer losses book on chromosome mutations written by
of fertility, but homozogotes do not. Thus, nat- one of the pioneers in the field. Though out
ural selection may disfavor heterozygotes while of print, this book remains available in many
favoring homozygotes either for the original libraries.
chromosome structure or for the mutation. Calos, Michele. Molecular Evolution of Chromo-
Accumulation of different chromosome muta- somes. New York: Oxford University Press,
tions in isolated populations of a species may 2003. Describes the role of chromosome mu-
eventually differentiate the chromosomes to tations in evolution.
Chromosome Structure 147
Miller, Orlando J., and Eeva Therman. Human structures called chromosomes (color bod-
Chromosomes. 4th ed. New York: Springer ies) within the nucleus that became visible
Verlag, 2001. A good textbook on human when they condensed as the cell prepared to di-
chromosomes, including common chromo- vide.
some mutations. The association of the condensed, visible
state of chromosomes with cell division caused
investigators to speculate that the chromosomes
played a role in the transmission of informa-
Chromosome Structure tion. Chromosome counts made before and af-
ter cell division showed that the chromosome
Fields of study: Cellular biology; Classical number remained constant from generation to
transmission genetics generation. When it was observed that the nu-
Significance: The separation of the alleles in the clei of two cells (the egg and the sperm) fused
production of the reproductive cells is a central fea- during sexual reproduction, the association be-
ture of the model of inheritance. The realization tween information transport and chromosome
that the genes are located on chromosomes and that composition was further strengthened. Ger-
chromosomes occur as pairs that separate during man biologist August Weismann, noting that
meiosis provides the physical explanation for the the chromosome number remained constant
basic model of inheritance. When chromosome from generation to generation despite the fus-
structure is modified, changes in information ing of cells, predicted that there must be a cell
transmission produce abnormal developmental division that reduced the chromosome num-
conditions, most of which contribute to early mis- ber in the egg and sperm cells. The reductional
carriages and spontaneous abortions. division, meiosis, was described in 1900.
Following the rediscovery of Gregor Men-
Key terms dels rules of inheritance in 1900, the work of
histones: a class of proteins associated with Theodor Boveri and Walter Sutton led to the
DNA 1903 proposal that the character-determining
homologous chromosomes: chromosomes factors (genes) proposed by Mendel were lo-
that have identical physical structure and cated on the chromosomes and that the factor
contain the same genes; humans have twenty- segregation that was a central part of the model
two pairs of homologous chromosomes and occurred because the like chromosomes of
a pair of sex chromosomes that are only par- each pair separated during the reductional di-
tially homologous vision that occurs in meiosis. This hypothesis,
karyotyping: an analysis or physical descrip- the chromosome theory of heredity, was con-
tion of all the chromosomes found in an or- firmed in 1916 by the observations of the un-
ganisms cells; often includes either a draw- usual behavior of chromosomes and the de-
ing or photograph of the chromosomes termining factors located on them by Calvin
spindle fibers: minute fibers composed of the Bridges.
protein tubulin that are involved in distrib-
uting the chromosomes during cell division Chromosome Structure and Relation to
Inheritance
Discovery of Chromosomes Role in With the discovery of the nucleic acids came
Inheritance speculation about the roles of DNA and the as-
The development of the microscope made it sociated proteins. During the early 1900s, it
possible to study what became recognized as was generally accepted that DNA formed a
the central unit of living organisms, the cell. structural support system to hold critical infor-
One of the most obvious structures within the mation-carrying proteins on the chromosomes.
cell is the nucleus. As study continued, dyes The identification of the structure of DNA in
were used to stain cell structures to make them 1953 by American biologist James Watson and
more visible. It became possible to see colored English physicist Francis Crick and the recogni-
148 Chromosome Structure
ary constrictions are sites of specific gene activ- evidence that these loops represent replication
ity. Both of these regions contain DNA base units along the chromosome, but how the DNA
sequence information that is specific to their molecule is freed from the histone proteins to
functions. be replicated is a major unsolved puzzle.
The condensation of the chromatin is not
Histones uniform over the entire chromosome. In the
The DNA of the chromosomes is wound regions immediately adjacent to the centro-
around special proteins called histones. This mere, the chromatin is tightly condensed and
results in an orderly structure that condenses remains that way throughout the visible cycle.
the DNA mass so that the bulky DNA does not All of the available evidence indicates that this
require as much storage space. The wrapped chromatin does not contain actively expressed
DNA units then fold into additional levels of genes. It also replicates later than the remain-
compaction, by means of a process called con- ing DNA. This more highly condensed chro-
densation. The exact processes involved in these matin is called heterochromatin (the other
higher levels of folding are not fully under- chromatin). The remaining chromatin is re-
stood, but the overall condensation reduces ferred to as euchromatin (true chromatin)
the bulk of the DNA nearly one thousandfold. because it contains actively expressed genes
If the DNA is removed from a condensed chro- and it replicates as a unit.
mosome, the proteins remain and have nearly
the same shape as the chromosome, indicating Giemsa Stain and Chromosome Painting
that it is the proteins that form the chromo- When chromosomes are treated with a dye
some shape. The presence of these proteins called Giemsa stain, regular banding patterns
and the fact that the DNA is wrapped around appear. The bands vary in width, but their posi-
them raises many questions about how the DNA tions on the individual chromosomes are con-
is copied in preparation for cell division and sistent. This makes the bands useful in identi-
how the DNA information is read for gene ac- fying specific chromosome regions. When a
tivity. These are areas of active research. chromosome has a structural modification,
The histone proteins form a structure called such as an inversionwhich results when two
a nucleosome (nuclear body). There are breaks occur and the region is reversed when
four kinds of histones, and two of each kind the fragments are rejoinedthe change in the
join together to form a cylinder-shaped nucleo- banding pattern makes it possible to recognize
some structure. The fibrous DNA molecule where it has occurred. When a loss of a chromo-
wraps around each nucleosome approximately somal region produces a deficiency disorder,
two and one-half times with a sequence of un- changes in the banding patterns of a chromo-
wound DNA between each nucleosome along some can identify the missing region. Karyo-
the entire length of the DNA molecule. The type analysis is a useful tool in genetic counsel-
structure, called chromatin, looks like a string ing because disorders caused by chromosome
of beads when isolated sections are viewed with structure modifications can be identified. Asso-
an electron microscope. When the chromatin is ciations between disorders and missing chro-
digested with enzymes that break the DNA back- mosome regions are useful in identifying which
bone in the unwound regions, repeated lengths functions are associated with specific regions.
of chromatin are recovered, showing that the Other stains produce different banding pat-
nucleosome wrapping is very regular. These terns and, when used in combination with the
nucleosome regions join together to form the Giemsa banding patterns, allow diagnosis of
additional folding as the chromosome con- structure modifications that can be quite com-
denses when the cell prepares for division. plex.
In addition to the histone proteins, nonhis- It is also possible to use fluorescent dyes, in a
tone proteins attach to the chromatin. With an process called chromosome painting, to iden-
electron microscope, chromatin loops can be tify the DNA of individual chromosomes,
seen extending from a protein matrix. There is which allows the recognition of small regions
Internal Structure of a Chromosome
DNA molecule
Chromosome
that have been exchanged between chromo- transmitted. Extreme changes in chromosome
somes that are too small to be recognized oth- structure that result in the moving of informa-
erwise. Color differences within chromosomes tion to another chromosome may have conse-
or at their tips clearly show which chromo- quences for how specific information is ex-
somes have exchanged DNA, how much DNA pressed; a change in position might result in
each has been exchanged, and where on the different regulation or in changes in how the
chromosomes the exchanges have taken place. information is transmitted during meiosis.
Many cancer cells, for example, have multiple Each chromosome has a specific arrange-
chromosome modifications, with DNA from ment of genes. Although homologous chromo-
two or three chromosomes associated in one somes exchange DNA during meiosis, as long
highly modified chromosome structure. as this process occurs normally, the gene ar-
rangement on the chromosomes remains un-
Chromosome Disorders changed. Position affects result when genes are
At the ends of the chromosomes are struc- moved to different regions of the same chro-
tures called telomeres, which are composed of mosome or to another chromosome. A normal
specific repetitive DNA sequences that help allele may show a mutant phenotype expres-
protect the ends of chromosomes from dam- sion in a new position in the chromosome set.
age and prevent DNA molecules from stick- The best-known case occurs when a gene is
ing together. Research that began in the early placed adjacent to a heterochromatic region.
1990s led to the discovery that the telomere re- The relocated DNA is condensed like the
gions of the chromosomes are shortened at heterochromatic-region DNA and normally ac-
each DNA replication. When the telomeres tive genes now remain inactive. Ninety percent
have been reduced to some critical point, the of patients with the disorder chronic myeloge-
cell is no longer able to divide and often dies nous leukemia have an exchange of material
not long after, a phenomenon called apoptosis. called a translocation, between chromosomes
Other observations indicate that the telomere 9 and 22. Chromosome 22 is shorter than nor-
is returned to its normal length in tumor cells, mal and is called the Philadelphia chromo-
suggesting that this might contribute to the some, after the city in which it was discovered.
long life of tumor cells, possibly making them The placing of a specific gene from chromo-
immortal. The relationship of cell age to telo- some 9 within the broken region adjacent to a
mere length and the mechanisms that lead to gene on chromosome 22 causes the uncon-
telomere shortening are not understood clearly, trolled expression of both of the genes and un-
but this is an area of active research because it controlled cell reproduction, the hallmark of
has implications for aging and cancer treat- leukemia.
ment. The separation of like chromosomes during
The DNA of each chromosome carries a meiosis occurs because the two chromosome
unique part of the information code in the se- arms are attached to a specific centromere.
quence of the bases. The specific sequences are When the centromere is moved to one of the
in linear order along the chromosome and poles, the arms are pulled along, ensuring
form linked sequences of genes called linkage movement of all of the material of the paired
groups. When the like chromosomes pair and chromosomes to the opposite poles and inclu-
separate during meiosis, one copy of each chro- sion in the newly formed cells. Translocations
mosome is transmitted to the offspring. During occur when chromosomes are broken and ma-
meiosis, there may be an exchange of material terial is placed in the wrong position by the re-
between the paired chromosomes, but this pair system, causing a chromosome region to
does not change the information content be- become attached to a different centromere.
cause the information is basically the same for This leads to an inability to properly separate
both chromosomes in any region. There may the regions of the arm, which can result in du-
be differences in the coding sequences, but plication of some of the chromosomal regions
functionally the same informational content is (when two copies of the same arm move to one
152 Chromosome Theory of Heredity
cell) or deficiencies (when none of the mate- Campbell, Neil. Biology. 6th ed. San Francisco:
rial from a chromosome arm moves into a cell). Benjamin Cummings, 2001. A college-level
This is a common outcome with translocation biology textbook that provides introductory
heterozygotes (individuals with both normal explanations of chromosomes.
chromosomes and translocated chromosomes Greider, Carol, and Elizabeth Blackburn.
in the same cells). Pairing of like chromosome Telomeres, Telomerase, and Cancer. Scien-
regions occurs, but rather than two chromo- tific American 274 (February, 1996). Contains
somes paired along their entire lengths, the a review of the nature of telomeres and their
arms of the two translocated chromosomes are importance in the lives of cells.
paired with the arms of their normal pairing Russell, Peter. Genetics. 5th ed. Menlo Park, Ca-
partners. The separation of the chromosomes lif.: Benjamin Cummings, 1998. A college-
produces duplications of material from one level textbook with an excellent discussion
chromosome arm or a deficiency of that mate- of chromosome structure and function.
rial 50 percent of the time. If these cells are in- Sharma, Archana, and Sumitra Sen. Chromo-
volved in fertilization, the offspring will show some Botany. Enfield, N.H.: Science Pub-
duplication or deficiency disorders. lishers, 2002. Focuses on the chromosome as
D. B. Benner, updated by Bryan Ness a vehicle of hereditary transmission, cover-
See also: Chromatin Packaging; Cell Cycle, ing topics such as structural details, identifi-
The; Cell Division; Central Dogma of Molecular cation of gene sequences at the chromo-
Biology; Chromosome Mutation; Chromosome some level, specific and genetic diversity in
Theory of Heredity; Chromosome Walking and evolution, and the genome as affected by en-
Jumping; Classical Transmission Genetics; Dihy- vironmental agents.
brid Inheritance; DNA Replication; DNA Struc-
ture and Function; Epistasis; Extrachromo-
somal Inheritance; Incomplete Dominance;
Mendelian Genetics; Mitosis and Meiosis; Mo-
lecular Genetics; Monohybrid Inheritance; Mul- Chromosome Theory of
tiple Alleles; Mutation and Mutagenesis; Non- Heredity
disjunction and Aneuploidy; Parthenogenesis;
Penetrance; Polygenic Inheritance; RNA Struc- Field of study: Classical transmission
ture and Function; Transposable Elements. genetics; History of genetics
Significance: The chromosome theory of heredity
Further Reading originated with American geneticist Walter Sut-
Adolph, Kenneth W., ed. Gene and Chromosome ton, who first suggested that genes were located on
Analysis. 3 vols. San Diego: Academic Press, chromosomes. This theory guided much of genetic
1993-1994. Covers a range of topics, includ- research in the early twentieth century, including
ing cDNA cloning methods, mammalian development of the earliest genetic maps based on
embryogenesis, microcell hybrids, tumor- linkage. In 1931, several experiments confirmed
suppressor genes, prenatal cytogenetics, the chromosome theory by demonstrating that cer-
and the polymerase chain reaction. tain rearrangements of the heritable traits (or
Bickmore, Wendy A. Chromosome Structural genes) were always accompanied by corresponding
Analysis: A Practical Approach. New York: Ox- rearrangements of the microscopically observable
ford University Press, 1999. Describes re- chromosomes.
search on chromatin and chromosome
structure, specifically examining the map- Key terms
ping of protein, a study of whole chromo- crossing over: the breakage of chromosomes
some structure and biochemical techniques followed by the interchange of the resulting
for analyzing the substructure of mamma- fragments; also, the recombination of genes
lian nuclei, and the experimental manipula- that results from the chromosomal rear-
tion of chromosome structure. rangement
Chromosome Theory of Heredity 153
genetic mapping: the locating of gene posi- in pairs? Why do different genes assort inde-
tions along chromosomes pendently? Where are the genes located? An-
independent assortment: the inheritance of swers to these questions were first suggested in
genes independently of one another when 1903 by a young American scientist, Walter
they are located on separate chromosomes Sutton, who had read about the rediscovery of
linkage: the frequent inheritance of two or Mendels work. By this time, it was already well
more genes together as a unit if they are lo- known that all animal and plant cells contain a
cated close together on the same chromo- central portion called the nucleus and a sur-
some rounding portion called the cytoplasm. Divi-
linkage mapping: a form of genetic mapping sion of the cytoplasm is a very simple affair: The
that uses recombination frequencies to esti- cytoplasm simply squeezes in two. The nucleus,
mate the relative distances between linked however, undergoes mitosis, a complex rear-
genes rangement of the rod-shaped bodies called
physical mapping: a form of genetic mapping chromosomes, which exist in pairs. Sex cells
that associates a gene with a microscopically (eggs or sperm) are haploid, with one chro-
observable chromosome location mosome from each pair. All other body cells,
called somatic cells, have a diploid chromo-
Mendels Law of Independent Assortment some number in which all chromosomes are
In a series of experiments first reported in paired. During mitosis, each chromosome be-
1865, Austrian botanist Gregor Mendel estab- comes duplicated; then the two strands (or
lished the first principles of genetics. Mendel chromatids) split apart and separate. One re-
showed that the units of heredity were inher- sult of mitosis is that the chromosome number
ited as particles that maintained their identity of each cell is always preserved. Sutton also no-
across the generations; these units of heredity ticed that eggs in most species are many times
are now known as genes. These genes exist as larger than sperm because of a great difference
pairs in all the bodys cells except for the egg in the amount of cytoplasm. The nuclei of egg
and sperm cells. When Mendel studied two and sperm are approximately equal in size, and
traits at a time (dihybrid inheritance), he dis- these nuclei fuse during fertilization, a process
covered that different genes were inherited in- in which two haploid sets of chromosomes
dependently of one another, a principle that combine to make a complete diploid set. From
came to be called the law of independent as- these facts, Sutton concluded that the genes
sortment. For example, if an individual inherits are probably in the nucleus, not the cytoplasm,
genes A and B from one parent and genes a and because the nucleus divides carefully and ex-
b from the other parent, in subsequent gen- actly while the cytoplasm divides inexactly. Also,
erations the combinations AB, Ab, aB, and ab if genes were in the cytoplasm, one would ex-
would all occur with equal frequency. Gene A pect the mothers contribution to be much
would go together with B just as often as with b, greater than the fathers, contrary to the re-
and gene B would go with A just as often as with peated observation that the parental contribu-
a. Mendels results were ignored for many years tions to heredity are usually equal.
after he published his findings, but his princi- Of all the parts of diploid cells, only the chro-
ples were rediscovered in 1900 by Erich Tscher- mosomes were known to exist in pairs. If genes
mak von Seysenegg in Vienna, Austria, Carl were located on the chromosomes, it would ex-
Erich Correns in Tbingen, Germany, and Hugo plain why they existed in pairs (except singly in
de Vries in Amsterdam, Holland. Organized re- eggs and sperm cells). In fact, the known be-
search in genetics soon began in various coun- havior of chromosomes exactly paralleled the
tries in Europe and also in the United States. postulated behavior of Mendels genes. Sut-
tons hypothesis that genes were located on
Suttons Hypothesis chromosomes came to be called the chromo-
Mendels findings had left certain important some theory of heredity. According to Suttons
questions unanswered: Why do the genes exist hypothesis, Mendels genes assorted indepen-
154 Chromosome Theory of Heredity
ther apart would be more common. Sturtevant (Neurospora crassa). In bacteria such as Escheri-
first used this technique in 1913 to determine chia coli, other methods of genetic mapping
the relative positions of six genes on one of the were developed based on the order in which
chromosomes of Drosophila. For example, the genes were transferred during bacterial conju-
genes for white eyes and vermilion eyes recom- gation. These mapping techniques reveal that
bined about 30 percent of the time, and the the genes in bacteria are arranged in a circle or,
genes for vermilion eyes and miniature wings more precisely, in a closed loop resembling a
recombined about 3 percent of the time. Re- necklace. This loop can break at any of several
combination between white eyes and minia- locations, after which the genes are transferred
ture wings took place 34 percent of the time, from one individual to another in the order of
close to the sum of the two previously men- their location along the chromosome. The or-
tioned frequencies (30 percent plus 3 per- der can be determined by interrupting the pro-
cent). Therefore, the order of arrangement of cess and testing to see which genes had been
the genes was: transferred before the interruption.
dictions of both genetic and chromosomal re- the color of the seed coat while the other pro-
sults. These studies greatly strengthened the duced either a starchy or waxy kernel. The pa-
case for the chromosomal theory. rental gene combinations (C with wx on the ab-
In 1931, Harriet Creighton and Barbara Mc- normal chromosome and c with Wx on the
Clintock were able to confirm the chromo- other chromosome) were always preserved in
somal theory of inheritance much more di- noncrossovers. However, a crossover between
rectly. Creighton and McClintock used corn the two genes produced two new gene combi-
plants whose chromosomes had structural ab- nations: C with Wx and c with wx.
normalities on either end, enabling them to In this cross, Creighton and McClintock ob-
recognize the chromosomes under the micro- served that the chromosomal appearance in
scope. One chromosome, for example, had a the offspring could always be predicted from
knob at one end and an attached portion of an- the phenotypic appearance: Seeds with color-
other chromosome at the other end, as shown less seed coats and starchy kernels had normal
in the figure headed Creighton and McClin- chromosomes, seeds with colored seed coats
tocks Cross. Creighton and McClintock then and waxy kernels had chromosomes with the
crossed plants differing in two genes located knob at one end and the extra interchanged
along this chromosome. One gene controlled chromosome segment at the other end, seeds
with colorless seed coats and waxy kernels had related to a genetic map based on linkage.
the interchanged segment but no knob, and Larger chromosome abnormalities included
seeds with colored coats and starchy kernels had inversions, in which a segment of a chromo-
the knob but not the interchanged segment. In some was turned end-to-end, and transloca-
other words, whenever the two genes showed tions, in which a piece of one chromosome be-
rearrangement of the parental combinations, came attached to another. There were also
a corresponding switch of the chromosomes abnormalities in which entire chromosomes
could be observed under the microscope. The were missing or extra chromosomes were pres-
interchange of chromosome segments was al- ent. Each of these chromosomal abnormalities
ways accompanied by the recombination of was accompanied by corresponding changes in
genes, or, in the words of the original paper, the genetic maps based on the frequency of re-
combination between linked genes. In cases in
cytological crossing-over . . . is accompanied by which the location of a chromosomal abnor-
the expected types of genetic crossing-over. . . . mality could be identified microscopically, this
Chromosomes . . . have been shown to exchange permitted an anchoring of the genetic map to a
parts at the same time they exchange genes as- physical location along the chromosome. The
signed to these regions.
correspondence between genetic maps and
chromosomal abnormalities provided impor-
In short, genetic recombination (the rearrang- tant additional evidence in support of the chro-
ing of genes) was always accompanied by mosomal theory. Other forms of physical map-
crossing-over (the rearranging of chromo- ping were developed decades later in mammals
somes). This historic finding established firm and bacteria. The increasingly precise map-
evidence for the chromosomal theory of he- ping of gene locations led the way to the devel-
redity. Later that same year, Curt Stern pub- opment of modern molecular genetics, includ-
lished a paper describing a very similar experi- ing techniques for isolating and sequencing
ment using fruit flies. individual genes.
The discovery of restriction endonuclease
Physical Mapping and Further enzymes during the 1970s allowed geneticists
Confirmation to cut DNA molecules into small fragments. In
Other evidence that helped confirm the 1980, a team headed by David Botstein mea-
chromosome theory came from the study of sured the sizes of these restriction fragments
rare chromosome abnormalities. In 1933, and found many cases in which the length of
Thomas S. Painter called attention to the large the fragment varied from person to person be-
salivary gland chromosomes of Drosophila. Ex- cause of changes in the DNA sequence. This
amination of these large chromosomes made type of variation is generally called a poly-
structural abnormalities in the chromosomes morphism. In this case, it was a polymorphism
easier to identify. When small segments of a in the length of the restriction fragments
chromosome were missing, a gene was often (known as a restriction fragment length poly-
found to be missing also. These abnormalities, morphism, or RFLP). The use of the RFLP
called chromosomal deletions, allowed the first technique has allowed rapid discovery of the
physical maps of genes to be drawn. In all cases, location of many human genes. The Human
the physical maps were found to be consistent Genome Project (an effort by scientists world-
with the earlier genetic maps (or linkage maps) wide to determine the location and sequence
based on the frequency of crossing over. of every human gene) would never have been
When Bridges turned his attention to the proposed had it not been for the existence of
bar eyes trait in fruit flies, he discovered that this mapping technique.
the gene for this trait was actually another kind Eli C. Minkoff
of chromosome abnormality called a duplica- See also: Cell Division; Chromosome Muta-
tion. Again, a chromosome abnormality that tion; Chromosome Structure; Classical Trans-
could be seen under the microscope could be mission Genetics; Genetic Code; Genetic Code,
158 Chromosome Walking and Jumping
Cracking of; Linkage Maps; Mendelian Genet- Scriver, Charles, et al., eds. The Metabolic and
ics; Mitosis and Meiosis; Model Organism: Dro- Molecular Bases of Inherited Disease. 8th ed. 4
sophila melanogaster; Restriction Enzymes; RFLP vols. New York: McGraw-Hill, 2001. An au-
Analysis; Transposable Elements. thority on heredity of disease and genetic in-
heritance, covering genetic perspectives, ba-
Further Reading sic concepts, how inherited diseases occur,
Botstein D., R. L. White, M. Skolnick, and R. W. diagnostic approaches, and the effects of
Davis. Construction of a Genetic Linkage hormones.
Map in Man Using Restriction Fragment Suzuki, D. T., et al. An Introduction to Genetic
Length Polymorphisms. American Journal of Analysis. 7th ed. New York: W. H. Freeman,
Human Genetics 32, no. 3 (1980): 314-331. 2000. A classic text updated to include dis-
Botsteins initial paper on the RFLP tech- cussions of the latest advances in genetics re-
nique. search.
Carlson, E. A. The Gene: A Critical History. 1966.
Reprint. Ames: Iowa State University Press,
1989. A classic text that examines the major
theories from the early to mid-twentieth cen-
tury concerning the structure of the gene. Chromosome Walking and
Cummings, Michael J. Human Heredity: Princi- Jumping
ples and Issues. 5th ed. Pacific Grove, Calif.:
Brooks/Cole, 2000. College text that surveys Fields of study: Genetic engineering and
topics such as genetics as a human endeavor; biotechnology; Techniques and
cells, chromosomes, and cell division; trans- methodologies
mission of genes from generation to genera- Significance: Chromosome walking and jumping
tion; cytogenics; the source of genetic varia- are mapping methods used to find defective genes
tion; cloning and recombinant DNA; genes that cause hereditary diseases. Walking is a much
and cancer; genetics of behavior; and genes slower process, whereas jumping has cut down the
in populations. time it takes to locate defective genes sometimes by
Lewin, B. Genes VII. New York: Oxford Univer- years. These techniques assist in curing diseases,
sity Press, 2001. Provides an integrated ac- seeking preventive measures, and detecting genetic
count of the structure and function of genes carriers.
and incorporates all the latest research in
the field, including topics such as accessory Key terms
proteins (chaperones), the role of the genomic library: a group of cloned DNA frag-
proteasome, reverse translocation, and the ments representative of an organisms ge-
process of X chromosome inactivation. nome
More than eight hundred full color illustra- kilobase pairs (kb): a measurement of 1,000
tions. base pairs in DNA
Peters, James A., ed. Classic Papers in Genetics. marker: a unique DNA sequence with a known
Englewood Cliffs, N.J.: Prentice-Hall, 1959. location with respect to other markers or
Includes many of the classic papers that con- genes
tributed to chromosomal theory, including
those in which Mendel established the prin- Gene Hunting
ciples of genetics, Sutton first proposed the Several geneticists autonomously recog-
chromosomal theory of heredity, Sturtevant nized the possibilities of chromosome walking
produced the first genetic map based on and jumping to locate genes. Hans Lehrach
linkage, and Creighton and McClintock suggested such techniques at the European
confirmed that the recombination of linked Molecular Biology Laboratory, and Sherman
genes always took place by a process that also Weissman posed similar methods at Yale Uni-
rearranged the chromosomes. versity. Weissmans student Francis S. Collins
Chromosome Walking and Jumping 159
elaborated his mentors chromosome-jumping time, because chromosome jumping uses much
concepts. Interested in identifying disease- larger fragments. Chromosome jumping is
causing genes, Collins sought to examine siz- achieved by selecting a large DNA segment
able areas of genetic material for unknown from the area where geneticists believe the de-
genes believed to be responsible for triggering sired gene is located and joining the ends to
erratic biochemical behavior. His novel explor- form a circle. This moves DNA sequences to-
atory method enabled researchers to span gether that naturally would occur at distances
chromosomes expeditiously and bypass repeti- of several kilobases. Researchers cut out and
tive or insignificant genetic information. clone these junctions to form libraries. They
Investigators have adopted the chromosome- use probes from the DNA sample to seek clones
jumping procedure as a reliable, efficient mo- with matching start and end sequences and
lecular biology tool. Gene searching became jump along the chromosome. After each jump,
less time-consuming and resulted in the identi- bidirectional walking is often done in the new
fication of defective genes that code for abnor- region. A combination of chromosome jump-
mal proteins and cause such diseases as cystic ing and walking can be done until the gene is
fibrosis. Understanding the nature of such mu- found.
tations makes the development of treatments
and cures more likely and can lead to the ability Gene Discovery
to detect the presence of the mutated gene in Chromosome walking to find the gene for
carriers. cystic fibrosis, CF, would have required eigh-
teen years, while chromosome jumping re-
Procedure duced that time to four years. Collaborating
Geneticists initiate chromosome walking and with Lap-Chee Tsui and researchers at To-
jumping by collecting genetic samples from rontos Hospital for Sick Children, Collins ex-
people who have a specific disease and from amined DNA from patients suffering from cys-
their close relatives. For walking, researchers tic fibrosis. Tsui realized that the CF gene was
select a cloned DNA fragment from a genomic located on chromosome 7. That chromosome
library that contains the marker closest to the consists of 150 million DNA base pairs. Using
gene being sought. A small part of the cloned markers Tsui made from chromosome 7 library
DNA fragment that is on the end nearest the fragments, researchers, applying chromosome
gene being sought is subcloned. The subcloned jumping, scanned the genetic material to tar-
fragment is then used to screen the genomic li- get where they should use chromosome walk-
brary for a clone with a fragment closer to the ing to find the CF gene.
gene. Then a small part of this new cloned frag- They discovered the CF gene in 1989. Analy-
ment is subcloned to be used to screen for the sis revealed that mutation is a deletion of DNA
next closer fragment. This series of steps is re- base pairs. This gene codes the cystic fibrosis
peated as many times as needed, until a frag- transmembrane conductance regulator (CFTR)
ment is found that appears to contain a gene. protein. Tsui determined that the shape of
This fragment is carefully analyzed, and if it CFTR and how it functions are affected by the
does contain the gene of interest, the process is mutated genes coding. The abnormal CFTR is
halted; if not, chromosome walking is contin- unable to create a release channel to remove
ued. Chromosome walking is slow, and repeti- chloride and sodium from cells. Mucus builds
tive DNA sequences or regions that do not ap- up, adhering to lungs and organs, and bacteria
pear in the library can halt the process. proliferate. Cystic fibrosis is the most frequent
Geneticists choose chromosome jumping to fatal hereditary disease in Caucasians. Geneti-
maneuver to genes more quickly and to bypass cists estimate that one in twenty-five white Amer-
troublesome regions of DNA. Using chromo- icans has a recessive CF gene, and one in two
some jumping, researchers can travel the same thousand white babies are born with cystic fi-
distance they can using chromosome walk- brosis. Internationally, researchers associated
ingand fartherin one step requiring less with Tsuis Toronto-based consortium continue
160 Classical Transmission Genetics
cross: the mating of parents to produce off- the same number and kinds of chromosomes,
spring during sexual reproduction and since each parent transmits one complete
gene: a sequence of base pairs that specifies a set of the chromosomes, it was thought that
product (either RNA or protein); the aver- there must be a process of cell division that re-
age gene in bacteria is one thousand base duces the parent number from two sets of chro-
pairs long mosomes to one set in the production of the
linkage: a relation of gene loci on the same egg or sperm cells. The parents would each
chromosome; the more closely linked two have twenty-three pairs (forty-six) chromo-
loci are, the more often the specific traits somes, but their reproductive cells would each
controlled by these loci are expressed to- contain only one of each chromosome (twenty-
gether three).
meiosis: the process of nuclear division during In the 1860s, the Austrian botanist Gregor
sexual reproduction that produces cells that Mendel repeated studies of inheritance in the
contain half the number of chromosomes as garden pea and, using the results, developed a
the original cell model of genetic transmission. The signifi-
sexual reproduction: reproduction that re- cance of Mendels work was not recognized
quires fusion of haploid gametes, each of during his lifetime, but it was rediscovered in
which contains one copy of the respective 1900. In that same year, the predicted reduc-
parents genes, as a first step tional cell division during reproduction was
fully described, and the science of genetics was
Discovery of Transmission Genetics born.
The desire to improve plant and animal pro-
duction is as old as agriculture. For centuries, A Study of Variation
humans have been using selective breeding In many respects, genetics is the study of
programs that have resulted in the production variation. It is recognized that a particular fea-
of thousands of varieties of plants and breeds of ture of an animal or plant is inherited because
animals. The Greek philosopher-scientist Hip- there is variation in the expression of that fea-
pocrates suggested that small bits of the body of ture, and variation in expression follows a rec-
the parent were passed to the offspring during ognizable inheritance pattern. For example, it
reproduction. These small bits of arms, heads, is known that blood types are inherited, both
stomachs, and livers were thought to develop because there is variation (blood types A, B,
into a new individual. Following the develop- and O) and because examination of family his-
ment of the microscope, it became possible to tories reveals patterns that show transmission
see the cells, the small building blocks of living of blood-type information from parents to chil-
organisms. Study of the cell during the 1800s dren.
showed that sexual reproduction was the result Variation in character expression may have
of the fusion of specialized cells from two par- one of two sources: environmental conditions
ents (eggs and sperm). It was also observed that or inherited factors. If a plant is grown on poor
these cells contained chromosomes (color soil, it might be short. The same plant grown on
bodies visible when the cells reproduced) and good soil might be tall. A plant that is short be-
that the number and kind of these chromo- cause of an inherited factor cannot grow tall
somes was the same in both the parents and the even if it is placed on richer soil. From this ex-
offspring. This suggested that the chromo- ample, it can be seen that there may be two dif-
somes carried the genetic information and that ferent ways to determine whether a specific
each parent transmitted the same number and character expression is environmentally or ge-
kinds of chromosomes. For example, humans netically determined: testing for environmen-
have twenty-three kinds of chromosomes. The tal influences and testing for inherited factors.
offspring receives one of each kind from each Many conditions are not so easily resolved as
parent and so has twenty-three chromosome this example; there may be many complex envi-
pairs. Since the parents and the offspring have ronmental factors involved in producing a con-
162 Classical Transmission Genetics
dition, and it would be impossible to test them ents in a cross have two different versions of the
all. Knowledge of inheritance patterns can, gene for the same characteristic. If, for exam-
however, help in determining whether inher- ple, one parent has the height genes tall/short
ited factors play a role in a condition. Cancer- and the other has the genes short/short, the
associated genes have been located using fam- cells produced by the tall/short parent will be
ily studies that show patterns consistent with a of two kinds: 1 2 carry the tall gene and 1 2 carry
genetic contribution to the disease. There are the short gene. The other parent has only one
certainly environmental factors that influence kind of gene for height (short), so all of its re-
cancer production, but those factors are not as productive cells will contain that gene. The off-
easily recognized. spring will be of two kinds: 1 2 will have both
The patterns of transmission genetics were genes (tall/short), and 1 2 will have only one
discovered because the experimenters focused kind of gene (short/short). Had it been known
their attention on single, easily recognized that the one parent had one copy for each ver-
characteristics. Mendel carefully selected seven sion of the gene, it could have been predicted
simple characteristics of the pea plant, such as that the offspring would have been of two kinds
height of the plant, color of the flower, and and that each would have an equal chance of
color of the seeds. The second reason for suc- appearing. Had it not been known that one of
cess was the use of carefully controlled crosses. the parents had the two versions of the gene,
The original parents were selected from variet- the appearance of two kinds of offspring would
ies that did not show variations in the charac- have revealed the presence of both genes. The
teristic of interest. For example, plants from a patterns are repeatable and are therefore use-
pure tall variety were crossed with plants from a ful in predicting what might happen or reveal-
pure short variety. Control of the information ing what did happen in a particular cross. For
passed by the parents allowed the experi- example, blood-type patterns or DNA variation
menter to follow the variation of expression patterns can be used to identify the children
from parents to offspring through a number of that belong to parents in kidnapping cases or
generations. in cases in which children are mixed up in a
hospital.
Transmission Patterns In a second example, the pattern is more
The classic genetic transmission pattern is complex, because both parents carry both ver-
the passing of information for each character- sions of the gene: a tall/short to tall/short
istic from each parent to each offspring. The cross. Each parent will produce 1 2 tall-gene-
offspring receives two copies of each gene. carrying cells and 1 2 short-gene-carrying cells.
(The term gene is used to refer to a character- Any cell from one parent may randomly join
determining factor; Mendels original termi- with any cell from the other parent, which
nology was factor.) Each parent also had two leads to the following patterns: 1 2 tall 1 2 tall =
copies of each gene, so in the production of the 4 tall/tall; 2 tall 2 short = 4 tall/short;
1 1 1 1
gene, the ratio could have been predicted; con- somes come together. This joining (pairing)
versely, by using the observed ratio, the informa- appears to specify that each chromosome in
tion content of the parents could be deduced. the pair will become attached to a motor unit
Using a blood-type example, if one parent has from an opposite side of the cell that will move
blood-type genes AO and the other parent has the chromosomes to opposite sides of the cell
the genes BO, the possible combinations ob- during cell division. The result is two new cells,
served in their offspring would be AB, AO, BO, each with only one of the chromosomes of the
and OO, each with the same probability of oc- original pair. This process is repeated for each
currence (1 2 A gene-bearing and 1 2 O gene- pair of chromosomes in the set.
bearing cells in one parent 1 2 B gene-bearing
and 1 2 O gene-bearing cells in the other par- Independent Genes
ent). Humans have practiced selective breeding
of plants and animals for centuries, but it was
Reductional Division only during the nineteenth and twentieth cen-
Transmission genetics allows researchers to turies that the patterns of transmission of in-
make predictions about specific crosses and ex- herited characters were understood. This
plains the occurrence of characteristic expres- change occurred because the experimenters
sions in the offspring. In genetic counseling, focused on a single characteristic and could un-
probabilities of the appearance of a genetic dis- derstand the pattern for that characteristic.
ease can be made when there is an affected Previous attempts had been unsuccessful be-
child in the family or a family history of the con- cause the observers attempted to explain a
dition. This is possible because, for most inher- large number of character patterns at the same
ited characteristics, the pattern is established time. Mendel expanded his model of transmis-
by the reduction of chromosome numbers that sion to show how observations become more
occurs when the reproductive cells are pro- complex as the number of characteristics ex-
duced and by the random union of reproduc- amined is expanded. Consider a plant with
tive cells from the two parents. The recognition three chromosomes and one simple character
that the genes are located on the chromosomes gene located on each chromosome. In the first
and the description of the reductional division parent, chromosome 1 contains the gene for
in which the like chromosomes separate, carry- tall expression, chromosome 2 contains the
ing the two copies of each gene into different gene for expression of yellow seed color, and
cells during the reductional division of meiosis, chromosome 3 contains the gene for purple
provide the basis of the regularity of the trans- flower color. In the other parent, chromosome
mission pattern. It is this regularity that allows 1 contains a gene for short height, chromo-
the application of mathematical treatments to some 2 contains a gene for green seed color,
genetics. Two genes are present for each char- and chromosome 3 contains a gene for white
acter in each individual, but only one is passed flower color. Each parent will transmit these
to each offspring by each parent; therefore, the genes to their offspring, who will have the
50 percent (or 1 2) probability becomes the basis genes tall/short, yellow/green, and purple/
for making predictions about the outcome of a white. In the production of reproductive cells,
cross for any single character. the reductional division of meiosis will pass on
The classical pattern of transmission genet- one of the character expression genes for each
ics occurs because specialized reproductive of the three characters. (It is important to re-
cells, eggs and sperm, are produced by a special member that the products of the reductional
cell reproduction process (meiosis) in which cell division have one of each chromosome. If
the chromosome number is reduced from two this did not occur, information would be lost,
complete sets to one set in each of the cells that and the offspring would not develop normally.)
result from the process. This reduction results The characteristics are located on different
because each member of a pair of chromo- chromosomes, and during the division process,
somes recognizes its partner, and the chromo- these chromosome pairs act independently.
164 Classical Transmission Genetics
This means that the genes that came from any which genes for thousands of different charac-
one parent (for example, the tall height, yellow ters are being transmitted.
seed, and purple flower expression genes from
the one parent) do not have to go together dur- Continuous Variation
ing the division process. Since chromosome The principles of transmission genetics were
pairs act independently, different segregation established by studying characters with discrete
patterns occur in different cells. The results expressionsplants were tall or dwarf, seeds
from one meiosis may be a cell with the tall, were yellow or green. In 1903, Danish geneti-
green, and purple genes and one with the cist Wilhelm Johannsen observed that charac-
short, yellow, and white genes. In the same teristics that showed continuous variation,
plant, another meiosis might produce a cell such as weight of plant seeds, fell into recog-
with the short, yellow, and purple genes, and nizable groups that formed a normal distri-
the second cell would have the tall, green, and bution. These patterns could also be explained
white genes. by applying the principles of transmission ge-
Since these genes are independent, height netics.
does not influence seed color or flower color, Assume a plant has two genes that influence
nor does flower color influence seed color or its height and that these genes are on two dif-
height. The determining gene for each charac- ferent chromosomes (for example, 1 and 3).
teristic is located on a different chromosome, Each gene has two versions. A tall gene stimu-
so the basic transmission model can be applied lates growth (increases the height), but a short
to each gene independently, and then the inde- gene makes no contribution to growth. A plant
pendent patterns can be combined. The tall/ with the composition tall-1/tall-1, tall-3/tall-3
short height genes will segregate so that 1 2 of would have a maximum height because four
the cells will contain the tall gene and 1 2 will genes would be adding to the plants height. A
contain the short gene. Likewise, the yellow/ short-1/short-1, short-3/short-3 plant would
green seed color genes will separate so that 1 2 of have minimum height because there would be
the cells will contain the yellow gene and 1 2 will no contribution to its height by these genes.
contain a green gene. Finally, 1 2 of the cells will Plants could have two contributing genes (tall-
contain a purple flower gene and 1 2 will contain 1/short-1, tall-3/short-3) or three contributing
a white gene. These independent probabilities genes (tall-1/short-1, tall-3/tall-3). The num-
can be combined because the probability of ber of offspring with each pattern would be de-
any combination is the product of the indepen- termined by the composition of the parents
dent probabilities. For example, the combina- and would be the result of gene segregation
tion tall, purple, white will occur with a proba- and transmission patterns. Many genes con-
bility of 1 2 1 2 1 2 = 1 8. This means that one tributing to a single character expression apply
should expect eight different combinations of to many interesting human characteristics,
these characters. The possible number of com- such as height, intelligence, amount of skin
binations for n chromosome pairs is 2n. For hu- pigmentation, hair color, and eye color.
mans, this means that any individual may pro-
duce 223 different chromosome combinations. Linkage Groups
This is the same idea as tossing three coins si- Mendels model of the transmission of genes
multaneously. Each coin may land with a head was supported by the observations of chromo-
or a tail up, but how each coin lands is indepen- some pair separation during the reductional
dent of how the other coins land. Knowledge of division, but early in the twentieth century, it
transmission patterns based on chromosome was recognized that some genes did not sepa-
separation during meiosis allows researchers to rate independently. Work in American geneti-
explain the basic pattern for a single genetic cist Thomas Hunt Morgans laboratory, espe-
character, but it also allows researchers to ex- cially by an undergraduate student, Alfred
plain the great variation that is observed Sturtevant, showed that each chromosome
among individuals within a population in contained determining genes for more than
Classical Transmission Genetics 165
one characteristic and established that genes markers have now been identified, which, in
located close together on the same chromo- theory, should greatly enhance the techniques
some stayed together during the separation of used to locate a faulty gene.
the paired chromosomes during meiosis. If a D. B. Benner
pea plant had a chromosome with the tall See also: Cell Division; Chromosome Muta-
height gene and, immediately adjacent to it, a tion; Chromosome Structure; Chromosome
gene for high sugar production, and if the Theory of Heredity; Dihybrid Inheritance; Epi-
other version of this chromosome had a gene stasis; Extrachromosomal Inheritance; Genetic
for short height and a gene that limited the Code; Genetic Code: Cracking of; Hybridiza-
sugar production, the most likely products tion and Introgression; Incomplete Dominance;
from meiosis would be two kinds of cells: one Lamarckianism; Linkage Maps; Mendelian Ge-
with the genes for tall height and high sugar netics; Mitochondrial Genes; Mitosis and Meio-
production and one with the genes for short sis; Monohybrid Inheritance; Multiple Alleles;
height and limited sugar production. These Nondisjunction and Aneuploidy; Parthenogen-
genes are said to be linked, or closely associ- esis; Penetrance; Polygenic Inheritance.
ated on the same chromosome, because they
go together as the chromosomes in the pair Further Reading
separate. It is generally accepted that humans Cummings, Michael J. Human Heredity: Princi-
contain approximately 21,000 genes, but there ples and Issues. 5th ed. Pacific Grove, Calif.:
are only twenty-three kinds of chromosomes. Brooks/Cole, 2000. College text that surveys
This means that each chromosome contains topics such as genetics as a human endeavor;
many different genes. Each chromosome is cells, chromosomes, and cell division; trans-
considered a linkage group, and one of the mission of genes from generation to genera-
goals of genetic study is to locate the gene re- tion; cytogenics; the source of genetic varia-
sponsible for each known characteristic to its tion; cloning and recombinant DNA; genes
proper chromosome. and cancer; genetics of behavior; and genes
A common problem in medical genetics is in populations.
locating the gene for a specific genetic disease. Gonick, Larry, and Mark Wheelis. The Cartoon
Family studies may show that the disease is Guide to Genetics. New York: Harper Peren-
transmitted in a pattern consistent with the nial, 1991. An easy-to-read presentation of
gene being on one of the chromosomes, but the basic concepts of transmission genetics.
there is no way of knowing its location. Varia- Lewis, Ricki. Human Genetics: Concepts and Appli-
tions in DNA structure are also inherited in the cations. 5th ed. New York: McGraw-Hill,
classic pattern, and these DNA pattern modifi- 2003. An introductory text for undergradu-
cations can be determined using modern mo- ates with sections on fundamentals, trans-
lecular procedures. DNA variation patterns are mission genetics, DNA and chromosomes,
analyzed for linkage to the disease condition. If population genetics, immunity and cancer,
a specific DNA pattern always occurs in individ- and the latest genetic technology.
uals with the disease condition, it indicates that Moore, John A. Science as a Way of Knowing. Re-
the DNA variation is on the same chromosome print. Cambridge, Mass.: Harvard University
and close to the gene of interest because it is Press, 1999. Traces the development of sci-
transmitted along with the disease-producing entific thinking with an emphasis on under-
gene. This information locates the chromo- standing hereditary mechanisms.
some position of the gene, allowing further Stansfield, William D. Schaums Outline of Theory
work to be done to study its structure. With the and Problems of Genetics. 3d ed. New York:
completion of the Human Genome Project, it McGraw-Hill, 1991. Provides explanations of
is predicted that tracking down the genes re- basic genetics concepts and an introduction
sponsible for genetic defects will be a much to problem solving.
faster process than before. Many more genetic
166 Cloning
Types of Cloning
Cloning There are three different definitions of a
clone. One is a group of genetically identical
Field of study: Genetic engineering and cells descended from a single common ances-
biotechnology tor. This type of clone is often made by plant
Significance: Cloning includes both gene cloning cell tissue culture in which a whole line of cells
and organismal cloning. Gene cloning, an impor- is made from a single cell ancestor. A second
tant technique for understanding how cells work, type of clone is a gene clone, or recombinant
has produced a multitude of useful products, in- DNA clone, in which copies of a DNA sequence
cluding human medicines. Organismal cloning are made by genetic engineering. A third type
includes reproductive cloning and therapeutic clon- of clone is an organism that is descended asex-
ing. Ethical and safety concerns have led to a con- ually from a single ancestor. A much-celebrated
sensus that human cloning should be banned, but example of an organismal clone is the sheep
therapeutic cloning is more controversial, since it Dolly (1997-2003), produced by placing the
could lead to treatments for many human diseases. nucleus of a cell from an ewes udder, with its
genetic material (DNA), into an unfertilized
Key terms egg from which the nucleus had been re-
cloning vector: a plasmid or virus into which moved.
foreign DNA can be inserted to amplify the
number of copies of the foreign DNA in the
host cell or organism DNA Cloning
DNA: dexoyribonucleic acid, a long-chain mac- DNA is cloned to obtain specific pieces of
romolecule, made of units called nucleo- DNA that are free from other DNA fragments.
tides and structured as a double helix joined Clones of specific pieces of DNA are important
by weak hydrogen bonds, that forms genetic for basic research. Once a piece of DNA is
material for most organisms cloned, it can be sequenced (to determine the
DNA hybridization: formation of a double- order of the four repeating nucleotides) to
stranded nucleic acid molecule from single- learn the details of genes within that DNA.
stranded nucleic acid molecules that have Where does the gene begin and end? What
complementary base sequences type of control regions does the gene have?
ligase: an enzyme that joins recombinant Cloned DNAs can be used as hybridization
DNA molecules together probes, where sequences that are complemen-
plasmid: a DNA molecule that replicates inde- tary to the cloned DNA can be detected. Such
pendently of chromosomes DNA hybridization is useful to detect similari-
recombinant DNA technology: methods ties between genes from different organisms,
used to splice a DNA fragment from one or- to detect the presence of specific disease genes,
ganism into DNA from another organism and to determine in what tissues that gene is ex-
and then clone the new recombinant DNA pressed. The gene is expressed when a messen-
molecule ger RNA (mRNA) is made from the gene and
reproductive cloning: cloning to produce the mRNA is translated into a protein product.
individual organisms A DNA clone is also used to produce the pro-
restriction enzyme: a protein (an enzyme) tein product for which that gene codes. When a
that recognizes a specific nucleotide se- clone is expressed, the protein made by that
quence in a piece of DNA and causes a gene can be studied or an antibody against that
sequence-specific cleavage of the DNA protein can be made. An antibody is used to
stem cells: cells that are able to divide indefi- show in which tissues of an organism that pro-
nitely in culture and to give rise to special- tein is found. Also, a DNA clone may be ex-
ized cells pressed because the gene codes for a useful
theraputic cloning: cloning to produce a product. This is a way to obtain large amounts
treatment for a disease of the specific protein.
Cloning 167
These five cows on an Iowa farm in April, 2000, were cloned by Robert Lanza and colleagues of Advanced Cell Technologies in
Worcester, Massachusetts. The cows cellsunlike those of the first cloned vertebrate, Dolly the sheepappeared to have a prolonged
youth. (AP/Wide World Photos)
168 Cloning
give rise to the hundreds of types of specialized bills that approve of embryonic stem cell re-
cells that comprise the adult body. Embryonic search. Such research might lead to treatments
stem cells can be isolated from three- to five- for diseases such as Parkinsons, diabetes, and
day-old embryos. Some tissues in the adult, Alzheimers. The research is controversial be-
such as bone marrow, brain, and muscle, con- cause embryos must be destroyed to obtain the
tain adult stem cells that can give rise to cell stem cells, and some groups believe that consti-
types of the tissue in which they reside. tutes taking a human life. The embryos used
A goal of research on stem cells is to learn are generally extra embryos left over from in vi-
how stem cells become specialized cells. Hu- tro fertilizations. In December, 2002, and Janu-
man stem cells could be used to generate tis- ary, 2003, a company called Clonaid announced
sues or organs for transplantation and to gen- the births of several babies they claimed were
erate specific cells to replace those damaged as the result of human cloning but then failed to
a result of spinal cord injury, stroke, burns, to produce any scientific evidence that the ba-
heart disease, diabetes, osteoarthritis, rheuma- bies were clones. February, 2003, the U.S. Con-
toid arthritis, and other conditions. gress considered a ban on both reproductive
and therapeutic cloning. In late February, the
Regulation of Organismal Cloning House passed the Human Prohibition Cloning
Until the cloning of the sheep Dolly in 1997, Act of 2003, banning the cloning of human be-
it was thought that adult specialized cells could ings but allowing limited research on some ex-
not be made to revert to nonspecialized cells isting stem cell lines.
that can give rise to any type of cell. However, The tension between scientific possibility,
Dolly was created from a specialized adult cell public policy, and societal values continues in
from a ewes udder. After the publicity about the arena of cloning. Through therapeutic
Dolly, U.S. president Bill Clinton asked the Na- cloning there is great potential for the treat-
tional Bioethics Advisory Commission to form ment of human diseases, but the ethical con-
recommendations about the ethical, religious, cerns about such procedures must be carefully
and legal implications of human cloning. In considered as well.
June, 1997, that commission concluded that at- Susan J. Karcher
tempts to clone humans are morally unaccept- See also: Animal Cloning; Biopharmaceuti-
able for safety and ethical reasons. There was a cals; Cloning: Ethical Issues; Cloning Vectors;
moratorium on using federal funds for human DNA Replication; DNA Sequencing Technol-
cloning. In January, 1998, the U.S. Food and ogy; Gene Therapy; Gene Therapy: Ethical and
Drug Administration (FDA) declared that it Economic Issues; Genetic Engineering; Ge-
had the authority to regulate human cloning netic Engineering: Agricultural Applications;
and that any human cloning must have FDA ap- Genetic Engineering: Historical Development;
proval. Genetic Engineering: Industrial Applications;
While there is general agreement in the Genetic Engineering: Medical Applications; Ge-
United States and in many other countries that netic Engineering: Risks; Genetic Engineering:
reproductive human cloning should be banned Social and Ethical Issues; Genetically Modified
because of ethical and safety concerns, there is (GM) Foods; Knockout Genetics and Knockout
ongoing debate about whether or not to allow Mice; Plasmids; Polymerase Chain Reaction;
therapeutic cloning to treat human disease or Restriction Enzymes; Reverse Transcriptase;
research cloning to study how stem cells de- Shotgun Cloning; Stem Cells; Synthetic Genes;
velop. The Human Cloning Prohibition Act of Transgenic Organisms; Xenotransplants.
2001 to ban both reproductive and therapeutic
cloning passed in the U.S. House of Represen- Further Reading
tatives, but the Senate did not support the ban. Boylan, Michael. Genetic Engineering. Chap-
The ban was again considered by the lawmak- ter 6 in Medical Ethics, edited by Michael
ers in 2002. In the meantime, individual states Boylan. Upper Saddle River, N.J.: Prentice
such as California and New Jersey have passed Hall, 2000. Considers the ethical concerns
170 Cloning: Ethical Issues
Cuttings can be removed from many species vast quantities of protein-based therapeutic
and induced to make roots. These cuttings are drugs. Commercial animals that are top pro-
then grown into full-size, genetically identical ducers, such as cows with high milk yields,
copies of the parent plant. The emergence of could also be cloned. Human replacement or-
crops that cannot be propagated in the stan- gans could be grown in precisely controlled en-
dard fashion, such as seedless navel oranges, vironments.
has led to whole groves of cloned siblings. Few However, cloning, if misapplied, has fright-
would suggest that such cloning is inherently ening possibilities in the minds of many. Al-
wrong or unethical. Animal cloning has been though only science fiction now, it is possible to
quietly occurring since the early 1990s. Eggs envision a future world of human clones de-
fertilized in vitro are allowed to develop to the signed to fill certain roles, as genetically pro-
eight-cell stage, at which point the cells are sep- grammed soldiers, workers, or even an elite so-
arated. Each individual cell then develops into ciety of perfect cloned individuals. Others
an embryo that is implanted in a female. Thus, have envisioned the possibility of cloning an ex-
a single zygote can be used to make eight iden- tra copy of themselves as donors of perfectly
tical individuals. This type of cloning has been matched organs during old age. Even the possi-
used routinely in animal husbandry to propa- bility that individuals might be cloned without
gate desirable genetic traits. their knowledge or permission has been antici-
In 1996, a team of scientists in Scotland pated.
headed by Ian Wilmut cloned a mammala
sheep named Dollyfrom adult cells for the Human Cloning
first time. While bioethicists had seen no wrong Something about human cloning chafes at
in cloning orange trees and embryonic mam- the human conscience. Bioethicist Karen Roth-
mals, they were troubled by the cloning of a enberg, in statements delivered to the U.S. Sen-
sheep. It is important to realize that the cloning ates Public Health and Safety Subcommittee
of Dolly was not the key bioethical issue. of the Labor and Human Resources Commit-
Rather, the issue that worried the ethicists was tee in the 1990s, suggested why society is made
the implication of the clones existence: that uneasy by the potential implications of human
scientists were only a small step away from clon- cloning. She broke her argument down into
ing a human. If bioethics is concerned with three Is. The first I is interdependence. Clon-
protecting the evolution of future generations ing makes humans uneasy because it requires
of humans, did the cloning of Dolly represent a only one parent. People are humbled because
potential threat? Could the natural progress of it takes two humans to produce a baby. If part of
humans toward an unknown evolutionary fu- the definition of humanity is the interdepen-
ture be sidetracked or derailed by the interven- dence upon one another to reproduce, then a
tion and effects of cloning? What would be the cloned human begs the question of just what is
social ramifications of human cloning? Would human. Rothenbergs second I is indetermi-
it have the potential to change humanity as it is nateness. Cloning removes all randomness
now known forever? Was cloning simply from human reproduction. With cloning, peo-
wrong? Christian bioethicists, for example, ple predetermine whether they want to repro-
were troubled by the implications of humans duce any physical or mental type available.
being able to manipulate themselves in this They can control all possible genetic variables
way, many considering it morally wrong. in cloning with a predicted outcome. However,
Many scientists, including Wilmut, were does the same genetic variability that decides
quick to point out that they would never sup- ones hereditary fate at conception also define
port human cloning but did not believe that some part of humanity? The last I is individual-
cloning itself was unethical. Most ethicists ity. It is disconcerting for people to imagine
agreed that cloning animals could help human ten or one hundred copies of themselves walk-
society in many ways. Genetically engineered ing around. Twins and triplets are common
animals had the potential to be used to create now, but what would such a vast change mean
172 Cloning: Ethical Issues
Chief executive of Clonaid Brigitte Boisselier (left) and the founder of the Raelian movement, Claude Vorilhon, announced in Janu-
ary, 2003, the birth of a human clone, as well as imminent births of other cloned children. Physical evidence and independent confir-
mation of the cloning were never offered and the announcement was concluded to be a hoax, but in the wake of media attention the is-
sue of human cloning became the focus of renewed public debate. (AP/Wide World Photos)
to individuality and the concept of the human worry. Many nonscientists miss the point that a
soul? In closing, Rothenberg asked whether clone is simply a genetically identical copy, not
the potential benefits of any scientific innova- a copy in every aspect. If someone were to have
tion [are] outweighed by its potential injury to cloned Albert Einstein, the cloned Einstein
our very concept of what it means to be hu- would not be identical behaviorally or in other
man. ways to the original. What made Einstein who
Andrew Scott of the Urban Institute takes a he was involved not merely his genes but also
different view. He believes that bioethics does his many life experiences, which are impossible
not apply to cloning but only to what happens to duplicate in a clone. The same would be true
after cloning. Cloning does not present a moral of a cloned child brought to life by grieving par-
dilemma to Scott, assuming that the process ents who have lost their original child in an ac-
does not purposely create abnormalities. cident. The clone would be like a twin, not the
Scott states that the clone [would] simply be same child.
another, autonomous human being . . . carry- Perhaps the right questions are not being
ing the same genes as the donor, and [living] asked. Better questions may be: Can humans be
life in a normal, functional way. He suggests trusted not to abuse the technology of cloning?
that as long as clones are not programmed to Can those in positions of power be trusted not
be human drones and are not used in an un- to use cloning to their advantage and the en-
ethical way, cloning should not be a bioethical dangerment of humanity? Probably the most
Cloning: Ethical Issues 173
basic question is, What compelling reason is makes each cell the potential equivalent of a
there to clone a human in the first place? Carl fertilized egg. While respect for life is renewed
B. Feldbaum, the president of the Biotechnol- from this insight, life is simultaneously cheap-
ogy Industry Organization, believes that peo- ened. If each cell contains all the genetic infor-
ple should be wary of anyone who asks them to mation needed to create a new individual, then
allow human cloning and states: what is a single cell worth among millions of
copies? The answer may be very little. When
In the future, society may determine that there one million or one hundred million potential
are sound reasons to clone certain animals to im-
copies exist, then one copy is worth almost
prove the food supply, produce biopharmaceuti-
cals, provide organs for transplantation and aid
nothing. Therefore, the two contrary feelings
in research. I can think of no ethical reason to ap- of reverence and irreverence linger side by
ply this technique to human beings, if in fact it side. The question one must ask is, Which will
can be applied. win out in the end?
James J. Campanella, updated by Bryan Ness
The ethical issues are even more compli- See also: Animal Cloning; Bioethics; Bio-
cated than they first appear. Is the actual pro- logical Weapons; Cloning; Cloning Vectors; Eu-
cess of cloning, as performed by Wilmut, ethi- genics; Eugenics: Nazi Germany; Gene Ther-
cal if applied to humans? Wilmuts cloning apy; Gene Therapy: Ethical and Economic
process produced many failures before Dolly Issues; Genetic Engineering: Medical Applica-
was conceived; only she survived of her 277 tions; Genetic Engineering: Risks; Genetic En-
cloned sisters. Her early death at the age of six gineering: Social and Ethical Issues; Genetics
was also potentially precipitated by the cloning in Television and Films; Knockout Genetics
process. Bioethicists question whether manipu- and Knockout Mice; Polymerase Chain Reac-
lating human embryos to produce clones with tion; Restriction Enzymes; Reverse Transcrip-
only a 0.4 percent success rate is moral; to tase; Shotgun Cloning; Stem Cells; Synthetic
someone who believes that human life begins Genes; Transgenic Organisms; Xenotrans-
at conception, the cloning procedure as per- plants.
formed by Wilmut would almost certainly be
unacceptable. Further Reading
Of course, these questions remain irrelevant Andrews, Lori B. The Clone Age: Adventures in the
in most of the world. As of 2003, many devel- New World of Reproductive Technology. New
oped nations had banned human cloning, in- York: Henry Holt, 1999. A lawyer specializ-
cluding the United States. There is also some ing in reproductive technology, Andrews ex-
question as to whether the technology has pro- amines the legal ramifications of human
gressed enough to make human cloning possi- cloning, from privacy to property rights.
ble. Some believe the technology has reached Baudrillard, Jean. The Vital Illusion. Edited by
this point and that cloning has been attempted Julia Witwer. New York: Columbia University
secretly, at least somewhere in the world. A few Press, 2000. A sociological perspective on
even speculate that somewhere it might have al- what human cloning means to the idea of
ready succeeded. Geneticists in several labora- what it means to be human.
tories have carried out human cloning through Bonnicksen, Andrea L. Crafting a Cloning Policy:
the very early stages of embryogenesis, but From Dolly to Stem Cells. Washington, D.C.:
there is no official case where it has been ac- Georgetown University Press, 2002. Political
complished to the point of a healthy child be- and policy issues surrounding human clon-
ing born. ing.
Cloning offers a new and perhaps frighten- Brannigan, Michael C., ed. Ethical Issues in Hu-
ing view of life and the biological universe and man Cloning: Cross-Disciplinary Perspectives.
brings with it a renewed respect for life. If al- New York: Seven Bridges Press, 2001. A col-
most any cell in the body can be used as the ba- lection of writings from a broad variety of
sis to clone an entirely new organism, this Western and non-Western traditions and per-
174 Cloning Vectors
kinds of enzymes: restriction enzymes and DNA kind is the lacZ gene, which encodes the en-
ligases. The plasmid DNA sequence must have zyme beta-galactosidase. This enzyme breaks
unique sites for restriction enzymes to cut. Cut- the disaccharide lactose into two monosaccha-
ting the double-stranded circular DNA at more rides. The pUC plasmid vector has a copy of the
than one site would cut the plasmid into pieces lacZ gene which has been carefully engineered
and would separate important functional parts to contain a multiple cloning site within it,
from one another. However, when a
restriction enzyme cuts the circular
plasmid at one unique site, it converts
it to a linear molecule. Linear, insert Cut DNA
molecules
DNA molecules, produced by cutting with restriction
DNA with the same restriction en- enzyme to Chromosomal DNA
zyme as was used to cut the plasmid generate Fragment
complementary to Be Cloned
vector, can be joined to cut plasmid sequences on
molecules using the enzyme DNA Vector DNA the vector and
ligase. This catalyzes the covalent join- the fragment
ing of the insert DNA and plasmid
DNA ends to create a circular, recom-
binant plasmid molecule. Most clon-
ing vectors have been designed to
Join vector and chromosomal
have many unique restriction enzyme DNA fragment, using
cutting sites all in one stretch of the the enzyme DNA ligase
vector sequence. This part of the vec-
tor is referred to as the multiple clon-
ing site.
In addition to an origin of replica-
tion and a multiple cloning site, most
vectors have a third element: a selec-
tive marker. In order for the vector to
replicate, it must be present inside
an appropriate host cell. Introducing
Recombinant DNA Molecule
the vector into cells is often a very in-
efficient process. Therefore, it is very Introduce into bacterium
useful to be able to select, from a
large population of host cells, those
rare cells that have taken up a vec-
tor. This is the role of the selectable
marker. The selectable marker is usu-
ally a gene that encodes resistance to Recombinant
DNA Molecule
an antibiotic to which the host is nor-
mally sensitive. For example, if a plas-
Bacterial
mid vector has a gene that encodes re- Chromosome
sistance to the antibiotic ampicillin,
only those E. coli cells that harbor a
Segments of DNA from any organism can be cloned by inserting the DNA
plasmid will be able to grow on media segment into a plasmida small, self-replicating circular molecule of DNA
containing ampicillin. separate from chromosomal DNA. The plasmid can then act as a cloning
Many vectors have an additional se- vector when it is introduced into bacterial cells, which replicate the plasmid
lective marker that is rendered inac- and its foreign DNA. This diagram from the Deparment of Energys Hu-
tive when a plasmid is recombinant. A man Genome Program site illustrates the process. (U.S. Department of
commonly used marker gene of this Energy Human Genome Program, http://www.ornl.gov/hgmis.)
176 Cloning Vectors
while maintaining the functionality of the ex- proteins needed to make a completed phage
pressed enzyme. When a DNA fragment is in- particle. In many cases, the final step of viral in-
serted into the multiple cloning site, the lacZ fection is the lysis of the host cell. This releases
gene is no longer capable of making functional the mature phage particles to infect nearby
beta-galactosidase. This loss of function can be host cells. Phage vectors have two advantages
detected by putting X-gal into the growth me- relative to plasmid vectors: First, viral delivery
dia. X-gal has a structure similar to lactose but of recombinant DNA to host cells is much more
cannot be broken down by beta-galactosidase. efficient than the transformation or electro-
Rather, beta-galactosidase modifies X-gal and poration procedures used to introduce plas-
produces a blue color. Thus, colonies of the mid DNA into host cells, and second, phage
bacterium E. coli containing recombinant plas- vectors can be used to clone larger fragments of
mids will be normal colored, whereas those insert DNA.
that have normal, nonrecombinant plasmids Viruses that infect cells other than bacteria
will be blue. Typical selection media then con- have been modified to serve as cloning vectors.
tain ampicillin and X-gal. The ampicillin only This permits cloning experiments using many
allows E. coli which contain a plasmid to grow, different kinds of host cells, including human
and the X-gal identifies which colonies have re- cells. Viral vectors, just like the natural viruses
combinant plasmids. from which they are derived, have specific host
There are a number of procedures for intro- and tissue ranges. A particular viral vector will
ducing the plasmid vector into the host cell. be limited for use in specific species and cell
Transformation is a procedure in which the types. The fundamental practice of all virally
host cells are chemically treated so that they based cloning vectors involves the covalent join-
will allow small DNA molecules to pass through ing of the insert DNA to the viral DNA to make
the cell membrane. Electroporation is a proce- a recombinant DNA molecule, introduction of
dure that uses an electric field to create pores the recombinant DNA into the appropriate
in the host cell membrane to let small DNA host cell, and then propagation of the vector
molecules pass through. through the natural mechanism of viral repli-
cation. There are two fundamentally different
Viruses and Cloning Vectors ways that viruses propagate in cells. Many vi-
In addition to plasmid cloning vectors, some ruses, such as the phages already described, en-
bacteriophages (or phages) have been modi- ter the host cell and subvert the cells biosyn-
fied to serve as cloning vectors. Bacteriophages, thetic machinery to its own reproduction, which
like other viruses, are infectious agents that are ultimately leads to lysis and thereby kills the
made of a genome, either DNA or RNA, that is host cell as the progeny viruses are released.
surrounded by a protective protein coat. Phage The second viral life strategy is to enter the host
vectors are used similarly to the way plasmid cell and integrate the viral DNA into the host
vectors are used. The vector and insert DNAs cell chromosome so that the virus replicates
are cut by restriction enzymes so that they sub- along with the host DNA. Such integrating vi-
sequently can be joined by DNA ligase. The ruses can be stably maintained in the host cell
newly formed recombinant DNA molecules for long periods. The retroviruses, of which
must enter an appropriate host cell to repli- the human immunodeficiency virus (HIV) is
cate. In order to introduce the phage DNA into an example, are a group of integrating viruses
cells, a whole phage particle must be built. This that are potentially useful vectors for certain
is referred to as packaging the DNA. The pro- gene therapy applications. Using cloning vec-
tein elements of the phage are mixed with the tors and host cells other than bacteria allows
recombinant phage DNA and packaging en- scientists to produce some proteins that bacte-
zymes to create an infectious phage particle. ria cannot properly make, permits experiments
Appropriate host cells are then infected with it. to determine the function of cloned genes,
The infected cells then make many copies of and is important for the development of gene
each recombinant molecule, along with the therapy.
Cloning Vectors 177
Two species of naturally occurring plant pathogenic of plant hormones and other compounds that cause
bacteria, Agrobacterium tumefaciens and Agrobacterium the plant cells to grow abnormally near the infection
rhizogenes, infect many plant species and have been site, producing characteristic tumors.
harnessed through biotechnology to effect per- Purposeful genetic transformation of plants re-
manent genetic transformation of plants. Virulent quires a tool that can be used to insert new genes into
(disease-causing) Agrobacterium species can infect a plant. This tool, regardless of its derivation, is
plants and transfer a small portion of their own bac- called a vector. To date, the most common means for
terial DNA, called T-DNA (transferred DNA), into stable genetic transformation of plants involves the
the plant. The T-DNA is actually a small fragment of use of vectors derived from bacteria of the genus Ag-
a large (approximately 200-kilobase-pair) plasmid robacterium. Biotechnologists have harnessed Agro-
called the Ti (tumor-inducing) plasmid in A. tume- bacterium to insert new genes of interest into plants by
faciens and the Ri (root-inducing) plasmid in A. rhizo- modifying the T-DNA segment of the bacterial DNA
genes. using standard recombinant methods. By deleting
The T-DNA fragment of the Ti plasmid is defined the genes on the T-DNA that cause tumors and then
on both ends by 24-base-pair direct repeat sequences inserting desirable genes in their place, a wide vari-
called the left-hand and right-hand border se- ety of vectors can be produced to transfer desirable
quences. The T-DNA fragment is released from the genes into plants. The genes transferred by way of
plasmid by the action of endonucleases, which cut Agrobacterium vectors become a permanent part of
the DNA at specific points within the right-hand and the plants genome. DNA from plants, animals, bac-
left-hand border sequences. The endonucleases are teria, and viruses can be introduced into plants in
two of the Vir (virulence) genes encoded on the Ti this way.
plasmid adjacent to the T-DNA. Several other Vir One major drawback of Agrobacterium transforma-
genes are produced when Agrobacterium cells are in- tion is that insertion of T-DNA into the plant genome
troduced into plant tissue, usually through a wound. is essentially random. The genes on the T-DNA seg-
Following infection of a plant, Agrobacterium cells ment may not be efficiently transcribed at their loca-
sense the presence of phenolic wound compounds tion or the insertion of T-DNA may knock out an im-
and the acidic environment within wounded plant portant plant gene by inserting in the middle of it.
tissues. These conditions trigger a series of several Therefore, a plant genetically transformed using an
Vir genes to produce Vir proteins that direct exci- Agrobacterium vector is not necessarily guaranteed to
sion of the T-DNA and facilitate transport and incor- perform as desired. A final drawback is that the vec-
poration of the T-DNA segment into the plants ge- tor works only with dicots, while many of the worlds
nome. Once the T-DNA is incorporated into the most important crops are monocots, such as wheat,
plant genome, expression of the T-DNA-encoded rice, corn, and many other grain crops.
genes causes the plant to produce unusual quantities Robert A. Sinnott
they can be produced much more cheaply in natural chromosomes are. YAC cloning tech-
bacteria. An added benefit of expression vec- nology allows very large chromosomes to be
tors is that actual human proteins are pro- subdivided into a manageable number of
duced by bacteria and therefore do not pro- pieces that can be organized (mapped) and
voke allergic reactions as frequently as insulin studied. YACs also provide the opportunity to
that is isolated from other species. study DNA sequences that interact over very
long distances. Since the development of YACs,
Artificial Chromosomes artificial chromosome vectors for a number of
In 1987, a new type of cloning vector was de- different host cells have been created.
veloped by David Burke, Maynard Olson, and
their colleagues. These new vectors, artificial Impact and Applications
chromosomes, filled the need created by the Cloning vectors are one of the key tools of re-
Human Genome Project (HGP) to clone very combinant DNA technology. Cloning vectors
large insert DNAs (hundreds of thousands to make it possible to isolate particular DNA se-
millions of base pairs in length). One of the quences from an organism and make many
goals of the HGPto map and ultimately se- identical copies of this one sequence in order
quence all the chromosomes of humans, as well to study the structure and function of that se-
as a number of other model organisms ge- quence apart from all other DNA sequences.
nomic sequencesrequired a vector capable Until the development of the polymerase chain
of propagating much larger DNA fragments reaction (PCR), cloning vectors and their host
than plasmid or phage vectors could propa- cells were the only means to collect many cop-
gate. The first artificial chromosome vector was ies of one particular DNA sequence. For long
developed in the yeast Saccharomyces cerevisiae. DNA sequences (those over approximately ten
All the critical DNA sequence elements of a thousand base pairs), cloning vectors are still
yeast chromosome were identified and iso- the only means to do this.
lated, and these were put together to create a Gene therapy is a new approach to treating
yeast artificial chromosome (YAC). The ele- and perhaps curing genetic disease. Many com-
ments of a YAC vector are an origin of replica- mon diseases are the result of defective genes.
tion, a centromere, telomeres, and a selectable Gene therapy aims to replace or supplement
marker suitable for yeast cells. A yeast origin of the defective gene with a normal, therapeutic
replication (similar to the origin of replication gene. One of the difficulties faced in gene ther-
of bacterial plasmids) is a short DNA sequence apy is the delivery of the therapeutic gene to
that the hosts replicative enzymes, such as the appropriate cells. Viruses have evolved to
DNA polymerase, recognize as a site to initiate enter cells, sometimes only a very specific sub-
DNA replication. In addition to replicating, the set of cells, and deliver their DNA or RNA ge-
new copies of a chromosome must be faithfully nome into the cell for expression. Thus viruses
partitioned into daughter cells during mitosis. make attractive vectors for gene therapy. An
The centromere sequence mediates the parti- ideal vector for gene therapy would replace vi-
tioning of the chromosomes during cell divi- ral genes associated with pathogenesis with
sion because it serves as the site of attachment therapeutic genes; the viral vector would then
for the spindle fibers in mitosis. Telomeres are target the therapeutic genes to just the right
the DNA sequences at the ends of chromo- cells. One of the concerns related to the use of
somes. They are required to prevent degrada- viral vectors for gene therapy is the random na-
tion of the chromosome and for accurate repli- ture of the viral insertion into the target cells
cation of DNA at the ends of chromosomes. chromosomes. Insertion of the vector DNA
YACs are used much as plasmid vectors are. into or near certain genes associated with in-
Very large insert DNAs are joined to the YAC creased risk of cancer could theoretically alter
vector, and the recombinant molecules are in- their normal expression and induce tumor for-
troduced into host yeast cells in which the artifi- mation.
cial chromosome is replicated just as the hosts Plasmid DNA vectors encoding immuno-
Color Blindness 179
genic proteins from pathogenic organisms are Cohen, Philip. Creators of the Forty-seventh
being tested for use as vaccines. DNA immuni- Chromosome. New Scientist 34 (November
zation offers several potential advantages over 11, 1995). Describes the efforts to develop
traditional vaccine strategies in terms of safety, human artificial chromosomes.
stability, and effectiveness. Genes from disease- Friedmann, Theodore. Overcoming the Ob-
causing organisms are cloned into plasmid ex- stacles. Scientific American 96 (June, 1997).
pression vectors that provide the regulatory Elaborates on the relative merits of different
signals for efficient protein production in hu- delivery systems for gene therapy.
mans. The plasmid DNA is inoculated intra- Hassett, Daniel E., and J. Lindsay Whitton.
muscularly or intradermally, and the muscle or DNA Immunization. Trends in Microbiology
skin cells take up some of the plasmid DNA and 307 (August, 1996). Reviews the process of
express the immunogenic proteins. The im- DNA immunization and compares it to tradi-
mune system then generates a protective im- tional vaccination strategies.
mune response. There are two traditional vac- Jones, P., and D. Ramji. Vectors: Cloning Appli-
cination strategies: One uses live, attenuated cations and Essential Techniques. New York:
pathogenic organisms, and the other uses killed J. Wiley, 1998. A laboratory manual that al-
organisms. The disadvantage of the former is lows quick and easy access to the key proto-
that, in rare cases, the live vaccine can cause dis- cols required by those working with vectors.
ease. The disadvantage of the latter strategy is Lu, Quinn, and Michael P. Weiner, eds. Cloning
that the killed organism does not enter the pa- and Expression Vectors for Gene Function Analy-
tients cells and make proteins like the normal sis. Natick, Mass.: Eaton, 2001. Reprints forty-
pathogen. Therefore, one part of the immune three articles from the journal BioTechnique
response, the cell-mediated response, is usually to provide an overview of topics such as clon-
not activated, and the protection is not as good. ing vectors and strategies, protein expression
In DNA immunization, the plasmids enter the and purification, gene tagging and epitope
patients cells, and the immunogenic proteins tagging strategies, and special purpose vec-
produced there result in a complete immune tors.
response. At the same time, there is no chance Watson, James, et al. Recombinant DNA. New
that DNA immunization will cause disease, be- York: W. H. Freeman, 1992. Nobel laureate
cause the plasmid vector does not carry all of Watson uses accessible language and dia-
the disease-causing organisms genes. grams to address the methods, underlying
Craig S. Laufer, updated by Bryan Ness concepts, and far-reaching applications of
See also: Animal Cloning; Biopharmaceuti- recombinant DNA technology. An excellent
cals; Cloning; Cloning: Ethical Issues; DNA reference for details on how the different
Replication; DNA Sequencing Technology; cloning vectors work and to what purposes
Gene Therapy; Genetic Engineering; Genetic each is particularly suited.
Engineering: Medical Applications; Genetic
Engineering: Risks; Genomic Libraries; Knock-
out Genetics and Knockout Mice; Plasmids;
Polymerase Chain Reaction; Protein Synthesis;
Restriction Enzymes; Reverse Transcriptase;
Color Blindness
Shotgun Cloning; Stem Cells; Synthetic Genes; Field of study: Diseases and syndromes
Telomeres; Transgenic Organisms; Xenotrans- Significance: Color blindness is a condition in peo-
plants. ple whose eyes lack one or more of the three color re-
ceptors present in most human eyes. It is an impor-
Further Reading tant condition to understand because so many
Anderson, W. French. Gene Therapy. Scien- people experience it to some degree. It is also a win-
tific American 124 (September, 1995). Pro- dow into the inner workings of the eye and a mar-
vides a good review of the promises and velous example of the workings of Mendelian ge-
problems of gene therapy. netics.
180 Color Blindness
netic information for the pigments in L and M Nathans, Jeremy. The Genes for Color Vi-
cones lies on the X chromosome. sion. In The Science of Color. Vol. 2 in Readings
The gene structures for M-cone and L-cone on Color, edited by Alex Byrne and David R.
pigments are 96 percent the same, so it is likely Hilbert. Cambridge, Mass.: MIT Press, 1997.
that one began as a mutation of the other. An account of how the genes for color blind-
Small mutations in either gene can slightly shift ness were discovered, for students with a
the color of peak absorption in the cones and good science background. Includes a series
produce an anomalous trichromat. Generally of color plates.
these mutations make M and L cones more Rosenthal, Odeda, and Robert H. Phillips.
alike. The similarity between the genes and the Coping with Color Blindness. Garden City Park,
fact that they are adjacent to each other on the N.Y.: Avery, 1997. A description of color
X chromosome can lead to a variety of copying blindness aimed at nonspecialists and cover-
errors during meiosis. People with normal color ing causes, testing, and coping strategies.
vision have one L-cone gene and one to three Wagner, Robert P. Understanding Inheri-
M-cone genes. The complete omission of ei- tance: An Introduction to Classical and Mo-
ther type of gene will result in severe red-green lecular Genetics. In The Human Genome Pro-
color blindness: protanopia or deuteranopia. ject: Deciphering the Blueprint of Heredity, edited
Hybrid genes that are a combination of L-cone by Necia Grant Cooper. Mill Valley, Calif.:
and M-cone genes lead to less severe types of University Science Books, 1994. A superb,
red-green color blindness, especially if there is well-illustrated discussion of Mendelian ge-
also a normal copy of the gene present. netics and disorders.
Red-green color blindness follows an X-gene
recessive inheritance pattern. Suppose that Web Sites of Interest
Grandfather has a defective X gene (and is Causes of Color. http://webexhibits.org/causes
therefore color blind) and Grandmother is ofcolor. A good introduction to light and
normal. Their male children are normal be- color, including the genetics of color blind-
cause they inherited their X genes from their ness. Includes demonstrations of how a scene
mother, but their female children will be carri- looks to people with different types of color
ers because they had to inherit one X gene blindness and how color blindness tests are
from their father. If the daughters married nor- constructed.
mal men, 50 percent of the grandsons got the Howard Hughes Medical Institute, Seeing,
defective gene from their mothers and were Hearing, and Smelling the World. http://
color blind, and 50 percent of the grandsons www.hhmi.org/senses. Site that includes the
were normal. Likewise, 50 percent of the articles Color Blindness: More Prevalent
granddaughters were normal and 50 percent Among Males and How Do We See Colors?
inherited the defective gene from their moth-
ers and became carriers.
Charles W. Rogers
See also: Classical Transmission Genetics; Complementation Testing
Congenital Defects; Dihybrid Inheritance; He-
reditary Diseases; Monohybrid Inheritance. Field of study: Techniques and
methodologies
Further Reading Significance: Complementation testing is used to
Hsia, Yun, and C. H. Graham. Color Blind- determine whether or not two mutations occur
ness. In The Science of Color. Vol. 2 in Readings within the same gene.
on Color, edited by Alex Byrne and David R.
Hilbert. Cambridge, Mass.: MIT Press, 1997. Key terms
A description of the genetics of color blind- allele: a form of a gene; each gene (locus) in
ness for students with a good science back- most organisms occurs as two copies called
ground. Includes a series of color plates. alleles
182 Complementation Testing
cistron: a unit of DNA that is equivalent to a several genes. Mutations at any one of these
gene; it encodes a single polypeptide genes may produce the same mutant pheno-
inborn errors of metabolism: conditions type. If the same mutant phenotype is observed
that result from defective activity of an en- in two different strains of an organism, there is
zyme or enzymes involved in the synthesis, no way, using simple observation, to determine
conversion, or breakdown of important mol- whether this shared mutant phenotype repre-
ecules within cells sents a mutation in the same or different genes,
locus (pl. loci): the location of a gene, often or loci. One way of solving this problem is
used as a more precise way to refer to a gene; through complementation testing. If the muta-
each locus occurs as two copies called alleles tions are alleles of the same locus, then a cross
between mutant individuals from the two strains
Finding Mutations will only produce offspring with the mutant
Most traits are the result of products from phenotype. In genetic terms, they fail to com-
Complementation
MALE FEMALE
Two genes (boxes) reside on one chromosome. Each parent has two copies of every
chromosome. The male parent is homozygous for a mutation in gene a (white box);
the female is homozygous for a mutation in gene b (gray box).
The offspring has one non-mutated copy of each gene and as a consequence has a
wildtype phenotype. The mutations therefore are said to complement each other.
Complementation Testing 183
plement each other and are therefore mem- genes required for a particular pathway. These
bers of the same complementation group. If studies formed the basis for the one gene-one
from the same cross, all the offspring are nor- enzyme hypothesis: Each gene encodes a sin-
mal; the two mutations are at the same locus gle enzyme required for a single step in a meta-
and they are said to complement each other. bolic pathway. This hypothesis has since been
Researchers often want to define multiple al- renamed the one gene-one polypeptide hy-
leles of a single gene in order to understand the pothesis because some enzymes consist of
genes function better. multiple polypeptides, each of which is en-
Often a researcher is interested in the ge- coded by a single gene.
netic control of a particular biological process,
such as the biochemistry of eye color in fruit The Biochemical Basis for
flies. As a first step, researchers often screen Complementation Testing
large numbers of individuals to find abnormal Complementation testing is useful for locat-
phenotypes involving the process in which they ing and identifying the genes affected by reces-
are interested. For instance, researchers study- sive or loss-of-function alleles. A researcher
ing eye color in fruit flies may screen hundreds crosses two organisms that are each homozy-
of thousands of fruit flies for abnormal eye col- gous for a recessive mutation. If these two al-
ors. Complementation testing is then used to leles affect the same gene, they will not comple-
organize the mutations into complementation ment each other, because the first-generation
groups. (F1) offspring will inherit one mutant copy of
the gene from one parent and a second mutant
Complementation Testing and Inborn copy of the gene from the other parent, thus
Errors of Metabolism having no normal copies of the gene. If the mu-
Human genetic diseases that affect the func- tations are alleles of two different genes, genes
tion of cellular enzymes are known as inborn A and B, the F1 offspring will receive a normal
errors of metabolism and were defined by Sir copy of A and a mutant copy of B from one par-
Archibald Garrod long before DNA was deter- ent and a mutant copy of A and a normal copy
mined to be the hereditary material. Garrod of B from the other, thus having one normal
studied families with alkaptonuria, a disease that copy of each of the two genes and having a wild-
causes urine to turn dark upon exposure to air. type (normal) phenotype. The mutations are
He determined that this biochemical defect said to complement each other.
was inherited in a simple Mendelian fashion. If a scientist is interested in a particular
George Beadle and Edward Tatum studied gene, obtaining as many alleles of that gene as
mutant strains of Neurospora and expanded on possible will lead to a better understanding of
Garrods work. They used radiation to gener- how the gene works and what parts of the gene
ate random mutations that resulted in strains are essential for function. One way to identify
of Neurospora that could not grow without spe- new alleles of a gene is through an F1 noncom-
cific nutritional supplements (essentially creat- plementation screen. In this type of screen, the
ing yeast with inborn errors of metabolism). researcher treats the model organism with radi-
Some of the mutant strains required the addi- ation or chemicals to increase the rate of muta-
tion of a specific amino acid to the media. Each tion. Any individuals from the screen that seg-
mutant strain had its own specific require- regate the desired phenotype (white eyes, for
ments for growth, and each strain was shown to example) in a Mendelian fashion are crossed
have a single defective step in a metabolic path- with individuals carrying a known mutation in
way. When strains that had different defects the gene of interest. If the progeny of this cross
were grown together, they were able to correct have white eyes (the mutant phenotype), then
each others metabolic defect. This correction the two mutations have failed to complement
was termed metabolic complementation. each other and are most likely alleles of the
Using complementation tests, Beadle and same gene. Such noncomplementation screens
Tatum were able to establish the number of have been used to identify genes involved in a
184 Complete Dominance
wide variety of processes ranging from embryo locus (pl. loci): a gene, located at a specific lo-
development in fruit flies to spermatogeneis in cation on a chromosome, which in humans
Caenorhabditis elegans. and many other organisms occurs in the
Michele Arduengo and Bryan Ness same location on homologous chromo-
See also: Biochemical Mutations; Chemical somes
Mutagens; Chromosome Mutation; Inborn Er- phenotype: the observed expression of a gene
rors of Metabolism; Linkage Maps; Mutation locus in an individual
and Mutagenesis; Model Organism: Caenorhab-
ditis elegans; Model Organism: Neurospora crassa. The Discovery and Definition of
Dominance
Further Reading Early theories of inheritance were based on
Hartl, D. L. Genetics: Analysis of Genes and Ge- the idea that fluids carrying materials for the
nomes. 5th ed. Boston: Jones and Bartlett, production of a new individual were transmit-
2001. An excellent introductory genetics ted to offspring from the parents. It was as-
textbook. sumed that substances in these fluids from the
Lewin, Benjamin. Genes VII. New York: Oxford two parents mixed and that the children would
University Press, 2001. Includes a summary therefore show a blend of the parents charac-
of complementation and a discussion of com- teristics. For instance, individuals with dark hair
plementation in bacterial systems as well. mated to individuals with very light hair were
expected to produce offspring with medium-
colored hair. The carefully controlled breeding
studies carried out in the 1700s and 1800s did
Complete Dominance not produce the expected blended phenotypes,
but no other explanation was suggested until
Field of study: Classical transmission Gregor Mendel proposed his model of inheri-
genetics tance. In the 1860s, Mendel repeated studies
Significance: Complete dominance represents one using the garden pea and obtained the same re-
of the classic Mendelian forms of inheritance. In sults seen by other investigators, but he counted
an individual that is heterozygous for a trait, the the numbers of each type produced from each
allele that displays complete dominance will deter- mating and developed his theory based on
mine the phenotype of the individual. Knowing those observations.
whether the pattern of expression of a trait is domi- One of the first observations Mendel dealt
nant or recessive helps in making predictions con- with was the appearance of only one of the pa-
cerning the inheritance of a particular genetic con- rental traits in the first generation of offspring
dition or disorder in a familys history. (the first filial, or F1, generation). For example,
a cross of tall plants and dwarf plants resulted
Key terms in offspring that were all tall. Mendel proposed
alleles: different forms of a gene at a specific that the character expression (in this case
locus; for each genetic trait there are typi- height) was controlled by a determining fac-
cally two alleles in most organisms, includ- tor, later called the gene. He then proposed
ing humans that there were different forms of this control-
genotype: a description of the alleles at a gene ling factor corresponding to the different ex-
locus pressions of the characteristic and termed these
heterozygote: an individual with two differ- alleles. In the case of plant height, one allele
ent alleles at a gene locus produced tall individuals and the other pro-
homozygote: an individual with two like al- duced dwarf individuals. He further proposed
leles at a gene locus that in the cross of a tall (D) plant and a dwarf
incomplete dominance: the expression of a (d) plant, each parent contributed one factor
trait that results when one allele can only for height, so the offspring were Dd. (Upper-
partly dominate or mask the other case letters denote dominant alleles, while low-
Complete Dominance 185
ercase letters denote recessive alleles.) These variations in phenotype expression and to ex-
plants contained a factor for both the tall ex- plain why a dominant allele behaves the way it
pression and the dwarf expression, but the does at the functional level. An enzymes func-
plants were all tall, so tall was designated the tion is determined by its structure, and that
dominant phenotype for the height trait. structure is coded for in the genetic informa-
Mendel recognized from his studies that the tion. The simplest situation is one in which the
determining factors occurred in pairseach gene product is an enzyme that acts on a spe-
sexually reproducing individual contains two cific chemical reaction that results in a specific
alleles for each inherited characteristic. When chemical product, the phenotype. If that en-
he made his crosses, he carefully selected pure zyme is not present or if its structure is modified
breeding parents that would have two copies of so that it cannot properly perform its function,
the same allele. In Mendels terminology, the then the chemical action will not be carried
parents would be homozygous: A pure tall par- out. The result will be an absence of the normal
ent would be designated DD, while a dwarf par- product and a phenotype expression that var-
ent would be designated dd. His model also ies from the normal expression. For example,
proposed that each parent would contribute melanin is a brown pigment produced by most
one factor for each characteristic to each off- animals. It is the product of a number of chemi-
spring, so the offspring of such a mating should cal reactions, but one enzyme early in the pro-
be Dd (heterozygous). The tall appearance of cess is known to be defective in albino animals.
the heterozygote defines the character expres- Lacking normal enzyme activity, these animals
sion (the phenotype) as dominant. Domi- cannot produce melanin, so there is no color in
nance of expression for any characteristic can- the skin, eyes, or hair. When an animal has the
not be guessed but must be determined by genetic composition cc (c designates colorless,
observation. When variation is observed in the or albino), it has two alleles that are the same,
phenotype, heterozygous individuals must be and neither can produce a copy of the normal
examined to determine which expression is ob- enzyme. Animals with the genetic composition
served. For phenotypes that are not visible, CC (C designates colored, or normal) have two
such as blood types or enzyme activity varia- copies of the allele that produces normal en-
tions, a test of some kind must be used to deter- zymes and are therefore pigmented. When ho-
mine which phenotype expression is present in mozygous normal (CC) and albino (cc) animals
any individual. are crossed, heterozygous (Cc) animals are pro-
Mendels model and the appearance of the duced. The c allele codes for production of an
dominant phenotype also explains the classic inactive enzyme, while the C allele codes for
3:1 ratio observed in the second (F2) genera- production of the normal, active enzyme. The
tion. The crossing of two heterozygous individ- presence of the normal enzyme promotes pig-
uals (Dd Dd) produces a progeny that is 1 4 DD, ment production, and the animal displays the
1 Dd, and 1 dd. Because there is a dominant pigmented phenotype. The presence of pig-
2 4
phenotype expression, the 1 4 DD and the 1 2 Dd ment in the heterozygote leads to the designa-
progeny all have the same phenotype, so 3 4 of tion that the pigmented phenotype is domi-
the individuals are tall. It was this numerical re- nant to albinism or, conversely, that albinism is
lation that Mendel used to establish his model a recessive phenotype because it is seen only in
of inheritance. the homozygous (cc) state.
The same absence or presence of an active
The Functional Basis of Dominance copy of an enzyme explains why blood types A
The development of knowledge about the and B are both dominant to blood type O.
molecular activity of genes through the 1950s When an A allele or a B allele is present, an ac-
and 1960s provided information on the nature tive enzyme promotes the production of a sub-
of the synthesis of proteins using the genetic stance that is identified in a blood test; the
code passed on in the DNA molecules. This blood type A expression or the blood type B ex-
knowledge has allowed researchers to explain pression is seen. When neither of these alleles
186 Complete Dominance
is present, the individual is homozygous OO. therefore, show dominance; rather, its enzyme
There is no detectable product present, and expression does.
the blood test is negative; therefore, the indi-
vidual has blood type O. When the A allele and Dominant Mutant Alleles
the B allele are both present in a heterozygous Dominance of a normal phenotype is fairly
individual, each produces an active enzyme, so easy to explain at the level of the functioning
both the A and the B product are detected in protein because the action of the normal prod-
blood tests; such an individual has blood type uct is seen, but dominance of mutant pheno-
AB. The two phenotypes are both expressed in types is more difficult. Polydactyly, the pres-
the heterozygote, a mode of gene expression ence of extra fingers on one hand or extra toes
called codominance. on one foot, is a dominant phenotype. The
When there are a number of alleles present mechanism that leads to this expression and
for the expression of a characteristic, a domi- numerous other developmental abnormalities
nance relation among the phenotype expres- is not yet understood. One insight comes from
sions can be established. In some animal coats, the genetic expression of enzymes that are
very light colors result from enzymes produced composed of two identical polypeptide sub-
by a specific allele that is capable of producing units. In this situation, the gene locus codes for
melanin but at a much less efficient rate than one polypeptide, but it takes two polypeptide
the normal version of the enzyme. In the rab- molecules joined together to form a functional
bit, chinchilla (c ch) is such an allele. In the Cc ch enzyme molecule. In order to function nor-
heterozygote, the normal allele (C) produces a mally, both of the polypeptide subunits must be
normal, rapidly acting enzyme, and the animal normal. A heterozygote can have one allele
has normal levels of melanin. The normal pig- coding for a normal polypeptide and the other
ment phenotype expression is observed be- allele coding for a mutant, nonfunctional poly-
cause the animals are dark in color, so this peptide. These polypeptides will join together
expression is dominant to the chinchilla pheno- at random to form the enzyme. The possible
type expression. In the heterozygote c chc, the combinations will be defective-defective, which
slow-acting enzyme produced by the c ch allele is results in a nonfunctional enzyme; defective-
present and produces pigment, in a reduced normal, which also results in a nonfunctional
amount, so the chinchilla phenotype expres- enzyme; and normal-normal, which is a nor-
sion is observed and is dominant to the albino mal, functional enzyme. The majority of the en-
phenotype expression. The result is a domi- zyme molecules will be nonfunctional, and their
nance hierarchy in which the normal pigment presence will interfere with the action of the
phenotype is dominant to both the chinchilla few normal units. The normal function will be,
and the albino phenotypes, and the chinchilla at best, greatly reduced, and the overall pheno-
expression is dominant to the albino expres- type will be abnormal. One form of hereditary
sion. blindness is dominant because the presence of
It is important to note that the dominant abnormal proteins interferes with the trans-
phenotype is the result of the protein pro- port of both protein types across a membrane
duced by each allele. In the previous examples, to their proper location in the cells that react to
both the albino allele and the chinchilla allele light. The abnormal phenotype appears in the
produce a producta version of the encoded heterozygote, so the abnormal phenotype is
enzymebut the normal allele produces a ver- dominant. A number of human disease condi-
sion of the enzyme that produces more pig- tions, including some forms of cancer, display a
ment. The relative ability of the enzymes to dominant mode of inheritance.
carry out the function determines the observed Sometimes a trait that appears to be domi-
phenotype expression and therefore the domi- nant is actually more complex. The Manx trait
nance association. The C allele does not inhibit in cats, which results in a very short, stubby tail,
the activity of either of the other two alleles or occurs only in heterozygous individuals. On
their enzyme products, and the allele does not, the surface, this would appear to be a simple
Congenital Defects 187
Writer Firdaus Kanga of Bombay was born with the disease osteogenesis imperfecta. A film based on his autobiographical novel
Try to Grow was produced in the mid-1990s. (AP/Wide World Photos)
Congenital Defects 189
unexpected that mistakes can happen, leading warnings. Frequently, ancient people sacri-
to congenital disorders. ficed such babies. It was thought that such
pregnancies resulted from women mating with
Causes of Birth Defects animals or evil spirits. Maternal impression has
Throughout history, examples of birth de- long been invoked as an explanation for birth
fects have been described by all cultures and defects, and from early Greek times until even
ethnic groups. Although the incidence of spe- relatively recent times, stories and superstitions
cific malformations may vary from group to abounded.
group, the overall incidence of birth defects Of the birth defects in which a specific cause
is probably similar in all people on earth. It is has been identified, it has been found that
estimated that three out of every hundred new- some are caused by genetic abnormalities, in-
borns have some sort of major or minor disor- cluding gene mutations and chromosomal
der. An additional 2 to 3 percent have malfor- changes, while others are caused by exposure
mations that fully develop sometime after birth. of the pregnant woman and her embryo or fe-
When it is also realized that perhaps another tus to some sort of environmental toxin such as
5 percent of all fertilized eggs have severe radiation, viruses, drugs, or chemicals.
enough malformations to lead to an early, spon-
taneous abortion, the overall impact of birth Examples of Birth Defects
defects is considerable. Many birth defects are caused by changes in
Humans have long sought an explanation the number or structure of chromosomes. The
for why some couples have babies afflicted with best-known chromosomal disorder is Down
serious birth defects. Such children were long syndrome, which results from individuals hav-
regarded as omens or warnings of a bad event ing an extra chromosome 21, giving them forty-
to come. The word teratology (Greek for seven chromosomes rather than the normal
monster causing) was coined by scientists to forty-six. A person with Down syndrome char-
reflect the connection of monster births with acteristically has a flattened face, square-shaped
190 Congenital Defects
ears, epicanthal folds of the eye, a short neck, identified. Because of this rather large gap in
poor muscle tone, slow development, and sub- knowledge, nonscientific explanations about
normal intelligence. Cystic fibrosis is an exam- the causes of birth defects flourish. What is
ple of a defect caused by a single gene. Affected known is that most congenital defects, whether
people inherit a recessive gene from each par- caused by a genetic factor or an environmental
ent. The disorder is physiological in nature and factor, are initiated during the embryonic peri-
results in a lack of digestive juices and the pro- od. It is also known that some disorders, such as
duction of thick and sticky mucus that tends to learning disorders, frequently result from dam-
clog the lungs, pancreas, and liver. Respiratory age to the fetus during the last three months of
infections are common, and death typically oc- pregnancy. Knowledge about what can be done
curs by the age of thirty. Cleft lip, or cleft palate, by parents to avoid toxic exposure and activity
is multifactorial in inheritance (some cases are that could cause birth defects is critical.
caused by chromosomal abnormalities or by Donald J. Nash
single-gene mutations). Multifactorial traits are See also: Albinism; Color Blindness; Con-
caused by many pairs of genes, each having a sanguinity and Genetic Disease; Cystic Fibrosis;
small effect, and are usually influenced by fac- Developmental Genetics; Down Syndrome;
tors in the environment. The result is that such Dwarfism; Fragile X Syndrome; Hemophilia;
traits do not follow precise, predictable pat- Hereditary Diseases; Hermaphrodites; Hun-
terns in a family. tingtons Disease; Inborn Errors of Metabo-
Genetic factors account for the great major- lism; Klinefelter Syndrome; Metafemales; Mi-
ity (perhaps 85 to 90 percent) of the birth de- tochondrial Diseases; Neural Tube Defects;
fects in which there is a known cause. The re- Phenylketonuria (PKU); Prader-Willi and An-
maining cases of known cause are attributed to gelman Syndromes; Prion Diseases: Kuru and
maternal illness; congenital infections; expo- Creutzfeldt-Jakob Syndrome; Pseudohermaph-
sure to chemicals, drugs, and medicines; and rodites; Sickle-Cell Disease; Tay-Sachs Disease;
physical factors such as X rays, carbon dioxide, Testicular Feminization Syndrome; Thalido-
and low temperature. The government warn- mide and Other Teratogens; Turner Syndrome;
ing on liquor bottles informs pregnant women XYY Syndrome.
that if they drink alcohol during a sensitive
period of prenatal development, they run the Further Reading
risk of having children with fetal alcohol syn- Berul, Charles I., and Jeffrey A. Towbin, eds.
drome. There is a wide variation in the effects Molecular Genetics of Cardiac Electrophysiology.
of alcohol on a developing fetus. Alcohol expo- Boston: Kluwer Academic, 2000. Reviews re-
sure can lead to an increased frequency of search regarding single-cell electrophysiol-
spontaneous abortion, and it depresses growth ogy, animal models, and hereditary diseases,
rates, both before and after birth. Facial fea- including structural anomalies.
tures of a child exposed to alcohol may include Edwards, Jesse E. Jesse E. Edwards Synopsis of
eye folds, a short nose, small mid-face, a thin Congenital Heart Disease. Edited by Brooks S.
upper lip, a flat face, and a small head. These Edwards. Armonk, N.Y.: Futura, 2000. A
characteristics are likely to be associated with comprehensive review of more than thirty-
mental retardation. Frequently, however, oth- five categories of congenital cardiac lesions.
erwise normal children have learning disor- Aimed at students, clinicians, and health
ders and only a mild growth deficiency. Varia- care providers.
tion in the symptoms of prenatal alcohol Harvey, Richard P., and Nadia Rosenthal, eds.
exposure has made it difficult to estimate the Heart Development. San Diego: Academic
true incidence of the fetal alcohol syndrome. Press, 1999. A broad discussion of the molec-
Estimates for the United States range from 1 to ular basis of cardiovascular development, in-
3 per 1,000 newborns. cluding the lineage origins and morphogen-
In 50 to 60 percent of babies born with a ma- esis of the developing cardiovascular system,
jor birth disorder, no specific cause can be the genetic dissection of cardiovascular de-
Consanguinity and Genetic Disease 191
velopment in a variety of model organisms, More than 600 cross-referenced entries are
and the molecular basis of congenital heart alphabetically arranged and cover genetic
defects. anomalies, diagnostic procedures, causes of
Kramer, Gerri Freid, and Shari Maurer. The Par- mutations, and high risk groups.
ents Guide to Childrens Congenital Heart De-
fects: What They Are, How to Treat Them, How Web Sites of Interest
to Cope with Them. Foreword by Sylvester March of Dimes Birth Defects Foundation.
Stallone and Jennifer Flavin-Stallone. New http://www.marchofdimes.com. Includes
York: Three Rivers Press, 2001. Collects the fact sheets and links to resources on birth de-
expertise of more than thirty leading ex- fects.
perts in pediatric cardiologycardiologists, Medline Plus. http://www.nlm.nih.gov/med
surgeons, nurses, nutritionists, counselors, lineplus. Medline, sponsored by the National
and social workersto give detailed answers Institudes of Health, is one of the first stops
to parents concerns of managing a childs for any medical question, and it offers infor-
heart defect. mation and references on most genetic dis-
Riccitiello, Robina, and Jerry Adler. Your Baby eases, birth defects, and disorders.
Has a Problem. Newsweek, Spring/Summer, National Birth Defects Network. http://
1997. Discusses how advances in medicine www.nbdpn.org. National support group
have reduced the number of birth defects with information, resources, links.
and how surgeries have been designed to National Institutes of Health, National Library
correct some birth defects before babies are of Medicine. http://www.nlm.nih.gov/
born. medlineplus/birthdefects.html. Govern-
Rossen, Anne E. Understanding Congenital ment site that includes dozens of links to re-
Disorders. Current Health 18 (May, 1992). A sources on birth defects, with information
useful article describing some congenital on genetics, treatments, statistics, and more.
disorders, including some that are not ap-
parent early in life, such as Huntingtons dis-
ease. Some of the environmental factors
causing congenital defects are also covered.
Tis the Season. Psychology Today 28 (1995). Consanguinity and Genetic
Describes how certain birth defects may be Disease
related to different seasons of the year and
also discusses some of the biological and en- Fields of study: Diseases and syndromes;
vironmental conditions that cause birth de- Population genetics
fects. Significance: The late onset of sexual maturity and
Tomanek, Robert J., and Raymond B. Runyan, the random mating habits of most humans make
eds. Formation of the Heart and Its Regulation. studying rare mutations in human populations
Foreword by Edward B. Clark. Boston: Birk- especially difficult. Small, isolated communities in
hauser, 2001. Details the major events in which mates are chosen only from within the popu-
heart development and their control via lation lead to consanguineous populations that
genes, cell-cell interactions, growth factors, can serve as natural laboratories for the study of
and other contributing elements. human genetics, especially in the area of human
Wynbrandt, James, and Mark D. Ludman. The disease.
Encyclopedia of Genetic Disorders and Birth De-
fects. 2d ed. New York: Facts On File, 2000. Key terms
Written for the general public, a guidebook alleles: genetic variants of a particular gene
to clinical and research information on he- consanguineous: literally, of the same
reditary conditions and birth defects. In- blood, or sharing a common genetic ances-
cludes a general essay on the basics of ge- try; members of the same family are consan-
netic science and its medical applications. guineous to varying degrees
192 Consanguinity and Genetic Disease
isolate: a community in which mates are cho- Among the Druse, a small Islamic sect, first-
sen from within the local population rather cousin marriages approach 50 percent of all
than from outside populations marriages. The Amish, Hutterites, and Dunkers
in the United States are each descended from
The Importance of Isolates small groups of original settlers who immi-
When studying the genetics of the fruit fly grated in the eighteenth and nineteenth centu-
or any other organism commonly used in the ries and rarely mated with people from outside
laboratory, a researcher can choose the geno- their religions.
types of the flies that will be mated and can ob-
serve the next few generations in a reasonable The Amish
amount of time. Experimenters can also choose There are many reasons the Amish serve as a
to mate offspring flies with their siblings or with good example of an isolate. The original immi-
their parents. As one might expect, this is not gration of Amish to America consisted of ap-
possible when studying the inheritance of hu- proximately two hundred settlers. In subse-
man characteristics. Thus, progress in human quent generations, the available mates came
genetics most often relies on the observation of from the descendants of the original settlers.
the phenotypes of progeny that already exist With mate choice this limited, it is inevitable
and matings that have already occurred. Many that some of the marriages will be consanguin-
genetic diseases only appear when a person is eous. Consanguinity increases as further mar-
homozygous for two recessive alleles; thus a riages take place between the offspring of con-
person must inherit the same recessive allele sanguineous marriages. Current estimates are
from both parents. Since most recessive alleles that the average degree of consanguinity of
are rare in the general population, the chance Amish marriages in Lancaster County, Pennsyl-
that both parents carry the same recessive al- vania, is at the level of marriages between sec-
lele is small. This makes the study of these dis- ond cousins.
eases very difficult. The chance that both par- Other factors that make the Amish good sub-
ents carry the same recessive allele is increased jects for genetic research are their high fertility
whenever mating occurs between individuals and their high level of marital fidelity. Thus, if
who share some of the same genetic back- both parents happen to be heterozygous for a
ground. These consanguineous matings pro- particular genetic disease, the chance that at
duce measurably higher numbers of offspring least one of the offspring will show the disease
with genetic diseases, especially when the de- is high. In families of two children, there is a 44
gree of consanguinity is at the level of second percent chance that at least one child will show
cousin or closer. the trait. This increases to 70 percent of the
In small religious communities in which families with four children and to more than 91
marriage outside the religion is forbidden, and percent of the families with eight children, a
in small, geographically isolated populations in common number among the Amish. Because
which migration into the population from the of the high marital fidelity, researchers do not
outside is at or near zero, marriages often oc- have to worry about illegitimacy when making
cur between two people who share some com- these estimates.
mon ancestry; therefore, the level of consan- Many genetic diseases that are nearly non-
guinity can be quite high. These communities existent in the general population are found
thus serve as natural laboratories in which to among the Amish. The allele for a type of
study genetic diseases. Geographically isolated dwarfism known as the Ellis-van Creveld syn-
mountain and island communities are found drome is found in less than 0.1 percent of the
in many areas of the world, including the Cau- general population; among the Lancaster
casus Mountains of Eurasia, the Appalachian Amish, however, the allele exists in approxi-
Mountains of North America, and many areas mately 7 percent of the population. Other ge-
in the South Pacific. Culturally isolated com- netic diseases at higher levels among the Amish
munities are also of worldwide distribution. include cystic fibrosis, limb-girdle muscular
Criminality 193
telligence quotient (IQ) and violent acts in one tion of Genetic Factors in Crime, a federally
Dutch family. Males who possess an extra Y chro- funded conference organized by philosopher
mosome (XYY syndrome males) also demon- David Wasserman. A similar symposium, Ge-
strate a variety of behavioral difficulties and are netics of Criminal and Antisocial Behaviour,
overrepresented in prisons and mental institu- was held in London in 1995. However, the pub-
tions. However, no link to criminal behavior lic remains highly suspicious of the motivation
has been established. for such research.
In all cases, such genetic abnormalities af- In an era in which genes have been impli-
fect numerous characteristics (often including cated in everything from manic depression to
mental capabilities) and manifest themselves the propensity to change jobs, the belief that
as any number of unassociated antisocial be- genes are responsible for criminal behavior is
haviors ranging from exhibitionism to arson. very enticing. However, such a belief may have
Since criminality simply refers to a violation of severe ramifications. To the extent that society
the law and since there are numerous types of accepts the view that crime is the result of
crimes and motivations for them (such as an- pathological and biologically deviant behavior,
ger, revenge, and financial gain), it is difficult it is possible to ignore the necessity to change
to make claims of definitive, nonenvironmen- social conditions such as poverty and oppres-
tal links between biochemical disorders and sion that are also linked to criminal behavior.
criminal behavior. Poorly defined, multifaceted Moreover, this view may promote the claim by
social descriptors (for example, violence, ag- criminals themselves that their genes made
gression, and intelligence) are usually used to them do it. While biochemical diagnosis and
represent such behaviors and, as such, cannot treatment with drugs may be simpler and there-
be considered true characters. As child psy- fore more appealing than social intervention,
chiatrist Michael Rutter has said, to claim that it is reminiscent of the days when frontal lobot-
there is a gene for crime is like saying theres a omy (surgery of the brain) was the preferred
gene for Roman Catholicism. method of biological intervention for aggres-
sive mental patients. In the future, pharmaco-
Impact and Applications logical solutions to social problems may be
Genetic links to criminality entered the pub- viewed as similarly inhumane.
lic spotlight in the early 1990s as part of the Lee Anne Martnez
U.S. governments Violence Initiative, champi- See also: Aggression; Alcoholism; Altruism;
oned by Secretary of Health and Human Ser- Behavior; Biological Determinism; Develop-
vices Louis Sullivan. The uproar began in 1992 mental Genetics; DNA Fingerprinting; Eugen-
when Frederick Goodwin, then director of the ics; Eugenics: Nazi Germany; Forensic Genetics;
Alcohol, Drug Abuse, and Mental Health Ad- Hardy-Weinberg Law; Heredity and Environ-
ministration, made comments comparing ur- ment; RFLP Analysis; Sociobiology; Steriliza-
ban youth to aggressive jungle primates. The tion Laws; XYY Syndrome.
public feared that research on genetic links to
criminality would be used to justify the dispro- Further Reading
portionate numbers of African Americans and Andreasen, Nancy C. Brave New Brain: Con-
Hispanics in the penal system. Psychiatrist Pe- quering Mental Illness in the Era of the Genome.
ter Breggin also warned that unproved genetic New York: Oxford University Press, 2001.
links would be used as an excuse to screen mi- Surveys the way in which advances in the un-
nority children and give them sedating drugs derstanding of the human brain and the hu-
to intervene in their impending aggression man genome are coming together in an am-
and criminality. After all, forced sterilization bitious effort to conquer mental illness.
laws had been enacted in thirty U.S. states in Faraone, Stephen V., Ming T. Tsuang, and
the 1920s to prevent reproduction by the fee- Debby W. Tsuang. Genetics of Mental Disorders:
bleminded and moral degenerate. In 1993, A Guide for Students, Clinicians, and Re-
public protest led to the temporary cancella- searchers. New York: Guilford Press, 1999. In-
Cystic Fibrosis 195
troduces the investigative methods of hu- ments funding of research on genetic links
man genetics as applied to mental disorders, to violence and crime.
their clinical applications, and some of the Wright, Robert. The Biology of Violence. The
biological, ethical, and legal implications of New Yorker 71 (March 15, 1995). Discusses
the investigative processes and conclusions. evolutionary psychologys view that violent
Fukuyama, Francis. Is It All in the Genes? Com- responses to oppressive environments may
mentary 104 (September, 1997). Compares be adaptive rather than genetically inflexi-
the philosophies of cultural versus biologi- ble.
cal effects on behavior.
Gilbert, Paul, and Kent G. Bailey Hove, eds. Web Sites of Interest
Genes on the Couch: Explorations in Evolution- Bioethics and Genetics at Bioethics.net. http://
ary Psychotherapy. Philadelphia: Brunner- bioethics.net/genetics. Site links to an arti-
Routledge, 2000. Examines models and in- cle exploring the debate about genetics and
terventions in psychotherapy based on evo- criminal behavior, entitled Not Guilty, by
lutionary findings and includes topics such Reason of Genetic Determinism, which in-
as psychotherapy in the context of Darwin- cludes a bibliography for further study.
ian psychiatry, Jungian analysis, gender, and
the syndrome of rejection sensitivity.
Rose, Steven. The Rise of Neurogenetic Deter-
minism. Nature 373 (February, 1995). Com- Cystic Fibrosis
ments on how technological advances have
revived genetic explanations for behavior. Field of study: Diseases and syndromes
Sapolsky, Robert. A Gene for Nothing. Dis- Significance: Cystic fibrosis, although a rare dis-
cover 18 (October, 1997). An entertaining ac- ease, is the most common lethal inherited disease
count of the complex interaction between among Caucasians in the United States and the
genes and the environment. United Kingdom. Advances in genetic screening
Wasserman, David, and Robert Wachbroit, eds. and treatment may someday result in the preven-
Genetics and Criminal Behavior. New York: tion or elimination of this disease.
Cambridge University Press, 2001. Explores
issues surrounding causation and responsi- Key terms
bility in the debate over genetic research epithelial cells: cells responsible for trans-
into criminal behavior. Chapters include porting salt and water
Understanding the Genetics of Violence recessive gene: a gene that in diploid organ-
Controversy, Separating Nature and Nur- isms gets expressed only when it represents
ture, Genetic Explanations of Behavior, both copies at a gene locus
On the Explanatory Limits of Behavioral
Genetics, Degeneracy, Criminal Behavior, Causes and Symptoms
and Looping, Genetic Plans, Genetic Dif- Cystic fibrosis is caused by an abnormal re-
ferences, and Violence, Crime, Genes, and cessive gene that must be inherited from both
Responsibility, Genes, Statistics, and parents. If both parents carry the gene, their
Desert, Genes, Electrotransmitters, and child has a 25 percent chance of inheriting the
Free Will, Moral Responsibility Without abnormal gene from both parents and thus
Free Will, Strong Genetic Influence and having the disease. The child has a 50 percent
the New Optimism, and Genetic Predis- chance of having one normal and one abnor-
positions to Violent and Antisocial Behav- mal gene, thus becoming a carrier of the dis-
ior. ease.
Williams, Juan. Violence, Genes, and Preju- Cystic fibrosis is chronic and has no known
dice. Discover 15 (November, 1994). Gives cure. Generally, symptoms are apparent shortly
an excellent account of the controversy and after birth and become progressively more seri-
debate that accompanied the U.S. govern- ous. Abnormally thick mucus blocks the ducts
196 Cystic Fibrosis
proteins difficult because certain enzymes are Research continues in an effort to deter-
depleted as a result of blocked ducts in the pan- mine the nature of the genetic defect that
creas. causes cystic fibrosis so that the normal func-
The affected person also undergoes daily tion of the defective gene can be replaced by
backslapping designed to break up the mucus specially designed therapies. Recent and ongo-
in the lungs. Antibiotics can reduce infections ing attempts at gene therapy have not yet been
of the lungs. In the 1990s, therapy involving successful. A corrected form of the gene has
the inhalation of a special enzyme began. This been engineered and recombinant adenovi-
enzyme helps break down the thick mucus so ruses have been used to try to deliver the cor-
that it is easier to cough out. In late 1997, a po- rected gene to epithelial cells in the lungs. The
tent antibiotic was recommended to the Food recombinant viruses can easily be inhaled by at-
and Drug Administration. This antibiotic, omizing a solution containing the viruses. Un-
called Tobi (tobramycin for inhalation), was fortunately, patients in clinical trials have often
the first inhaled antibiotic and appeared to in- developed immune responses to the adenovi-
crease the lung function of some cystic fibrosis ruses and the transfer efficiency of the adenovi-
patients. ruses was too low to cause much lasting im-
Once scientists discovered the cystic fibrosis gene, tory epithelium with a detergent-like substance
CF, and its protein product, cystic fibrosis trans- found in normal lungs as a way of increasing virus up-
membrane regulator (CFTR), attempts at gene ther- take by the epithelium. This system has had success
apy were quickly initiated. Since most of the life- in mice and has led to longer-term improvements of
threatening complications of this disease are seen in lung function. These researchers speculate that
the respiratory system, that system became the main long-tem improvement occurs when some epithelial
target for gene replacement therapy. stem cells have had defective DNA replaced by the
Early attempts at gene therapy involved the at- DNA for functional CFTR. In Cleveland, researchers
tachment of a functional CF gene to a virus that acts have tried to insert the CF gene directly into cells
as a vector and the subsequent introduction of this vi- without a viral vector. They have accomplished this
rus to the respiratory epithelium in an aerosol. Sev- by compacting the DNA into a particle small enough
eral problems arose. Although a cystic fibrosis pa- to enter the cell.
tients immune system does not function properly, Another novel gene therapy has been labeled
especially in the respiratory system, the immune sys- SMaRT by its proponents. This therapy takes advan-
tem is active enough to prevent many of the viruses tage of the need to remove introns (noncoding in-
from entering the target cells. Those that did pene- tervening sequences) from pre-messenger RNA
trate and inserted the normal CF gene induced only (pre-mRNA) in eukaryotes and then to splice the
a transient benefit. This most likely occurred be- exons (coding sequences) together to form func-
cause of the high turnover rate of surface epithelial tional mRNA. In this procedure, multiple copies of
cells. The epithelial cells could incorporate the gene a minigene that contain a good copy of the exon
that codes for normal CFTR, but cells that had not that normally contains the defect in the CF gene are
been repaired would soon replace the repaired cells. introduced to the epithelial cells. When the pre-
Continued aerosol applications were also not help- mRNA is processed, there are so many more copies
ful, because the body began producing antibodies to of the corrected exon that it is usually spliced into
the viral vector, which further reduced the viruss the CFTR mRNA. This technique has the advantage
ability to enter cells and introduce an active CF gene. of not disrupting the cells normal regulation of
Another problem was the inflammation caused by the CFTR protein. However, the viruses involved
the virus itself. in the transfer of the minigenes face the same barri-
To surmount some of these difficulties, other ap- ers that all viral vectors face in cystic fibrosis gene
proaches have been tried. A team of Australian re- therapy.
searchers has looked at preconditioning the respira- Richard W. Cheney, Jr.
198 Cytokinesis
provement. Researchers still hope to improve tems affected, transplantation (lung and
gene therapy methods and eventually find ways liver), hospitalization, terminal care, special
either to cure cystic fibrosis fully or at least to re- populations, and laboratory testing.
duce some of the more serious symptoms. Shale, Dennis. Cystic Fibrosis. London: British
Genetic testing for cystic fibrosis can locate Medical Association, 2002. Topics include
the defect responsible for the disease in about clinical management, genetic disorders and
75 percent of afflicted people. Since cystic fi- developments, lung injury, transplantation,
brosis can cause more than one hundred other and nutrition.
genetic mutations, however, a simple test to de- Sternberg, S. Cystic Fibrosis Puzzle Coming
tect the variations may be very difficult to de- Together. Science News 151 (February 8,
velop. In addition, the symptoms of the disease 1997). An informative overview of the lung
can vary from severe to extremely mild. Re- symptoms.
search focuses on the development of inex- Travis, John. Cystic Fibrosis Controversy. Sci-
pensive and accurate diagnosis as well as sound ence News 151 (May 10, 1997). Discussion of a
genetic counseling in order to reduce the oc- controversial treatment for cystic fibrosis.
currence of the disease. In early 1997, the Na- Yankaskas, James R., and Michael R. Knowles,
tional Institutes of Health (NIH) recommended eds. Cystic Fibrosis in Adults. Philadelphia:
that all couples planning to have children Lippincott-Raven, 1999. Advances in medi-
should be offered the option of testing for the cine have meant longer survival for cystic fi-
cystic fibrosis gene mutations. brosis patients and thus a gradual evolution
Virginia L. Salmon, updated by Bryan Ness of the clinical manifestations of the disorder.
See also: Amniocentesis and Chorionic Vil- Details the typical pulmonary and gastroin-
lus Sampling; Biochemical Mutations; Chro- testinal/nutritional problems of patients, as
mosome Mutation; Chromosome Walking and well as the challenges of adult patients, like
Jumping; Congenital Defects; Gene Therapy; diabetes mellitus, osteoporosis, and preg-
Gene Therapy: Ethical and Economic Issues; nancy, that were once relatively uncommon.
Genetic Counseling; Genetic Engineering; Ge-
netic Screening; Genetic Testing: Ethical and Web Sites of Interest
Economic Issues; Hereditary Diseases; Human Cystic Fibrosis Foundation. http://www.cff.org.
Genetics; Inborn Errors of Metabolism; Multi- This national organizations site includes in-
ple Alleles. formation on the genetics of cystic fibrosis.
Dolan DNA Learning Center, Your Genes Your
Further Reading Health. http://www.ygyh.org. Sponsored by
Hodson, Margaret E., and Duncan M. Geddes, the Cold Spring Harbor Laboratory, this site,
eds. Cystic Fibrosis. 2d ed. New York: Oxford a component of the DNA Interactive Web
University Press, 2000. Focuses on the diag- site, offers information on more than a dozen
nosis and management of cystic fibrosis and inherited diseases and syndromes, including
its complications, also giving an extensive re- cystic fibrosis.
view of cystic fibrosis, including chapters on
both clinical and basic science.
Oliwenstien, Lori. How Salt Can Kill. Discover
18 (January, 1997). Discusses the link be-
tween salt and the lungs.
Cytokinesis
Orenstein, David M., Beryl J. Rosenstein, and Field of study: Cellular biology
Robert C. Stern. Cystic Fibrosis: Medical Care. Significance: Cytokinesis is a process, usually oc-
Philadelphia: Lippincott Williams & Wilkins, curring concurrent with mitosis, in which the cyto-
2000. Examines the principles and practices plasm and organelles are divided into two new
of cystic fibrosis care, providing chapters on cells. In eukaryotes, mitosis and meiosis involve
the molecular and cellular bases of the dis- division of the nucleus, while cytokinesis is the di-
ease and its diagnosis, the major organ sys- vision of the cytoplasm.
Cytokinesis 199
early telophase, an initially barrel-shaped sys- will eventually grow and differentiate into a ma-
tem of microtubules called a phragmoplast ture ovum, or egg. Another daughter cell, the
forms between the two daughter nuclei. The secondary polar body, receives almost no cyto-
cell plate is then initiated as a disk suspended in plasm. This concentration of cytoplasm is nec-
the phragmoplast. essary for the success of sexual reproduction
The cell plate is formed by fusion of secre- because a major function of the mature ovum is
tory vesicles derived from the Golgi apparatus. to nourish the developing embryo following
Apparently, the carbohydrate-filled vesicles are fertilization.
directed to the division plane by the phragmo- Ming Y. Zheng
plast microtubules, possibly with the help of See also: Cell Cycle, The; Cell Division; Mi-
motor proteins. The vesicles contain matrix tosis and Meiosis; Polyploidy; Totipotency.
molecules, hemicelluloses, and/or pectins. As
the vesicles fuse, their membranes contribute Further Reading
to the formation of the plasma membrane on Grant, M. C. The Trembling Giant. Discover,
either side of the cell plate. When enough vesi- October, 1993. Excellent illustrations on
cles have fused, the edges of the cell plate asexual reproduction (by reference to the
merge with the original plasma membrane aspen tree) through mitosis of plant cells
around the circumference of the cell, complet- and tissues.
ing the separation of the two daughter cells. Murray, A. W., and Tim Hunt. The Cell Cycle: An
In between the two plasma membranes is the Introduction. New York: W. H. Freeman,
middle lamella. Each of the two daughter cells 1993. An informative overview for both stu-
then deposits a primary wall next to the middle dents and general readers, without too
lamella and a new layer of primary wall around much scientific jargon. Bibliographical ref-
the entire protoplast. This new wall is continu- erences, index.
ous with the wall at the cell plate. The original Murray, A. W., and M. W. Kirschner. What
wall of the parent cell stretches and ruptures as Controls the Cell Cycle. Scientific American,
the daughter cells grow and expand. March, 1991. An illuminating description of
a group of proteins that are involved in cell
Cytokinesis in Sexual Reproduction cycle control. The synthesis, processing, and
In animal oogenesis, the formation of ova, degradation of these proteins seems to regu-
or eggs, occurs in the ovaries. Although the late the progression of a cell through various
daughter cells resulting from the two meiotic stages of the cell cycle.
divisions receive equal amounts of genetic ma- Shaul, Orit, Marc van Montagu, and Dirk Inze.
terial, they do not receive equal amounts of cy- Regulation of Cell Divisions in Arabidopsis.
toplasm. Instead, during each division, almost Critical Reviews in Plant Sciences 15 (1996): 97-
all the cytoplasm is concentrated in one of the 112. A review of what is known about plant
two daughter cells. In meiosis I, unequal parti- cell cycle regulation and cell divisions. For
tioning of cytoplasm during cytokinesis pro- serious students.
duces the first polar body almost void of cyto- Staiger, Chris, and John Doonan. Cell Divi-
plasm, and the secondary oocyte with almost all sions in Plants. Current Opinion in Cell Biol-
cytoplasm from the mother cell. During meio- ogy 5 (1993): 226-231. A condensed version
sis II, cytokinesis again partitions almost all cy- on plant cell divisions. Provides a quick over-
toplasm to one of the two daughter cells, which view.
Developmental Genetics In the seventeenth century, the preforma-
Field of study: Developmental genetics tionism hypothesis was advanced to answer
Significance: The discovery of the genes responsible these questions by asserting that a miniature
for the conversion of a single egg cell into a fully organism existed in the sperm or eggs. After
formed organism has greatly increased our under- fertilization, this miniature creature simply grew
standing of development. Common developmental into the fully formed adult. Some microscopists
mechanisms exist for diverse organisms and exper- of the time claimed to see a homunculus, or
imental manipulation of particular genes could little man, inside each sperm cell. That the
potentially lead to treatments or cures for cancers preformationism hypothesis was ill-conceived
and developmental abnormalities in humans. became apparent when others noted that de-
velopmental abnormalities could not be ex-
Key terms plained satisfactorily, and it became clear that
differentiation: the process by which a cell another, more explanatory hypothesis was
changes its phenotype, or outward appear- needed to account for these inconsistencies.
ance, and becomes different from its parent In 1767, Kaspar Friedrich Wolff published
cell, usually by altering its gene expression his epigenesis hypothesis, in which he stated
epigenesis: the formation of differentiated that the complex structures of chickens devel-
cell types and specialized organs from a sin- oped from initially homogeneous, structure-
gle, homogeneous fertilized egg cell without less areas of the embryo. Many questions re-
any preexisting structural elements mained before this new hypothesis could be
gene expression: the combined biochemical validated, and it became clear that the chick
processes, called transcription and transla- embryo was not the best experimental system
tion, that convert the linearly encoded infor- for answering them. Other investigators focused
mation in the bases of DNA into the three- their efforts on the sea squirt, a simpler organ-
dimensional structures of proteins ism with fewer differentiated tissues.
induction: an easily observed event in which a Work with the sea squirt, a tiny sessile marine
cell or group of cells signals an adjacent cell animal often seen stuck to submerged rocks, led
to pursue a different developmental path- to the notion that development followed a mo-
way and so become differentiated from its saic pattern. The key property of mosaic devel-
neighboring cells opment was that any cell of the early embryo,
morphogen: a chemical compound or protein once removed from its surroundings, grew only
made by cells in an egg that creates a concen- into the structure for which it was destined or
tration gradient affecting the developmen- determined. Thus the early embryo consisted
tal fate of surrounding cells by altering their of a mosaic of cell types, each determined to be-
gene expression or their ability to respond come a particular body part. The determinants
to other morphogens for each embryonic cell were found in the cells
cytoplasm, the membrane-bound fluid sur-
Early Hypotheses of Development in rounding the nucleus. Other scientists, most no-
Diverse Organisms tably Hans Driesch in 1892 and Theodor Boveri
From the earliest times, people noted that a (working with sea urchin embryos) in 1907,
particular organism produced offspring very noted that a two-cell-stage embryo could be
much like itself in structure and function, and teased apart into separate cells, each of which
the fully formed adult consisted of numerous grew into a fully formed sea urchin. These re-
cell types and other highly specialized organs sults appeared to disagree with the mosaic devel-
and structures, yet it came from one simple egg opmental mechanism. Working from an earlier
cell. How could such simplicity, observed in the theory, the germ-plasm theory of August Weis-
egg cell, give rise to such complexity in the adult mann (1883), Driesch and Boveri proposed a
and always reproduce the same structures? new mechanism called regulative development.
202 Developmental Genetics
The key property of regulative development from one organism to another. Soon after fer-
was that any cell separated from its embryo tilization, during the very start of embryogen-
could regulate its own development into a com- esis, specific zones with defining, yet structure-
plete organism. In contrast to mosaic develop- less, characteristics were observed. These zones
ment, the determinants for regulative develop- consisted of gradients of different biochemical
ment were found in the nuclei of embryonic compounds, some of which were morphogens,
cells, and Boveri hypothesized that gradients of and they seemed to function by an induction
these determinants, or morphogens, controlled process. Some of these morphogen gradients
the expression of certain genes. Chromosomes existed in the egg before fertilization; thus it
were assumed to play a major role in controlling became evident that the egg was not an entirely
development; however, how they accomplished amorphous, homogeneous cell but one with
this was not known, and Weismann mistakenly some amount of preformation. This preforma-
implied that genes were lost from differenti- tion took the form of specific morphogen gra-
ated cells as more and more specific structures dients.
formed. After these early embryonic events and
In spite of the inconsistencies among the more cell divisions, in which loosely structured
several hypotheses, a grand synthesis was soon patterns of morphogen gradients were estab-
formed. Working with roundworm, mollusc, sea lished to form the embryos polar axes, the
urchin, and frog embryos, investigators realized cells aggregated into a structure called a blas-
that both mosaic and regulative mechanisms tula, a hollow sphere of cells. The next stage
operate during development, with some organ- involved the migration of cells from the surface
isms favoring one mechanism over the other. of the blastula to its interior, a process called
The most important conclusion coming from gastrulation. This stage is important because it
these early experiments suggested that certain forms three tissue types: the ectoderm (for skin
genes on the chromosomes interacted with and nerves), the mesoderm (for muscle and
both the cytoplasmic and nuclear morphoge- heart), and the endoderm (for other internal
netic determinants to control the proliferation organs). Continued morphogenesis generates
and differentiation of embryonic cells. What a neurula, an embryo with a developing ner-
exactly were these morphogens, where did they vous system and backbone. During axis forma-
originate, and how did they form gradients in tion and cell migrations, the embryonic cells
the embryo? How did they interact with genes? are continually dividing to form more cells that
are undergoing differentiation into specialized
The Morphology of Development tissue types such as skin or muscle. Eventually,
Before the how and why mechanistic ques- processes referred to as organogenesis trans-
tions of morphogens could be answered, more form a highly differentiated embryo into one
answers to the what happens when questions with distinct body structures that will grow into
were needed. Using new, powerful microscopes a fully formed adult.
in conjunction with cell-specific stains, many
biologists were able to precisely map the move- Experimental Systems for Studying
ments of cells during embryogenesis and to Developmental Genes
create fate maps of such cell migrations. Fate In order to understand the details of devel-
maps were constructed for sea squirt, round- opment, biologists normally study organisms
worm, mollusc, sea urchin, and frog embryos, with the simplest developmental program,
which showed that specific, undifferentiated ones with the fewest differentiated cell types
cells in the early embryo gave rise to complex that will still allow them to answer fundamental
body structures in the adult. questions about the underlying processes. Sea
In addition, biologists observed an entire squirts and roundworms have been valuable,
stepwise progression of intervening cell types but they exhibit a predominantly mosaic form
and structures that could be grouped into vari- of development and are not the best systems
ous stages and that were more or less consistent for studying morphogen-dependent induction.
Developmental Genetics 203
Bahri Karacay, a postdoctoral fellow at the University of Iowa, studies the development of the nervous system in a mouse embryo as
part of a project that seeks to treat brain tumors in humans. (AP/Wide World Photos)
Frog embryogenesis, with both mosaic and reg- tive genetic system already existed in Drosophila,
ulative processes, was well described and con- making it easier to create and analyze mutants.
tributed greatly to answering the what and The person who best used the fruit fly sys-
when questions of sequential events, but no ef- tem and greatly contributed to the understand-
fective genetic system existed for examining ing of developmental genetics was Christiane
the role of genes in differentiation necessary Nsslein-Volhard, who shared a 1995 Nobel
for answering the why and how questions. Prize in Physiology or Medicine with Edward B.
The issue was finally resolved by focusing Lewis and Eric Wieschaus.
once again on the morphogens. These media-
tors of cellular differentiation were found only The Genes of Development
in trace amounts in developing embryos and The first important developmental genes
thus were difficult if not impossible to isolate in discovered in Drosophila were the latest acting
pure form for experimental investigation. An in morphogenesis, which led to the isolation of
alternative to direct isolation of morphogens the gene for one of the morphogens control-
was to isolate the genes that make the morpho- ling the anterior-posterior axis of the embryo,
gens. The organism deemed most suitable for the bicoid gene. The study of mutants, such as
such an approach was the fruit fly Drosophila me- those with legs in place of antennae, allowed
lanogaster, even though its development was the discovery of many other developmental
more complex than that of the roundworm. genes, referred to generally as homeotic
Fruit flies could be easily grown in large num- genes.
bers in the laboratory, and many mutants could The bicoid genes discovery validated the gra-
be generated quickly; most important, an effec- dient hypothesis originally proposed by Boveri
204 Developmental Genetics
because its gene product functioned as a typi- the segment identity of previously differenti-
cal morphogen. It was a protein that existed in ated cell groups.
the highest concentration at the eggs anterior
pole and diffused to lower concentrations to- Pattern Formation
ward the posterior pole, thus forming a gradi- Through the use of highly specific stains to
ent. Through the use of more fruit fly mutants, track the morphogens in normal and mutant
geneticists showed that the BICOID protein embryos, a fascinating picture of the interac-
stimulated the gene expression of another tions among developmental genes has
early gene, called hunchback, which in turn af- emerged. Even before fertilization, shallow,
fected the expression of other genes: Krppel poorly defined gradients are established by
and knirps. The BICOID protein controls the genes of the mother, such as the bicoid gene
hunchback gene by binding to the genes con- and related genes. These morphogen gradients
trol region. establish the anterior-to-posterior and dorsal-
Since these initial discoveries, a plethora of to-ventral axes. After fertilization, these mor-
new developmental genes have been discov- phogens bind to the control regions of gap
ered. It is now clear that some fifty genes are in- genes, whose protein products direct the for-
volved in development of a fruit fly larva from mation of broadly defined zones which will
an egg, with yet more genes responsible for de- later develop into several specific segments.
velopment of the larva into an adult fly. These The gap proteins then bind to the control re-
genes are grouped into three major categories: gions of pair-rule genes, whose protein prod-
maternal effect genes, segmentation genes, ucts direct further refinements in the segmen-
and homeotic genes. Maternal effect genes in- tation process. The last group of segmentation
clude the bicoid gene. These genes, located in genes, the segment polarity genes, direct the
special nurse cells of the mother, make pro- completion of the segmentation patterns ob-
teins that contribute to the initial morphogen servable in the embryo and adult fly, includ-
gradients along the eggs axes before fertiliza- ing definition of the anterior-posterior orienta-
tion. Segmentation genes comprise three sub- tion of each segment. Homeotic genes then
groups: gap, pair-rule, and segment polarity define the specific functions of the segments,
genes. Each of these types of segmentation including what appendages will develop from
genes determines a different aspect of the seg- each one. Mutations in any of these develop-
ments that make up a developing fruit fly. The mental genes cause distinct and easily observed
hunchback, Krppel, and knirps genes are all gap changes in the developing segment patterns.
genes. Homeotic genes ultimately determine Genes such as hunchback, giant, gooseberry, and
Ear
Head Forebrain Eye
Heart bulge Nose and
Notochord Umbilical mouth
Lower spine cord Limb buds
Tail Umbilical cord
Caenorhabditis elegans, a free-living soil nematode (a then used to track the fates of cells in animals that
type of worm) 1 millimeter in length, has proved in- had been experimentally manipulated. Using a fine
valuable as a model organism for studying develop- laser beam, scientists could kill a single cell at some
ment. In addition to its small size, it has a rapid life cy- point in development of the animal, then determine
cle, going from egg to sexual maturity in three and a what changes, if any, awaited the remaining cells.
half days and living only two to three weeks. The pres- These studies proved that the C. elegans cell lineage is
ence of rudimentary physiological systems, includ- invariant; that is, every worm underwent exactly the
ing digestive, nervous, muscular, and reproductive same sequence of cell divisions and differentiation.
systems, enables comparative studies between Cae- Studies on cell fate and lineage mapping also led
norhabditis and higher organisms, such as mice and to the discovery that specific cells in the lineage al-
humans. Because the animal is transparent, the for- ways die through programmed cell death. Robert
mation of every cell in the 959-celled adult can be ob- Horvitz, another of Brenners students, discovered
served microscopically and manipulated to illumi- two death genes in C. elegans as well as genes that
nate its developmental program. protect against cell death and direct the elimination
In 1963 Sydney Brenner set out to learn every- of the dead cell. He also identified the first counter-
thing there was to know about Caenorhabditis elegans. parts of the death gene in humans.
In a 1974 publication he demonstrated how spe- The characterization of the invariant cell lineage
cific mutations could be induced in the C. elegans ge- of C. elegans and the genetic linkages have been of
nome through chemical mutagenesis and showed great value to understanding basic principles of de-
how these mutations could be linked to specific velopment, including signaling pathways in multicel-
genes and specific effects on organ development. lular organisms and pathways controlling cell death.
Proving the utility of the organism as a genetic model This knowledge has been invaluable to medicine,
encouraged a cadre of researchers to pursue re- where it has helped researchers to understand mech-
search with C. elegans. anisms by which bacteria and viruses invade cells and
One of Brenners students, John Sulston, devel- has provided insights into the cellular mechanisms
oped techniques to track and study cell divisions in involved in neurodegenerative diseases, autoim-
the nematode, from fertilized egg through adult. Mi- mune disorders, and cancer. For their pioneering
croscopic examination of individual cell nuclei of work in the genetic regulation of organ develop-
the animal as it developed, along with electron mi- ment and programmed cell death Brenner, Sulston,
croscopy of serial sections of the animal, enabled sci- and Horvitz were awarded the 2002 Nobel Prize in
entists to trace each of the adult worms 959 cells Physiology or Medicine.
back to a single fertilized egg. This lineage map was Karen E. Kalumuck
hedgehog were all named with reference to the mental processes in all organisms has emerged
specific phenotypic changes that result from from the elegant work with Drosophila mutants:
improper control of segmentation. Finer and finer patterns of differentiated cells
Homeotic genes are often called the mas- are progressively formed in the embryo along
ter genes because they control large numbers its major axes by morphogens acting on genes
of other genes required to make a whole wing in a cascading manner, in which one gene set
or leg. Several clusters of homeotic genes have controls the next in the sequence until a highly
been discovered in Drosophila. Mutations in a complex pattern of differentiated cells results.
certain group of genes of the bithorax complex Each cell within its own patterned zone then re-
result in adult fruit flies with two sets of wings. sponds to the homeotic gene products and
Similarly, mutations in some of the genes in the contributes to the formation of distinct, identi-
antennapedia complex can result in adult fruit fiable body parts.
flies with legs, rather than antennae, on the Another important corollary principle was
head. substantiated by the genetic analysis of devel-
A general principle applying to develop- opment in Drosophila and other organisms.
206 Developmental Genetics
In direct contrast to Weismanns implication test his human gene isolates. He and his re-
about gene loss during differentiation, con- search group made great progress in under-
vincing evidence showed that genes were not standing the role of the MSX2 gene as inducer
systematically lost as egg cells divided and ac- of surrounding cells in the developing em-
quired distinguishing features. Even though a bryo. When this induction process fails because
muscle cell was highly differentiated from a of defective MSX2 genes, the fate of cells des-
skin cell or a blood cell, each cell type retained tined to participate in skull and bone forma-
the same numbers of chromosomes and genes tion and fusion changes, and craniosynostosis
as the original, undifferentiated, but fertilized occurs.
egg cell. What changed in each cell was the pat- A clear indication of the powerful cloning
tern of gene expression, so that different pro- methods developed in the late 1980s was the
teins were made by specific genes while other discovery and isolation in 1990 of an important
genes were turned off. The morphogens, work- mouse developmental gene called brachyury
ing in complex combinatorial patterns during (short tails). The genes existence in mutant
the course of development, determined which mice had been inferred from classical genetic
genes would stay on and which would be studies sixty years prior to its isolation. In 1997,
turned off. Craig Basson, Quan Yi Li, and a team of co-
workers isolated a similar gene from humans
Impact and Applications and named it T-box brachyury (TBX5). Dis-
The discovery and identification of the de- covered first in mice, the T-box is one of those
velopmental genes in Drosophila and other highly conserved subregions of a gene, and it
lower organisms led to the discovery of simi- allowed Basson and Li to find the human gene.
larly functioning genes in higher organisms, in- When mutated or defective in humans, TBX5
cluding humans. The base-pair sequences of causes a variety of heart and upper limb malfor-
many of the developmental genes, especially mations referred to as Holt-Oram syndrome.
shorter subregions coding for sections of the TBX5 codes for an important morphogen af-
morphogen that bind to the control regions fecting the differentiation of embryonic cells
of target genes, are conserved, or remain the into mesoderm, beginning in the gastrulation
same, across diverse organisms. This conserva- phase of embryonic development. These dif-
tion of gene sequences has allowed researchers ferentiated mesodermal cells are destined to
to find similar genes in humans. For example, form the heart and upper limbs.
some forty homeobox genes have been found One of the important realizations emerging
in mice and humans, even though only eight from the explosive research into developmen-
were initially discovered in Drosophila. Some of tal genetics in the 1990s was the connection
the late-acting human homeobox genes are re- between genes that function normally in the
sponsible for such developmental abnormali- developing embryo but abnormally in an adult,
ties as fused fingers and extra digits on the causing cancer. Cancer cells often display prop-
hands and feet. One of the most interesting ab- erties of embryonic cells, suggesting that can-
normalities is craniosynostosis, a premature fu- cer cells are reverting to a state of uncontrolled
sion of an infants skull bones that can cause division. Some evidence indicates that mutated
mental retardation. In 1993, developmental bi- developmental genes participate in causing can-
ologist Robert Maxson and his research group cer. Taken together, the collected data from
at the University of Southern Californias many isolated human developmental genes,
Norris Cancer Center were the first to demon- along with powerful reproductive and cloning
strate that a mutation in a human homeobox technologies, promise to lead to cures and pre-
gene MSX2 was directly responsible for cranio- ventions for a variety of human developmental
synostosis and other bone/limb abnormalities abnormalities and cancers.
requiring corrective surgeries. Maxson made Chet S. Fornari, updated by Bryan Ness
extensive use of knockout mice, genetically See also: Aging; Animal cloning; Cell Cycle,
engineered mice lacking particular genes, to The; Cell Division; Congenital Defects; Cytoki-
Diabetes 207
nesis; DNA Structure and Function; Evolution- 2000. Designed for researchers, a consider-
ary Biology; Genetic Engineering; Hereditary ation of the next phase of biology following
Diseases; Homeotic Genes; In Vitro Fertiliza- the sequencing of several large genomes (ac-
tion and Embryo Transfer; Model Organism: complished at the turn of the millennium):
Caenorhabditis elegans; Model Organism: Dro- determining the functions of genes and the
sophila melanogaster; Model Organism: Mus interplay between them and their protein
musculus; RNA Structure and Function; Stem products.
Cells; Telomeres; Totipotency; X Chromosome
Inactivation. Web Sites of Interest
Institute for Developmental Genetics. http://
Further Reading www.gsf.de/idg. Based in Germany, main-
Beurton, Peter, Raphael Falk, and Hans-Jorg tains data on mouse and zebra fish genetics
Rheinberger, eds. The Concept of the Gene in to unravel the molecular genetic networks
Development and Evolution: Historical and controlling neuronal pattern formation,
Epistemological Perspectives. New York: Cam- neuronal specification and differentiation
bridge University Press, 2000. A collection of during development.
essays that examines the question of what Society for Developmental Biology. http://
genes actually are, for philosophers and his- sdb.bio.purdue.edu. Professional society for
torians of science. biologists and geneticists interested in prob-
Bier, Ethan. The Coiled Spring: How Life Begins. lems of development and growth of organ-
Cold Spring Harbor, N.Y.: Cold Spring Har- isms. Site links to developmental biology
bor Laboratory Press, 2000. A basic over- sites and features the Developmental Biol-
view of the development of embryos in both ogy Cinema, which links to video sequences
plants and animals. of developing organisms.
Cronk, Quentin C. B., Richard M. Bateman, Virtual Library of Developmental Biology, So-
and Julie A. Hawkins, eds. Developmental Ge- ciety for Developmental Biology. http://
netics and Plant Evolution. New York: Taylor & sdb.bio.purdue.edu. Primarily a collection
Francis, 2002. Developmental genetics for of annotated links to laboratories by subject
botanists. or organism, useful for its lists of depart-
DePamphilis, Melvin L., ed. Gene Expression at ments, programs, and organizations.
the Beginning of Animal Development. New York:
Elsevier, 2002. Developmental genetics for
zoologists.
Gilbert, Scott F. Developmental Biology. Sunder-
land, Mass.: Sinauer Associates, 2003. Pres- Diabetes
ents a detailed description of all aspects of
development. Field of study: Diseases and syndromes
Lewin, Benjamin. Genes VII. New York: Oxford Significance: Diabetes mellitus is a syndrome in
University Press, 2001. Includes a compre- which the body cannot metabolized glucose appro-
hensive, clear discussion of genes and devel- priately. The subsequent elevated levels cause sig-
opment, with excellent illustrations. nificant damage to the eyes, heart, kidneys, and
Nsslein-Volhard, Christiane. Gradients That other organs. Diabetes is a significant public
Organize Embryo Development. Scientific health problem with more than 17 million persons
American (August, 1996). The Nobel laure- affected in the United States alone, of whom more
ate reports on findings from the Drosophila than 90 percent have adult-onset (Type II) dia-
studies. betes.
Nsslein-Volhard, Christiane, and J. Kratzsch-
mar, eds. Of Fish, Fly, Worm, and Man: Lessons Key terms
from Developmental Biology for Human Gene autoimmune response: an immune response
Function and Disease. New York: Springer, of an organism against its own cells
208 Diabetes
locus (pl. loci): the physical location of a however, some kind of trigger in the environ-
gene, which in most organisms occurs as two ment must be present. The environmental trig-
copies called alleles, one copy on each of the ger, possibly a viral infection like measles or
chromosomes in a homologous pair mumps, triggers an autoimmune response; that
is, the persons own immune system aids in the
Types of Diabetes destruction of the beta cells, those responsible
Diabetes mellitus actually comprises a num- for the secretion of insulin, in the pancreas.
ber of different diseases, broadly categorized Typically, autoantibodies appear a few years
into Type I and Type II diabetes. In both forms, ahead of the actual disease. The first recogniz-
the bodys ability to process sugars is impaired, able symptom is a condition called pre-diabetes
with consequences that can lead to death if un- in which the usual insulin release in response
treated. Genetics plays a role in both types of di- to elevated blood sugar levels in the blood is di-
abetes, although both are thought to be the re- minished. At a certain point, most commonly
sult of the interaction between genetics and the between the ages of ten and fourteen, the per-
environment. son develops full-blown diabetes, with exces-
Glucose is a simple sugar that is required by sive thirst and urination, as well as weight loss
all cells for normal functioning. Most of the despite adequate or increased caloric intake. If
bodys glucose initially comes from carbohy- untreated, the person can become comatose or
drates broken down during digestion. Normally, even die. Regular treatment with insulin (by in-
the glucose level in a persons blood rises when jection or by an insulin pump) is required for
carbohydrates are ingested. When the blood the rest of the persons life. There is also evi-
glucose reaches a certain level, it triggers the dence that weight reduction and exercise can
pancreas to release insulin, which causes the alleviate symptoms to some extent.
glucose level in the blood to drop by increasing The earliest evidence for a genetic basis for
its uptake in muscle, fat, the liver, and the gut. Type I diabetes was the observation by epi-
One theory is that as the glucose level drops, demiologists that it often occurs in families. In
the person becomes hungry. Eating begins a white Americans, the risk of diabetes is 0.12 per-
new cycle of blood sugar elevation and insulin cent overall, but in children of persons with dia-
response. betes the risk is much greater, 1-15 percent.
Patients with either type of diabetes have dif- Worldwide, the incidence of Type I diabetes is
ficulty metabolizing glucose, with a subsequent highest in Scandinavia, Northern Europe, and
rise in fasting and postprandial blood sugar lev- areas of the United States where Scandinavian
els. In Type I diabetes, also called juvenile- immigrants settled. The lowest incidence of this
onset or insulin-dependent diabetes, this is due type of diabetes is in China and parts of South
to destruction of the insulin-secreting cells in America.
the pancreas. In Type II, also called adult-onset, The genetic basis for developing Type I dia-
maturity-onset, or non-insulin-dependent dia- betes appears not so much to involve mutant
betes, cells become resistant to the effects of in- genes per se, but rather a bad combination of
sulin even though the pancreas is still produc- particular alleles. Most of the genes implicated
ing some insulin. Both types lead to increased so far are found in the major histocompatibility
risk of heart and vascular disease, kidney prob- complex, known as the HLA (human leuko-
lems, blindness, neurological problems, and cyte antigen) complex. Certain combinations
other serious medical consequences. of alleles at these loci seem to confer a much
higher susceptibility than normal. Some of the
Type I Diabetes autoantigens themselves have also been identi-
Type I diabetes mellitus is a chronic autoim- fied, insulin being one of them, which should
mune disease that results from a combination be no surprise. In addition, a rare type of auto-
of genetic and environmental factors. Certain immune diabetes, resembling Type I, occurs
persons are born with a genetic susceptibility to as part of a syndrome called autoimmune
the disease. Before the disease can develop, polyendocrinopathy-candidiasis-ectodermal
Diabetes 209
dystrophy (APECED), which is caused by muta- ing important components of the insulin secre-
tion in Aire, an autoimmune regulator gene. Al- tion pathways, and other genes involved in glu-
though the function of Aire is not known, ex- cose homeostasis. Mutations are very diverse
pression of the gene has been detected in the and can include mutation not only in the genes
thymus, pancreas, and adrenal cortex, and de- themselves but also in transcription factors and
velopmental studies suggest that mutations in control sequences. As more genes and their
Aire might cause the thymus (which is integral mutant alleles are discovered, better treatment
to proper immune system function) to develop options should become available, possibly even
incorrectly. some that are tailored to specific types of muta-
tions.
Type II Diabetes Treatments for Type II diabetes available at
Diabetes mellitus Type II is by far the more the beginning of the twenty-first century in-
common type of diabetes. For example, about clude such lifestyle changes as increased activ-
90 percent of diabetics in the United States ity and weight loss, as well as oral drugs that in-
have Type II. It is a disease that occurs primarily crease tissue sensitivity to circulating insulin,
in older adults, although the incidence in stimulate increased insulin secretion, or alter
younger people is increasing as the incidence insulin action. Some patients may ultimately
of obesity increases and as more children lead have to add insulin to their treatment regimen.
sedentary lives. The children at greatest risk in Once the genetic factors have been completely
the United States are those from ethnic minor- elucidated for both types of diabetes, treat-
ity backgrounds. ments to modify the genes may become a real-
Type II diabetes appears to be a group of dis- ity.
eases, rather than a single disease, in which Rebecca Lovell Scott and Bryan Ness
there are two defects: (1) beta-cell dysfunction, See also: Autoimmune Disorders; Bacterial
leading to somewhat decreased production of Genetics and Cell Structure; Biopharmaceuti-
insulin (although elevated levels of insulin also cals; Cloning; Gene Therapy: Ethical and Eco-
occur), and (2) tissue resistance to insulin. As nomic Issues; Genetic Engineering; Heart Dis-
with Type I, it appears that people who develop ease; Hereditary Diseases.
Type II are born with a genetic susceptibility
but the development of actual disease is de- Further Reading
pendent upon an environmental trigger. Some American Diabetes Association. American Diabe-
possible triggers include aging, sedentary life- tes Association Complete Guide to Diabetes: The
style, and abdominal obesity. Obesity plays a Ultimate Home Reference from the Diabetes Ex-
particularly significant role in the development perts. New York: McGraw-Hill, 2002. Written
of Type II diabetes. Among North Americans, for the consumer, this book includes every-
Europeans, and Africans with Type II diabetes, thing a person with diabetes or a caregiver
between 60 and 70 percent are obese. needs to know, including information on
As with Type I, epidemiologic evidence sug- symptoms, complications, exercise and nu-
gests a strong genetic component to Type II di- trition, blood sugar control, sexual issues,
abetes. In identical twins over forty years of age, drug therapies, insulin regimes, and day-
for example, the likelihood is about 70 percent care.
that the second twin will develop Type II diabe- _______. Type II Diabetes. 3d ed. New York:
tes once the first twin has developed the dis- McGraw-Hill, 2000. Includes a broad range
ease. Diabetes Type II is also found in nearly of information, from who gets Type II diabe-
100 percent of obese Pima Indians and some tes and warning signs to diet plans and self-
Pacific Islanders. care guides.
Mutant alleles for a number of genes have Becker, Gretchen. The First Year: Type 2 Diabetes,
been implicated in susceptibility and develop- An Essential Guide for the Newly Diagnosed. New
ment of Type II diabetes. The first genes to be York: Marlowe, 2001. The author suffers
implicated were the insulin gene, genes encod- from Type II diabetes and provides firsthand
210 Dihybrid Inheritance
gene. Therefore the monohybrid seeds are het- the segregation of W and w was independent of
erozygous Ww. Since these two alleles will sepa- the segregation of G and g. Mendel called this
rate during meiosis when pollen and eggs are independent assortment. Thus, of the 3 4 of
produced, 1 2 of the eggs and pollen will be W the seeds that are round, 3 4 should be yellow
and 1 2 will be w. Mendel called this segrega- and 1 4 should be green, so that 3 4 3 4 = 9 16 should
tion. When the eggs and pollen combine ran- be round and yellow, and 3 4 1 4 = 3 16 should be
domly during fertilization, 1 4 will produce WW round and green. Of the 1 4 of the seeds that are
seeds, 1 2 will produce Ww seeds, and 1 4 will pro- wrinkled, 3 4 should be yellow and 1 4 green, so
duce ww seeds. Since W is dominant to w, both that 1 4 3 4 = 3 16 should be wrinkled and yellow,
the WW and Ww seeds will be round, producing and 1 4 1 4 = 1 16 should be wrinkled and green.
3 round and 1 wrinkled seeds. When Mendel This relationship can be seen in the table
4 4
crossed a purebred yellow-seed plant with a headed Dihybrid Inheritance and Sex Link-
purebred green-seed plant, he observed an en- age.
tirely analogous result in which the yellow al-
lele (G) was dominant to the green allele (g). Sex Chromosomes
Once Mendel was certain about the nature Humans and many other species have sex
of monohybrid inheritance, he began to exper- chromosomes. In humans, normal females have
iment with two traits at a time. He crossed pure- two X chromosomes and normal males have
bred round, yellow pea plants with purebred one X and one Y chromosome. Therefore, sex-
wrinkled, green plants. As expected, the dihy- linked traits, which are controlled by genes on
brid seeds that were produced were all round the X or Y chromosome, are inherited in a dif-
and yellow, the dominant form of each trait. He ferent pattern than the genes that have already
planted the dihybrid seeds and allowed them to been described. Since there are few genes on
fertilize themselves. They produced 9 16 round, the Y chromosome, most sex-linked traits are
yellow seeds; 3 16 round, green seeds; 3 16 wrin- controlled by genes on the X chromosome.
kled, yellow seeds; and 1 16 wrinkled, green Every daughter gets an X chromosome from
seeds. Mendel was able to explain this dihybrid each parent, and every son gets an X from his
ratio by assuming that in the dihybrid flowers, mother and a Y from his father. Human red-
Pollen
W;G W;g w;G w;g
Note: Semicolons indicate that the two genes are on different chromosomes.
212 Dihybrid Inheritance
green color blindness is controlled by the re- color-blind male, 1 16 albino male, and 1 16 albino,
cessive allele (r) of an X-linked gene. A red- red-green color-blind male. Note that the prob-
green color-blind woman (rr) and a normal ability of normal coloring is 1 4 and the probabil-
man (R Y) will have normal daughters (all het- ity of albinism is 1 4 in both sexes. There is no
erozygous Rr) and red-green color-blind sons change in the inheritance pattern for the gene
(r Y). Conversely, a homozygous normal that is not sex linked.
woman (RR) and a red-green color-blind man
(r Y) will have only normal children, since their Other Examples of Dihybrid Inheritance
sons will get a normal X from the mother (RY) A hereditary trait may be controlled by more
and the daughters will all be heterozygous (Rr). than one gene. To one degree or another, al-
A heterozygous woman (Rr) and a red-green most every hereditary trait is controlled by
color-blind man (r Y) will have red-green color- many different genes, but often one or two
blind sons (r Y) and daughters (rr), and normal genes have a major effect compared with all the
sons (RY) and daughters (Rr) in equal num- others, so they are called single-gene or two-
bers. gene traits. Dihybrid inheritance can produce
A dihybrid woman who is heterozygous for traits in various ratios, depending on what the
red-green color blindness and albinism (a re- gene products do. A number of examples will
cessive trait that is not sex linked) can make be presented, but they do not exhaust all of the
four kinds of eggs with equal probability: R;A, possibilities.
R;a, r;A, and r;a. A normal, monohybrid man The comb of a chicken is the fleshy protu-
who is heterozygous for albinism can make berance that lies on top of the head. There are
four kinds of sperm with equal probability: R;A, four forms of the comb, each controlled by a
R;a, Y;A, and Y;a. By looking at the table headed different combination of the two genes that
Mixed Sex-Linked and Autosomal Traits, it is control this trait. The first gene exists in two
easy to predict the probability of each possible forms (R and r), as does the second (P and p).
kind of child from this mating. In each case, the form represented by the up-
The probabilities are 6 16 normal female, 2 16 percase letter is dominant to the other form.
albino female, 3 16 normal male, 3 16 red-green Since there are two copies of each gene (with
Sperm
A;R a;R A;Y a;Y
A A;r Y A a;r Y
A A;R r A a;R r
A;r red-green red-green
normal female normal female
Eggs
A a;r Y a a;r Y
A a;R r a a;r r
a;r red-green albino, red-green
normal female albino female
color-blind male color-blind male
Note: Semicolons indicate that the two genes are on different chromosomes.
Dihybrid Inheritance 213
Partial Dominance
Pollen
A;B A;b a;B a;b
Note: Semicolons indicate that the two genes are on different chromosomes. Dihybrid ratios may change if both genes
are on the same chromosome.
the exception of genes on sex chromosomes), B are dominant to a and b, respectively. The bit-
the first gene can be present in three possible ter dihybrid would have the gene combination
combinations: RR, Rr, and rr. Since R is domi- Aa;Bb. When it fertilizes itself, it would produce
nant, the first two combinations produce the 9 A_;B_, which would be bitter, and 3 A_;bb, 3
16 16 16
same trait, so the symbols R_ and P_ can be aa;B_, and 1 16 aa;bb, all of which would be sweet.
used to represent either of the two combina- Clearly, both the A allele and the B allele are
tions. Chickens with R_;P_ genes have what is needed in order to synthesize cyanide. If either
called a walnut comb, which looks very much is missing, the clover will be sweet.
like the meat of a walnut. The gene combina-
tions R_;pp, rr;P_, and rr;pp produce combs that Absence of Dominance
are called rose, pea, and single, respectively. If In all of the previous examples, there was
two chickens that both have the gene combina- one dominant allele and one recessive allele.
tion Rr;Pp mate, they will produce progeny that Not all genes have dominant and recessive al-
are 9 16 walnut, 3 16 rose, 3 16 pea, and 1 16 single (see leles. If a purebred snapdragon with red flow-
Table 1 for an explanation of these numbers). ers (RR) is crossed with a purebred snapdragon
White clover synthesizes small amounts of with white flowers (rr), all the monohybrid
cyanide, which gives clover a bitter taste. There progeny plants will have pink flowers (Rr). The
are some varieties that produce very little cya- color depends on the number of R alleles pres-
nide (sweet clover). When purebred bitter clo- ent: two Rs will produce a red flower, one R will
ver is crossed with some varieties of purebred produce a pink flower, and no Rs will produce a
sweet clover, the progeny are all bitter. How- white flower. This is an example of partial dom-
ever, when the hybrid progeny is allowed to inance or additive inheritance.
fertilize itself, the next generation is 9 16 bitter Consider a purebred red wheat kernel
and 7 16 sweet. This is easy to explain if it is as- (AA;BB) and a purebred white wheat kernel
sumed that bitter/sweet is a dihybrid trait. The (aa;bb)(see the table headed Partial Domi-
bitter parent would have the gene combination nance). If the two kernels are planted and the
AA;BB and the sweet parent aa;bb, where A and resulting plants are crossed with each other,
214 Diphtheria
the progeny dihybrid kernels will be light red Wolf, Jason B., et al. Epistasis and the Evolution-
(Aa;Bb). If the dihybrid plants grown from the ary Process. New York: Oxford University
dihybrid kernels are allowed to self-fertilize, Press, 2000. Primary focus is on the role of
they will produce 1 16 red (AA;BB), 4 16 medium gene interactions (epistasis) in evolution.
red (AA;Bb and Aa;BB), 6 16 light red (AA;bb, Leading researchers examine how epistasis
Aa;Bb, and aa;BB), 4 16 very light red (Aa;bb and impacts the evolutionary processes in over-
aa;Bb), and 1 16 white (aa;bb). The amount of red view, theoretical, and empirical chapters.
pigment depends on the number of alleles (A
and B) that control pigment production. Al-
though it may appear that this is very different
than the example in the first table, they are in Diphtheria
fact very similar.
All of the inheritance patterns that have Fields of study: Bacterial genetics; Diseases
been discussed are examples of independent and syndromes
assortment, in which the segregation of the al- Significance: Diphtheria is an acute bacterial dis-
leles of one gene is independent of the segrega- ease known best for damaging the respiratory sys-
tion of the alleles of the other gene. That is ex- tem. Afflicted individuals die from this as well as
actly what would be expected from meiosis if from damage to the heart, nerves, and kidney. Ge-
the two genes are not on the same chromo- netic research has led to better understanding of
some. If two genes are on the same chromo- diphtherias cause, action, and treatment.
some and sufficiently close together, they will
not assort independently and the progeny ra- Key terms
tios will not be like any of those described. In anaphylaxis: a severe, sometimes fatal aller-
that case, the genes are referred to as linked gic reaction
genes. antibodies: proteins that help identify and de-
James L. Farmer stroy foreign pathogens and other mole-
See also: Chromosome Theory of Heredity; cules in the body
Classical Transmission Genetics; Complete antitoxin: a vaccine containing antibodies
Dominance; Dihybrid Inheritance; Epistasis; against a specific toxin
Incomplete Dominance; Linkage Maps; Men- cutaneous: related to or affecting skin
delian Genetics; Monohybrid Inheritance;
Multiple Alleles. Diphtheria Symptoms and Cure
The acute bacterial disease diphtheria is
Further Reading caused by rod-shaped Corynebacterium diph-
Madigan, Michael M., et al., eds. Brock Biology of theriae (C. diphtheriae), discovered in 1883 by
Microorganisms. 10th ed. Englewood Cliffs, Edwin Klebs and Friedrich Lffler. Diphtheria
N.J.: Prentice Hall, 2002. A college-level text involves the respiratory tract, nerves, and heart
organized into six units on the principles of in ways that can be lethal. After 1950, the dis-
microbiology, evolutionary microbiology and ease became uncommon in industrialized na-
microbial diversity, immunology and patho- tions because of immunization by vaccination
genicity, microbial diseases, and microor- with antitoxin originally isolated from horses
ganisms as tools for industry and research. by Emil Adolf von Behring in the 1880s. In
Tortora, Gerard. Microbiology: An Introduction. such nations, diphtheria is contracted by con-
7th ed. San Francisco: Benjamin Cummings, tact with travelers coming from developing na-
2001. An accessible introduction to the basic tions, where it is much more common, who
principles of microbiology, the interaction may be asymptomatic carriers or have active
between microbe and host, and human dis- diphtheria.
eases caused by microorganisms. Gives a C. diphtheriae usually enters the body through
general overview of antibiotics and how bac- mucous membranes of the mouth or nose,
terial resistances to antibiotics occur. though it can also enter via breaks in the skin
Diphtheria 215
(cutaneous route). After infection and a two- to nature of diphtheria, all people positive for C.
five-day incubation period, diphtherias first diphtheriae must be kept in bed, isolated, and
symptoms are localized inflammation that kills treated until symptoms and bacteria are absent
cells in the respiratory tract or skin. Respira- after antibiotic therapy stops. This may require
tory diphtheria initially appears as a sore throat four to six weeks.
in which a dirty gray membrane (diphtheria
pseudomembrane) forms and spreads through Genetics and Diphtheria
the respiratory system. The pseudomembrane Diphtheria symptoms are caused by diph-
(made mostly of dead cells, bacteria, and white theria toxin, a protein so lethal that 6 micro-
blood cells) causes a husky voice and is accom- grams will kill a 150-pound human. Most often,
panied by swollen lymph glands. In severe cases, the toxin first localizes in respiratory mucosa
diphtheria kills by heart failure or throat paral- cells or cutaneous sites, where it causes diph-
ysis as little as one day after the initial symp- theria pseudomembrane or skin lesions by in-
toms appear. Fortunately, such lethality occurs teracting with the protein translocase. Translo-
mostly in unimmunized individuals. Cutane- case is essential to synthesis of proteins needed
ous C. diphtheriae infections most often pro- for body cell growth, survival, and reproduc-
duce only skin lesions, though they can cause tion. Diphtheria toxin and translocase interact
death if the bacteria spreads widely through through a process called adenine ribosylation,
the blood and damages the heart, nerves, and similar to that in cholera. Diphtherial adenine
kidneys. Damage depends upon the bacterial ribosylation inactivates translocase, preventing
entry site, individual immunization status, and its action and killing affected cells. Dead respi-
the amount of toxin made. ratory cells form diphtheria pseudomembrane,
Although most people in industrialized na- which closes off the throat. In skin, toxin-killed
tions are immunized, the consequences of cells cause skin lesions. Destruction of nerve,
diphtheria can be so severe that therapy by heart, and kidney cells leads to damage in those
diphtheria antitoxin should begin as soon as tissues.
symptoms suggest the disease. Cure of diphthe- The diphtheria pseudomembrane may cut
ria requires, in addition to the antitoxin, de- off breathing. In such cases, suffocation is pre-
struction of all C. diphtheriae in afflicted individ- vented by a tracheotomy (a surgical incision in
uals. Immunization is the first line of defense, the neck that creates an airway). Major causes
so it is crucial to ensure that the suspected of quick diphtheria fatality are damage to
diphtheria sufferer is not sensitive to antitoxin nerves and the heart. The toxin is a protein
because incautious antitoxin administration made by genes that are present only in certain
may cause lethal anaphylaxis in sensitive peo- strains, and C. diphtheriae strains that do not
ple. Individual sensitivity is identified by produce the toxin are harmless. In addition,
scratch tests with diluted antitoxin. In sensitive genetic studies have identified interaction of
people, desensitization is achieved through the the toxin with respiratory mucosa cell translo-
sequential administration of increasing doses case as well as similar action in many other tis-
of antitoxin in an intensive care unit until effec- sues. Use of bacterial genetics has also enabled
tive doses are safely reached. more scientific production of diphtheria anti-
Diphtheria is so dangerous that all patient toxin. The antitoxin is useful to visitors of re-
contacts are tested for C. diphtheriae. Afflicted gions where the disease is common. Its univer-
individuals are given penicillin, erythromycin, sal use has led to a worldwide decrease in diph-
and/or antitoxin, depending on the presence, theria fatalities to fewer than five deaths per
absence, and severity of diphtheria symptoms. million people. The immunization is effective
Though adequate universal immunization is a for ten years.
sure diphtheria control, booster shotslike
those for tetanus prophylaxisshould be given Impact and Applications
every ten years in addition to childhood shots. Diphtheria has long been a serious, world-
Because of the extremely infectious and fatal wide threat. During the twentieth century, its
216 DNA Fingerprinting
danger greatly diminished in industrialized na- fifteen countries describe their preferred
tions with the advent of antitoxin and the wide techniques for managing hundreds of com-
use of antibiotics to kill C. diphtheriae. In poorer mon disorders affecting every organ system.
nations, diphtheria still flourishes and is a se- Stratton, Kathleen R., Cynthia J. Howe, and
vere threat, partly because of less advanced Richard B. Johnston, Jr., eds. DPT Vaccine
medical practices and the publics fear of im- and Chronic Nervous System Dysfunction: A New
munization. Analysis. Washington, D.C.: National Acad-
Prevention of diphtheria relies mostly on im- emy Press, 1994. Examines nervous system
munization via antitoxin. The isolation and diseases in infancy and childhood, their etiol-
identification of diphtheria toxin and the de- ogy, and the adverse effects of the vaccines.
velopment of antitoxin have depended on ge-
netic methods that now protect most people Web Site of Interest
from the disease. Wherever it afflicts people, Diphtheria Hub. http://www.healthubs.com/
diphtheria treatment also requires the use of diptheria. Provides dozens of links to infor-
antibiotics. Hence, advanced diphtheria pre- mation on diphtheria, including overviews,
vention and treatment will be best effected by diagnosis, and treatment.
using genetic, immunologic, and biochemical
methods to produce vaccines effective for more
than ten years and to produce more potent
antibiotics. Efforts toward these ends will most DNA Fingerprinting
likely utilize molecular genetics to clearly de-
fine why diphtheria is intractable to lifelong Field of study: Human genetics and social
vaccination. Especially valuable will be DNA se- issues
quence analysis, when a genome sequence be- Significance: DNA fingerprinting includes a va-
comes available. riety of techniques in which individuals are
Sanford S. Singer uniquely identified through examination of spe-
See also: Cholera; Emerging Diseases; He- cific DNA sequences that are expected to vary
reditary Diseases; Smallpox. widely among individuals. Uses for these technolo-
gies include not only practical applications in fo-
Further Reading rensic analysis and paternity tests but also basic
Beers, Mark H., and Robert Berkow, eds. The research in paternity, breeding systems, and ecolog-
Merck Manual of Diagnosis and Therapy. 17th ical genetics for many nonhuman species.
ed. Whitehouse Station, N.J.: Merck Re-
search Laboratories, 1999. Contains medi- Key terms
cal details on epidemiology, symptoms, diag- microsatellite: a type of VNTR in which the
nosis, treatment, outbreak management, and repeated motif is 1 to 6 base pairs; synonyms
antitoxin sensitivity. include simple sequence repeat (SSR) and
Parker, James N., ed. Diphtheria: The Official Pa- short tandem repeat (STR)
tients Sourcebook: A Revised and Updated Direc- minisatellite: a type of VNTR in which the re-
tory for the Internet Age. San Diego: ICON peated motif is 12 to 500 base pairs in length
Health, 2002. Tells patients how to look for polymerase chain reaction (PCR): a labora-
information covering virtually all topics re- tory procedure for making millions of iden-
lated to diphtheria, from the essentials to tical copies of a short DNA sequence
the most advanced areas of research. variable number tandem repeat (VNTR): a
Rakel, Robert E., et al., eds. Conns Current Ther- type of DNA sequence in which a short se-
apy. Philadelphia: W. B. Saunders, 2003. De- quence is repeated over and over; chromo-
scribes the latest advances in therapeutics, in- somes from different individuals frequently
cluding a succinct overview of diphtheria and have different numbers of the basic repeat,
its treatment for general readers. More than and if many of these variants are known, the
three hundred leading practitioners from sequence is termed a hypervariable
DNA Fingerprinting 217
Genetic Differences Among Individuals Imagine a simple DNA base sequence, such
All individuals, with the exception of twins AAC (adenine-adenine-cytosine), which is re-
and other clones, are genetically unique. Theo- peated at a particular place (or locus) on a
retically it is therefore possible to use these ge- human chromosome. One chromosome may
netic differences, in the form of DNA se- have eleven of these AAC repeats, while an-
quences, to identify individuals or link samples other might have twelve or thirteen, and so on.
of blood, hair, and other features to a single in- If one could count the number of repeats on
dividual. In practice, individuals of the same each chromosome, it would be possible to spec-
species typically share the vast majority of their ify a diploid genotype for this chromosomal lo-
DNA sequences; in humans, for example, well cus: An individual might have one chromo-
over 99 percent of all of the DNA is identical. some with twelve repeats, and the other with
For individual identification, this poses a prob- fifteen. If there are many different chromo-
lem: Most of the sequences that might be exam- somal variants in the population, most individ-
ined are identical (or nearly so) among ran- uals will have different genotypes. This is the
domly selected individuals. The solution to this conceptual basis for most DNA fingerprinting.
problem is to focus only on the small regions of DNA fingerprint data allow researchers or
the DNA that are known to vary widely among investigators to exclude certain individuals: If,
individuals. These regions, termed hypervari- for instance, a blood sample does not match an
able, are typically based on repeat sequences in individual, that individual is excluded from fur-
the DNA. ther consideration. However, if a sample and
A criminalist at the Phoenix Police Department prepares samples of DNA taken from a crime scene for comparison to the DNA finger-
prints of suspects. (AP/Wide World Photos)
218 DNA Fingerprinting
an individual match, this is not proof that the by a DNA sequence which is repeated, one copy
sample came from that individual; other indi- right after another, at a particular locus on a
viduals might have the same genoytpe. If a sec- chromosome. Chromosomes vary in the num-
ond locus is examined, it becomes less likely ber of repeats present.
that two individuals will share the same geno- VNTRs are often subcategorized based on
type. In practice, investigators use enough in- the length of the repeated sequence. Minisatel-
dependent loci that it is extremely unlikely that lites, like the Jeffreys repeat, include repeat
two individuals will have the same genotypes units ranging from about twelve to several hun-
over all of the loci, making it possible to identify dred bases in length. The total length of the
individuals within a degree of probability ex- tandemly repeated sequences may be several
pressed as a percentage, and very high percent- hundred to several thousand bases. Many dif-
ages are possible. ferent examples have since been discovered,
and they occur in virtually all eukaryotes. In
The First DNA Fingerprints fact, the Jeffreys repeat first discovered in hu-
Alec Jeffreys, at the University of Leicester in mans was found to occur in a wide variety of
England, produced the first DNA fingerprints other species.
in the mid-1980s. His method examined a Shorter repeat sequences, typically 1 to 6
twelve-base sequence that was repeated one bases in length, were subsequently termed mi-
right after another, at many different loci in crosatellites. In humans, AC (adenine-cytosine)
the human genome. Once collected from an and AT (adenine-thymine) repeats are most
individual, the DNA was cut using restriction common; an estimate for the number of AC re-
enzymes to create DNA fragments that con- peat loci derived from the Human Genome
tained the repeat sequences. If the twelve-base Project suggests between eighty thousand and
sequence was represented by more repeats, the ninety thousand different AC repeat loci spread
fragment containing it was that much longer. across the genome. Every eukaryote studied to
Jeffreys used agarose gel electrophoresis to sep- date has had large numbers of microsatellite
arate his fragments by size, and he then used a loci, but they are much less common in prokar-
specialized staining technique to view only the yotes.
fragments containing the twelve-base repeat.
For two samples from the same individual, each The Polymerase Chain Reaction
fragment, appearing as a band on the gel, The development of the polymerase chain
should match. This method was used success- reaction (PCR) in the mid-1980s, and its wide-
fully in a highly publicized rape and murder spread use and optimization in DNA labs a
case in England, both to exonerate one suspect few years later offered an alternative approach
and to incriminate the perpetrator. to DNA fingerprinting. The PCR technique
While very successful, this method had cer- makes millions of copies of short segments of
tain drawbacks. First, a relatively large quantity DNA, with the chromosomal location of the
of DNA was required for each sample, and re- fragments produced under the precise control
sults were most reliable when each sample com- of the investigator. PCR is extremely powerful
pared was run on the same gel. This meant that and can be used with extremely small amounts
small samples, such as individual hairs or tiny of DNA. Because the fragments amplified are
blood stains, could not be used, and also that it small, PCR can also be used on partially de-
was difficult to store DNA fingerprints for use graded samples. The size and chromosomal lo-
in future investigations. cation of the fragments produced depends on
the DNA primers used in the reaction. These
Variable Number Tandem Repeat Loci are short, single-stranded DNA molecules that
The type of sequence Jeffreys exploited is are complementary to sequences that flank the
now included in the category of variable num- region to be amplified.
ber tandem repeats (VNTRs). This type of DNA With this approach, an investigator must
sequence is characterized, as the name implies, find and determine the DNA sequence of a re-
DNA Fingerprinting 219
Co-founder of the San Diego DNA laboratory Annette Peer testifies about DNA evidence at the David Westerfield murder trial on
June 20, 2002. (AP/Wide World Photos)
gion containing a VNTR. Primers are designed colors. The fragments are then loaded in
to amplify the VTNR region, together with polyacrylamide DNA gels of the type used for
some flanking DNA sequences on both ends. DNA sequencing and separated by size. The
The fragments produced in the reaction are fluorescent colors and sizes of the fragments
then separated by length using gel electrophor- are determined automatically, using the same
esis so that differences in length, attributable to automated machines typically used for DNA se-
different numbers of the repeat, become ap- quencing.
parent. For a dinucleotide repeat like AC, frag- DNA fingerprint data generated in this way
ments representing different numbers of re- are easily stored and saved for future compari-
peats, and hence different alleles, differ by a sons. Since each allelic variant is represented
multiple of two. For instance, a researcher by a specific DNA fragment length, and be-
might survey a number of individuals and find cause these are measured very precisely, the ini-
fragments of 120, 122, 124, 128, and 130 base tial constraint of running samples for compari-
pairs in length. son on the same gel is avoided.
locus has many known alleles, in some cases seum, Medical, and Forensic Speciments. New
more than forty; the genetic variation is well York: Springer-Verlag, 1994. Written when
characterized, and databases of variation within DNA fingerprinting was just coming to the
a variety of ethnic groups are available. fore and films such as Jurrasic Park were in
In addition to its role in criminal cases, this theaters, this collection of papers by first-
technique has seen widespread use to establish generation researchers reflects the broad
or exclude paternity, in immigration law to applications of the technology, including
prove relatedness, and to identify the remains paleontological investigations.
of casualties resulting from military combat Hummel, Susanne. Fingerprinting the Past: Re-
and large disasters. search on Highly Degraded DNA and Its Applica-
tions. New York: Springer-Verlag, 2002. Man-
Other Uses for VNTR Genotyping ual about typing ancient DNA.
Soon after VNTRs were discovered in hu- Rudin, Norah, and Keith Inman. An Introduc-
mans and used for DNA fingerprinting, re- tion to Forensic DNA Analysis. Boca Raton,
searchers demonstrated that the same or simi- Fla.: CRC Press, 2002. An overview of many
lar types of sequences were found in all animals, DNA typing techniques, along with numer-
plants, and other eukaryotes. The method pio- ous examples and a discussion of legal impli-
neered by Jeffreys was, only a few years later, cations.
used for studies of paternity in wild bird popu- Wambaugh, Joseph. The Blooding. New York:
lations. Since then, microsatellite analysis has Bantam Books, 1989. The policeman-turned-
come to dominate studies of relatedness, pater- writer offers a fascinating account of the
nity, breeding systems, and other questions of British rape and murder case in which DNA
individual identification in wild species of all fingerprinting was first used.
kinds, including plants, insects, fungi, and ver-
tebrates. Researchers now know, for example, Web Sites of Interest
that among the majority of birds which appear Earls Forensic Page. http://members.aol.com/
monogamous, between 10 and 15 percent of all EarlNMeyer/DNA.html. Summarizes how
progeny are fathered by males other than the DNA fingerprinting works and its use in
recognized mate. crime investigations and in determining pa-
Paul R. Cabe ternity.
See also: Criminality; Forensic Genetics; Iowa State University Extension and Office of
Genetic Testing; Genetics, Historical Develop- Biotechnology, DNA Fingerprinting in Agri-
ment of; Human Genetics; Paternity Tests; Re- cultural Genetics Programs. http://www
petitive DNA. .biotech.iastate.edu/biotech_info_series.
Site links to a comprehensive and illustrative
Further Reading article on the role of DNA fingerprinting in
Burke, Terry, R., Wolf, G. Dolf, and A. Jeffreys, agriculture.
eds. DNA Fingerprinting: Approaches and Appli-
cations. Boston: Birkhauser, 2001. Describes
repetitive DNA and the broad variety of prac-
tical applications to law, medicine, politics,
policy, and more. Aimed at the layperson.
Fridell, Ron. DNA Fingerprinting: The Ultimate
DNA Isolation
Identity. New York: Scholastic, 2001. The his- Fields of study: Genetic engineering and
tory of the technique, from its discovery to biotechnology; Molecular genetics
early uses. Aimed at younger readers and Significance: Before it can be manipulated and
nonspecialists. studied, DNA must be isolated from other sub-
Herrmann, Bernd, and Susanne Hummel, eds. stances such as complex carbohydrates, proteins,
Ancient DNA: Recovery and Analysis of Genetic and RNA. The isolation process is central to bio-
Material from Paleographic, Archaeological, Mu- technology and genetic engineering.
DNA Isolation 221
Discussions of DNA isolation usually concern isola- pending on the nature of the cell membrane and
tion of DNA from the nucleus. While the nucleus is whether there is a cell wall) are employed to break
the location of most of the genetic information in open the cells and release the cytoplasmic contents.
the cell, DNA molecules also exist in other organ- The lysis of the cells is usually done in an osmotically
elles, such as mitochondria and chloroplasts. Chro- stabilized buffer. The solutes in this buffer match the
mosomes of these organelles, referred to as nonnu- concentration of the solutes inside the mitochon-
clear or cytoplasmic DNA, contain a small subset of dria, which prevents the mitochondria from burst-
genes, mostly encoding proteins needed by these ing when the cells are lysed.
organelles. Once the cells are lysed, the lysate is centrifuged
Most standard DNA isolation techniques isolate at low speed (usually between one thousand and
both nuclear and nonnuclear DNA together. For a three thousand times the force of gravity) to remove
person working with nuclear DNA, this is usually not nuclei, membrane fragments, and other debris. The
a concern because the amount of nuclear DNA is resulting supernatant contains the mitochondria in
much greater than the amount of nonnuclear DNA. suspension. To concentrate the mitochondria, the
In working with nonnuclear DNA however, the pres- supernatant is centrifuged at high speed (twelve
ence of nuclear DNA can often cause problems. thousand times the force of gravity). The pellet
Some techniques used to examine nonnuclear DNA, formed by this centrifugation will contain mitochon-
such as the polymerase chain reaction (PCR), are dria and can be suspended in a small volume of liq-
not affected by the presence of nuclear DNA, but for uid to create a concentrated suspension of mito-
other techniques, pure nonnuclear DNA is required. chondria. This suspension may be treated with the
Isolation strategies for nonnuclear DNA usually enzyme DNase, which will degrade any nuclear DNA
involve two steps. The first step is the isolation of in- that remains without crossing the intact mitochon-
tact mitochondria or chloroplasts from the cells, fol- drial membrane. The enzyme will then be deacti-
lowed by the lysing of the mitochondria or chloro- vated, and the mitochondria will be lysed. Lysis of the
plasts to release the DNA so it can be purified. The mitochondria is achieved by adding a strong deter-
process is the same for isolation of both mitochon- gent to the suspension of the mitochondria. Once
drial and chloroplast DNA. Isolation of intact mito- the mitochondria have been lysed, the free mito-
chondria (for example) requires that the mem- chondrial DNA can be purified just as nuclear DNA
branes of the cells be lysed in a way that does not would be, using phenol extraction and ethanol pre-
rupture the mitochondria. To achieve this goal, gen- cipitation.
tle mechanical, chemical, or enzymatic methods (de- Douglas H. Brown
into two layers. If the two layers are mixed vigor- solve the DNA but forces salts present to go into
ously and separated by centrifugation, the phe- solution. The DNA is then reisolated by spool-
nol will move from the DNA extract into the ing or centrifugation and dried to remove all
CIA layer. At this point the extractremoved traces of ethanol. At this point, only DNA and
to a new test tubecontains RNA, DNA, and RNA are left; this mixture can be dissolved in a
salt. low-salt buffer containing the enzyme RNase,
The extract is next mixed with 100 percent which degrades any RNA present, leaving pure
ethanol, inducing the DNA to precipitate out DNA.
in long strands. The DNA strands may be iso- Technological advances have allowed depro-
lated by either spooling the sticky DNA around teinization by the use of spin columns with-
a glass rod or by centrifugation. If spooled, the out the employment of toxic phenol. The raw
DNA is placed in a new test tube; if centrifuged, DNA extract is placed on top of a column con-
the liquid is decanted from the pellet of DNA. taining a chemical matrix that binds proteins
The precipitated DNA, with salt and RNA pres- but not DNA; the column is then centrifuged in
ent, is still not pure. It is washed for a final time a test tube. The raw extract passes through the
with 70 percent ethanol, which does not dis- chemical matrix and exits protein-free into the
DNA Repair 223
collection tube. These newer methods not only lying concepts, and far-reaching applica-
increase safety and reduce the production of tions of recombinant DNA technology.
toxic waste; they are also much faster. Weissman, Sherman M., ed. cDNA Preparation
James J. Campanella and Characterization. San Diego: Academic
See also: Ancient DNA; DNA Replication; Press, 1999. Examines the analysis and map-
DNA Sequencing Technology; DNA Structure ping of messenger RNA, gene mapping
and Function; RFLP Analysis; RNA Isolation; DNA, complementary isolation and purifi-
RNA Structure and Function. cation DNA, and chromosome-mapping
methods. Includes six pages of plates, illus-
Further Reading trations.
Gjerde, Douglas T., Christopher P. Hanna, and
David Hornby. DNA Chromatography. Wein-
heim, Germany: Wiley-VCH, 2002. In chap-
ters about instrumentation and operation,
chromatographic principles, size-based sep- DNA Repair
arations, purification of nucleic acids, RNA
chromatography, and special techniques, Field of study: Molecular genetics
among others, this book bridges the chasm Significance: To protect the integrity of their genetic
between the work of analytic chemists and material, cells are able to correct damage to DNA.
molecular biologists. Illustrated. Many of these mechanisms are found in organ-
Mirsky, Alfred. The Discovery of DNA. Scien- isms ranging from bacteria to humans, indicating
tific American, June, 1968. The fascinating that they evolved early in the history of life. Disrup-
story of Friedrich Mieschers work. tion of DNA repair mechanisms in humans has
Roe, Bruce A., Judy S. Crabtree, and Akbar S. been associated with the development of cancers.
Khan, eds. DNA Isolation and Sequencing. New
York: John Wiley & Sons, 1996. Focus is on Key terms
protocol, describing the most commonly base: the component of a nucleotide that gives
used methods for DNA isolation, DNA se- it its identity and special properties
quencing, sequence analysis, and allied mo- nucleotide: the basic unit of DNA, consisting
lecular biology techniques. Illustrated. of a five-carbon sugar, a nitrogen-containing
Sambrook, Joseph, and David W. Russell, eds. base, and a phosphate group
Molecular Cloning: A Laboratory Manual. 3d
ed. 3 vols. Cold Spring Harbor, N.Y.: Cold DNA Structure and DNA Damage
Spring Harbor Laboratory Press, 2001. A All living things are continually exposed to
standard for researchers, covering plasmids, agents such as radiation or chemicals that can
bacteriophage, high-capacity vectors, gel damage their genetic material. In addition,
electrophoresis, eukaryotic genomic DNA damage to DNA can occur spontaneously, or as
preparation and analysis, eukaryotic mRNA, a by-product of other cellular processes. Be-
polymerase chain reaction techniques, and cause DNA is the blueprint for directing the
more. Bibliographical references and index. functions of the cell; it must be accurately
Trevors, J. T., and J. D. van Elsas, eds. Nucleic maintained. The integrity of DNA also assures
Acids in the Environment. New York: Springer, that all daughter cells receive the same genetic
1995. A laboratory manual that details mo- information. DNA damage can include a
lecular biological techniques such as DNA/ change in the meaning of a gene (a mutation),
RNA extraction and purification, and poly- a break in a DNA molecule, or the abnormal
merase chain reaction methods. Illustrated. joining of two DNA molecules. To a bacterial
Watson, James, et al. Recombinant DNA. New cell, DNA damage may mean death. To a multi-
York: W. H. Freeman, 1992. Uses accessible cellular organism, damaged DNA in some of its
language and exceptional diagrams to give a cells may mean loss of function of organs or tis-
concise background on the methods, under- sues or it may lead to cancer.
224 DNA Repair
A brief overview of the structure of DNA will in the backbone of one or both strands of the
clarify how it can be damaged. DNA is assem- double helix. Breaks can block DNA replica-
bled from nucleotides, of which there are four tion, create problems during cell division, or
types, each defined by the base it contains. If cause rearrangements of the chromosomes.
the DNA double helix is pictured as a twisted DNA replication itself can cause problems by
ladder, the outside supports (sometimes re- inserting an incorrect base or an additional or
ferred to as the backbone of the DNA) are al- too few bases in a new strand. While DNA repli-
ternating units of sugar and phosphate, and cation errors are not DNA damage as such, they
the rungs of the ladder are bases. There are can also lead to mutations and are subject to re-
four types of bases found in DNA: the double- pair.
ring purines, adenine and guanine, and the
single-ring pyrimidines, cytosine and thymine. DNA Repair Systems
The structure of each base allows it to pair with DNA repair systems are found in most or-
only one other base: adenine pairs with thy- ganisms. Even some viruses, such as bacterio-
mine, and cytosine pairs with guanine. Base phages (which infect bacteria) and herpes-
pairing holds the two strands of the double he- viruses (which infect animals), are capable of
lix together and is essential for the synthesis of repairing some damage to their genetic mate-
new DNA molecules (DNA replication) and for rial. The DNA repair systems of single-celled or-
the transfer of information from DNA to RNA ganisms, including bacteria and yeasts, have
in the process of transcription. DNA replica- been extensively studied for many years. In the
tion is carried out by an enzyme called DNA 1980s and 1990s, techniques including the
polymerase, which reads the information (the use of recombinant DNA methods revealed
sequence of bases) on a single strand of DNA, that DNA repair systems of multicellular organ-
brings the appropriate nucleotide to pair with isms such as humans, animals, and plants are
the existing strand one nucleotide at a time, quite similar to those of microorganisms.
and joins it to the end of a growing chain. In ad- Scientists generally classify DNA repair sys-
dition to copying entire long strands of DNA tems into three categories on the basis of com-
every time a cell divides, DNA polymerases are plexity, mechanism, and the fate of the dam-
also responsible for repairing short, damaged aged DNA. Damage reversal systems are the
regions of DNA. Transcription occurs through simplest: They usually require only a single en-
a process similar to DNA replication, except zyme to directly act on the damage and restore
that an RNA polymerase copies only a portion it to normal, usually in a single step. Damage
of one of the strands of DNA (a gene), making removal systems are somewhat more compli-
an RNA copy. The RNA can then direct the pro- cated: These involve cutting out and replacing
duction of a particular protein, which is the ul- a damaged or inappropriate base or section of
timate product of the most genes. nucleotides and require several proteins to act
One of the most frequent forms of DNA together in a series of steps. Damage toler-
damage is loss of a base. Purines are particu- ance systems are those that respond to and act
larly unstable, and many are lost each day in hu- on damaged DNA but do not actually repair
man cells. If a base is absent, the DNA cannot the original damage. Instead, they are ways for
be copied correctly during DNA replication. cells to cope with DNA damage in order to con-
Another common type of DNA damage is a py- tinue growth and division.
rimidine dimer, an abnormal linkage between
two cytosines, two thymines, or a cytosine and a Damage Reversal Systems
thymine next to each other in a DNA strand. Photoreactivation is one of the simplest and
These are caused by the action of ultraviolet perhaps oldest known repair systems: It consists
light on DNA. A pyrimidine dimer creates a dis- of a single enzyme that can split pyrimidine
tortion in the double helix that interferes with dimers in the presence of light. An enzyme
the processes of DNA replication and transcrip- called photolyase catalyzes this reaction; it is
tion. Another form of DNA damage is a break found in many bacteria, lower eukaryotes, in-
DNA Repair 225
sects, and plants but seems to be absent in with the damaged bases (around twenty-seven
mammals (including humans). A similar gene nucleotides in humans) is removed from the
is present in mammals but may code for a pro- double helix, leaving a short gap that can be
tein that functions in another type of repair. filled by DNA polymerase using the intact nu-
X rays and some chemicals such as peroxides cleotides in the other DNA strand as a guide. In
can cause breaks in the backbone of DNA. Sim- the last step, DNA ligase rejoins the strand. Mu-
ple breaks in one strand are rapidly repaired by tants that are defective in nucleotide excision
the enzyme DNA ligase. Mutant strains of mi- repair have been isolated in many organisms
croorganisms with reduced DNA ligase activity and are extremely sensitive to mutation induc-
tend to have high levels of recombination since tion by ultraviolet light and similar-acting
DNA ends are very sticky and readily join with chemical mutagens. Humans with the heredi-
any other fragment of DNA. While recombina- tary disease xeroderma pigmentosum are sun-
tion is important in generating genetic diver- light-sensitive and have a very high risk of skin
sity during sexual reproduction, it can also be cancers on sun-exposed areas of their bodies.
dangerous if DNA molecules are joined inap- These individuals have defective copies of
propriately. The result can be aberrant chro- genes that code for proteins involved in nucle-
mosomes that do not function properly. otide excision repair. A comparison of the
genes defective in xeroderma pigmentosum
Damage Removal Systems patients and those involved in nucleotide exci-
Damage removal systems are accurate and sion repair in simpler organisms reveals a great
efficient but require the action of several en- deal of similarity, indicating that this repair sys-
zymes and are more energetically expensive tem evolved early in the history of life.
to the cell. There are three types of damage re- Mismatch repair occurs during DNA repli-
moval systems that work in the same general cation as a last spell check on its accuracy. By
way but act on different forms of DNA dam- comparing mutation rates in Escherichia coli
age. In base excision repair, an enzyme called bacteria that either have or lack mismatch re-
a DNA glycosylase recognizes a specific dam- pair systems, scientists have estimated that this
aged or inappropriate base and cuts the base- process adds between one hundred and one
sugar linkage to remove the base. Next, the thousand times more accuracy to the replica-
backbone is cut by another protein that re- tion process. It is carried out by a group of pro-
moves the baseless sugar; then a new nucleo- teins that can scan DNA and look for incor-
tide is inserted to replace the damaged one by a rectly paired bases (or unpaired bases). The
DNA polymerase enzyme. Finally, the break in incorrect nucleotide is removed as part of a
the backbone is sealed by DNA ligase. There short stretch, and then the DNA polymerase
are a number of specific glycosylases for partic- gets a second try to insert the correct sequence.
ular types of DNA damage caused by radiation In 1993, Richard Fishel, Bert Vogelstein, and
and chemicals. their colleagues isolated the first genes for hu-
The nucleotide excision repair system man mismatch repair proteins and showed that
works on DNA damage that is bulky and that they are very similar to those of the bacterium
creates a block to DNA replication and tran- Escherichia coli and the simple eukaryote bakers
scription, such as ultraviolet-induced pyrimi- yeast. Further studies in the 1990s revealed
dine dimers and some kinds of DNA damage that mismatch repair genes are defective in
created by chemicals. It probably does not rec- people with hereditary forms of colon cancer.
ognize a specific abnormal structure but sees a
distortion in the double helix. Several proteins Damage Tolerance Systems
joined in a complex scan the DNA for helix dis- Not all DNA damage is or can be removed
tortions. When one is found, the complex immediately; some of it may persist for a while.
binds to the damage and creates two cuts in the If a DNA replication complex encounters DNA
DNA strand containing the damaged bases on damage such as a pyrimidine dimer, it will nor-
either side of the damage. The short segment mally act as a block to further replication of
226 DNA Repair
In 1953, James Watson and Francis Crick enormous diversity necessary to encode the
published a model for the atomic structure of blueprint of every organism. A key feature of
DNA. Their model was based on known chemi- the double-stranded DNA molecule is that
cal properties of DNA and X-ray diffraction bases have strict pairing restrictions: A can only
data obtained from Rosalind Franklin and pair with T; G can only pair with C. Thus if a par-
Maurice Wilkins. The structure itself made it ticular base is known on one strand, the corre-
clear that DNA was indeed the molecule of he- sponding base is automatically known on the
redity and provided evidence for how it might other. Each strand can serve as a template, or
be copied. The molecule resembles a ladder. mold, dictating the precise sequence of bases
The rails are composed of repeating units on the other. This feature is fundamental to the
of sugar and phosphate, forming a backbone process of DNA replication.
for the molecule. Each rung consists of a pair The genome (the complete DNA content of
of nitrogenous bases, one attached to each of an organism) stores all the genetic information
the two rails and held together in the middle that determines the features of that organism.
through weak bonds called hydrogen bonds. The features are expressed when the DNA is
Since there are thousands to hundreds of mil- transcribed to a messenger molecule, mRNA,
lions of units on a DNA molecule, the hydro- which is used to construct a protein. The pro-
gen bonds between each pair of bases add up to teins encoded by the organisms genes in its
a strong force that holds the two strands to- DNA carry out all of the activities of the cell.
gether. DNA, then, consists
of two strands, each con-
sisting of a repeating sugar-
phosphate backbone and
Nucleus
nitrogenous bases with the Chromosomes
two strands held together
by base-pair interactions.
The two strands are ori-
ented in opposite direc-
tions. The ends of a linear
DNA molecule can be dis- Separating
strands of
tinguished by which part parent DNA Daughter
of the backbone sugar is helix
exposed and are referred A
T
to as the 5 (five prime) C
G
end and the 3 end, named C
for a particular carbon G
A
atom on the ribose sugar. If T A
one DNA strand is oriented Thymine T
5 to 3, its complementary
partner is oriented 3 to 5. Deoxyribose Daughter
This organization has im- helix
portant implications for Hydrogen
the mechanism of DNA Phosphate
Carbon
replication. Oxygen
There are four different A single nucleotide
bases: adenine (A), gua- This illustration from the Human Genome Program of the Department of Energy shows
nine (G), cytidine (C), and the basic context of DNA replication from the cellular nucleus, which contains the chromo-
thymine (T). They can be somes, to the separation of DNA strands and their replication at the molecular and atomic
arranged in any order on a levels into daughter helixes. (U.S. Department of Energy Human Genome Pro-
DNA strand, allowing the gram, http://www.ornl.gov/hgmis.)
DNA Replication 229
a b
a
At left, a double-stranded DNA molecule, with its sides formed by sugar-phosphate molecules and its rungs formed by base pairs.
Replication begins at point (a), with the separation of a base pair as a result of the action of a special initiator protein (b). The mole-
cule splits, or unzips, in opposite directions (c) as each parental strand is used as a template for the daughter strand, which is
formed when bases form hydrogen bonds with their appropriate mate bases to form new ladder rungs. Finally (right), one paren-
tal strand and its newly synthesized daughter strand form a new double helix, while the other parental strand and its daughter
strand form the second double helix. (Kimberly L. Dawson Kurnizki)
short piece of RNA, or primer, is extended us- strand is synthesized away from the direction of
ing DNA nucleotides by the enzymes of DNA fork movement. Since the lagging-strand DNA
synthesis, called DNA polymerases. The RNA synthesis and fork movement are in opposite
primer is later removed and replaced by DNA. directions, this strand of DNA must be made in
Nucleotide monomers align with the exposed short pieces that are later joined. Lagging-
template DNA strand one at a time and are strand synthesis is therefore said to be discon-
joined by the DNA polymerase. The joining of tinuous. These short intermediates are called
nucleotides into a growing DNA chain requires Okazaki fragments, named for their discoverer,
energy. This energy is supplied by the nucleo- Reiji Okazaki. Overall, DNA replication is said
tide monomers themselves. A high-energy to be semidiscontinuous.
phosphate bond in the nucleotide is split, and The DNA synthesis machine operating at
the breakage of this high-energy bond provides the replication fork is a complex assembly of
the energy to drive the polymerase reaction. proteins. Many different activities are neces-
The two strands of DNA are not synthesized sary to carry out the process of DNA replication
in the same way. The two strands are oriented efficiently. Several proteins are necessary to
opposite one another, but DNA synthesis only recognize the unwound origin and assemble
occurs in one direction: 5 to 3. Therefore, one the rest of the complex. Primase must function
strand, called the leading strand, is synthesized to begin both new strands and is then required
continuously in the same direction that the periodically throughout synthesis of the lag-
replication fork is moving, while the lagging ging strand. A doughnut-shaped clamp called
DNA Replication 231
PCNA functions as a processivity factor to the DNA ahead of the replication fork. This
keep the entire complex attached to the DNA strain is alleviated through the action of topo-
until the job is completed. Helicase is continu- isomerase enzymes. Single-strand binding pro-
ously required to unwind the template DNA teins are needed to stabilize the regions of
and move the fork along the parent molecule. unwound DNA that exist before the DNA is ac-
As the DNA is unwound, strain is created on tually copied. Finally, an enzyme called ligase is
A detailed schematic of DNA replication, in which a double-standard parent helix splits apart and reassembles into two identical
daughter helixes. The amino acid base pairs are reproduced exactly, because cytosine (C) pairs only with guanine (G), and adenine
(A) pairs only with thymine (T). (Electronic Illustrators Group)
232 DNA Replication
necessary to join the regions replicated from the biology and ethics of manipulating mam-
different origins and to attach all of the Oka- malian genomes. The technology now exists to
zaki fragments of the lagging strand. All of clone human beings, although such experi-
these proteins are part of a well-orchestrated, ments are not likely to be carried out. More rel-
efficient machine ideally suited to its task of evant is the potential impact on agriculture. It
copying the genetic material. is now possible to select for animals that have
DNA polymerases are not perfect. At a rela- the most desirable traits, such as lower fat con-
tively low frequency, they can add an incorrect tent or disease resistance, and create herds of
nucleotide to a growing chain, one that does genetically identical animals. Of direct rele-
not match the template strand as dictated by vance to humans is the potential impact on the
the base-pairing rules. However, because the understanding of fertility and possible new
DNA molecules are so extremely large, novel treatments for infertility.
mechanisms for proofreading have evolved to A new class of genetic diseases was discov-
ensure that the genetic material is copied accu- ered in the 1980s called triplet repeat diseases.
rately. DNA polymerases can detect the misin- Regions of DNA consist of copies of three nu-
corporation of a nucleotide and use an addi- cleotides (such as CGG) that are repeated up to
tional enzymatic activity to correct the mistake. fifty times. Through unknown mechanisms re-
Specifically, the polymerase can back up and lated to DNA replication, the number of re-
cut out the last nucleotide added, then try peats may increase from generation to genera-
again. With this and other mechanisms to cor- tion, at some point reaching a threshold level at
rect errors, the observed error rate for DNA which disease symptoms appear. Diseases
synthesis is a remarkable one error in every bil- found to conform to this pattern include frag-
lion nucleotides added. ile X syndrome, Huntingtons disease (Hun-
tingtons chorea), and Duchenne muscular
Impact and Applications dystrophy.
DNA replication is a fundamental cellular The process of aging is closely related to
process: Proper cell growth cannot occur with- DNA replication. Unlike bacteria, eukaryotic
out it. It must be carefully regulated and tightly organisms have linear chromosomes. This poses
controlled. Despite its basic importance, the problems for the cell, both in maintaining in-
details of the mechanisms that regulate DNA tact chromosomes (ends are unstable) and in
replication are poorly understood. Even with replicating the DNA. The replication machin-
all of the checks and balances that have evolved ery cannot copy the extreme ends of a linear
to ensure a properly replicated genome, occa- DNA molecule, so organisms have evolved al-
sional mistakes do occur. Attempting to repli- ternate mechanisms. The ends of linear chro-
cate a genome damaged by chemical or other mosomes consist of telomeres (short, repeated
means may simply lead to death of a single cell. DNA sequences that are bound and stabilized
Far more ominous are genetic errors that lead by specific proteins), which are replicated by a
to loss of regulating mechanisms. Without reg- separate mechanism using an enzyme called
ulation, cell growth and division can proceed telomerase. Telomerase is inactivated in ma-
without normal limits, resulting in cancer. ture cells, and there may be a slow, progressive
Much of the focus for the study of cell growth loss of the telomeres that ultimately leads to the
and regulation is to set a foundation for the un- loss of important genes, resulting in symptoms
derstanding of how cancer cells develop. This of aging. Cancer cells appear to have reacti-
knowledge may lead to new techniques for se- vated their telomerase, so potential anticancer
lective inhibition or destruction of cancer cells. therapies are being developed based on this in-
Manipulation of DNA replication and cell formation.
cycle control are the newest tools for progress Michael R. Lentz
in genetic engineering. In early 1997, the first See also: Animal Cloning; Cancer; Cell Cy-
successful cloning of an adult mammal, Dolly cle, The; Cell Division; Cloning; DNA Sequenc-
the sheep, raised important new issues about ing Technology; DNA Structure and Function;
DNA Sequencing Technology 233
Genetic Code; Genetic Engineering; Molecular Holmes, Frederic Lawrence. Meselson, Stahl,
Genetics; Mutation and Mutagenesis; Protein and the Replication of DNA: A History of the
Structure; Protein Synthesis; Restriction En- Most Beautiful Experiment in Biology. New Ha-
zymes; RNA Structure and Function; RNA Tran- ven, Conn.: Yale University Press, 2001.
scription and mRNA Processing; Telomeres. Traces the evolution of Matthew Meselson
and Frank Stahls 1957 landmark experi-
Further Reading ment, which confirmed that DNA replicates
Abstracts of Papers Presented at the 2001 Meeting on as predicted by the double helix structure
Eukaryotic DNA Replication: September 5-Septem- Watson and Crick had recently proposed. Il-
ber 9, 2001. Arranged by Thomas Kelly and lustrations.
Bruce Stillman. Cold Spring Harbor, N.Y.: Kornberg, Arthur. For the Love of Enzymes: The
Cold Spring Harbor Laboratory, 2001. This Odyssey of a Biochemist. Reprint. Cambridge,
annual meeting results in similar publica- Mass.: Harvard University Press, 1991. Korn-
tions yearly. berg discovered the enzymes that replicate
Cann, Alan J. DNA Virus Replication. New York: DNA and was awarded the Nobel Prize for
Oxford University Press, 2000. Gives an anal- his work. This autobiography is a rich history
ysis of protein-protein interactions in DNA of the process of science and discovery.
virus replication, covering all major DNA vi- Watson, James. The Double Helix. New York: Si-
rus groups: hepatitis B virus, papillomavirus, mon and Schuster, 2001. Watsons account
herpes simplex virus, Epstein-Barr virus, of the race to solve the structure of the DNA
Kaposis sarcoma herpesvirus (KSHV), hu- molecule.
man cytomegalovirus, and adenoviruses. Il-
lustrated.
Cotterill, Sue, ed. Eukaryotic DNA Replication: A
Practical Approach. New York: Oxford Univer- DNA Sequencing Technology
sity Press, 1999. Serves as a comprehensive
lab manual that describes key aspects of cur- Field of study: Genetic engineering and
rent techniques for investigating DNA repli- biotechnology
cation in eukaryotes. More than one hun- Significance: The genetic code is contained in the
dred reliable protocols, including methods ordered, linear arrangement of the four DNA nu-
for studying the origin of replication, repli- cleotides: adenine, cytosine, guanine, and thy-
cation proteins, and the synthesis of telo- mine. Determining this sequence is called DNA
meres. sequencing. Advances in DNA sequencing tech-
DePamphilis, Melvin L., ed. Concepts in Eukary- nology have increased speed and accuracy of se-
otic DNA Replication. Cold Spring Harbor, quencing by several orders of magnitude.
N.Y.: Cold Spring Harbor Laboratory Press,
1999. A broad account of the basic princi- Key terms
ples of DNA replication and related func- automated fluorescent sequencing: a mod-
tions such as DNA repair and protein phos- ification of dideoxy termination sequencing
phorylation. One chapter surveys the most which uses fluorescent markers to identify
recent advances in the field. the terminal nucleotides, allowing the auto-
Drlica, Karl. Understanding DNA and Gene Clon- mation of sequencing in which robots can
ing: A Guide for the Curious. Rev. ed. New York: carry out large scale projects
Wiley, 2003. An excellent introduction to base pair (bp): often used as a measure of the
the basic properties of DNA and its modern size of a DNA fragment or the distance along
applications. Consists of four sections: basic a DNA molecule between markers; both the
molecular biology, manipulation of DNA, singular and plural are abbreviated bp
insights gained through the use of gene Maxam-Gilbert sequencing: A method of
cloning (including a chapter on retrovi- base-specific chemical degradation to deter-
ruses), and human genetics. mine DNA sequence
234 DNA Sequencing Technology
primer: A short piece of single-stranded DNA sisted of triplet codons in 1961. However, there
that can hybridize to denatured DNA and was no system to read the sequence and un-
provide a start point for extension by a DNA cover the actual words that spelled out the code
polymerase of life.
Sanger sequencing: Also known as dideoxy The discovery of rapid sequencing methods
termination sequencing, a method using in the 1970s created a flood of new discoveries
nucleotides that are missing the 3 hydroxyl in biology. The coding region and control ele-
group in order to terminate the polymeriza- ments could be identified and compared. The
tion of new DNA at a specific nucleotide sequence changes in different alleles of the
same gene could be identified, homologous
The Need for Sequencing genes could be identified in divergent species,
DNA was first discovered in the 1869 as a vis- and evolutionary changes could be studied.
cous material in pus, and its basic chemical Today, an entire genome can be sequenced,
composition was well established by the 1930s. meaning the identification of every nucleotide
By 1950, the critical role of DNA as the heredi- in the correct order along every chromosome,
tary material was clearly determined. In the in a matter of months. This ability to sequence
1950s, the classic papers by James Watson and the genomes of entire organisms has created a
Francis Crick and Matthew Meselson and whole new field called genomics, the study and
Frank Stahl gave scientists a clear picture of the comparison of whole genomes of different or-
structure and mode of replication of DNA. ganisms. Sequencing is now at the core of many
Crick demonstrated that the genetic code con- of the new discoveries in biology.
A DNA sequencing program at work, displaying the bar-code-like DNA sequence on a computer screen. (AP/Wide World Photos)
hundreds of base pairs in length but differ by essary to denature the DNA to separate the
only a single nucleotide. The DNA is labeled strands before separating them by size so that
with either radioactive or fluorescent markers the fragments will correspond in length to the
so that the bands can be detected. distance from the terminal phosphate label to
the cleavage point. The method requires dan-
Maxam-Gilbert Sequencing gerous chemicals and does not easily lend itself
Organic chemists working with DNA have to automation, so it is rarely used today.
identified many chemicals that react with spe-
cific bases and cleave the backbone of the Sanger Sequencing
strand at that location. To sequence DNA with This method requires that the sequence of a
this method, the DNA fragment to be se- short stretch of DNA adjacent to the region to
quenced is isolated and the 5 end of only one be sequenced is known so that a short synthetic
of the strands is labeled by the placement in the oligonucleotide can be made which can hy-
terminal phosphate of the radioactive atom bridize onto the region to act as a primer for
phosphorus 32. This creates the endpoint. In DNA synthesis in the direction of the DNA to
separate tubes, the DNA is reacted with chemi- be sequenced. This is usually not a problem,
cals that will cleave at one of the four nucleo- since the DNA to be sequenced is often cloned
tides. Since only one strand is broken, it is nec- into a plasmid vector whose sequence is known.
236 DNA Sequencing Technology
The DNA is denatured and the primer is al- properties when they bind. Currently, the tech-
lowed to anneal. A DNA polymerase is added nology allows interaction only with specific se-
and extends the DNA for a short distance in the quences. However, the goal is to develop new
presence of radioactive nucleotides, which la- systems that will generate electrical outputs in-
bels the new DNA. The reaction is then divided dicative of the sequence of the DNA with which
into four equal parts and added into four sepa- the chip interacts. This would allow the genera-
rate reaction tubes. Each tube contains all four tion of new data at phenomenal rates, would
DNA nucleotides, but a small percentage of allow field scientists to sequence the genomes
one nucleotide is missing the 3 hydroxyl of new organisms instantly, and would allow po-
group. Without the hydroxyl group, no more lice investigators to generate sequence evidence
bases can be added and the reaction termi- right at the crime scene. While such develop-
nates. Since the dideoxy nucleotide constitutes ments would be very exciting from a scientific
only a small percentage of the available nucleo- perspective, they would also open many new
tides, the reactions will terminate at random questions about personal privacy as prospective
places along the DNA strand. Since the termi- employers (and mates) could easily scan a per-
nated fragment is attached to the larger tem- sons genome for undesirable sequences.
plate strand, the DNA must be denatured be- J. Aaron Cassill
fore gel electrophoresis so that the size will See also: Cloning; Cloning Vectors; DNA
correspond accurately to the position of the Replication; Genetic Code; Genetic Engi-
terminated base. neering; Genome Libraries; Genome Size;
Genomics; Human Genome Project; Knockout
Automated Sequencing Genetics and Knockout Mice; Model Organ-
Automated sequencing is a variant of Sanger ism: Escherichia coli; Molecular Clock Hypothe-
sequencing. Each of the four dideoxy bases has sis; Polymerase Chain Reaction; Population
a different fluorescent dye attached. When the Genetics; Pseudogenes; Repetitive DNA; Re-
elongation is blocked, the fragment will also be striction Enzymes; Reverse Transcriptase; RFLP
labeled with a specific color indicating which Analysis; Shotgun Cloning; Synthetic Genes;
nucleotide is in the terminal position. As a re- Transposable Elements.
sult, four separate reactions (one for each nu-
cleotide) are not needed. Also, the polymerase Further Reading
chain reaction (PCR), which requires much Maxam, Allan M., and Walter Gilbert. A New
smaller amounts of DNA, is often used in auto- Method for Sequencing DNA. Proceedings of
mated sequencers. The reaction products are the National Academy of Sciences 74 (1977):
electrophoresed through a narrow tube of 560. The original description of sequencing
polyacrylamide with a laser and fluorescence by chemical cleavages.
detector at the bottom. As the different-sized Reilly, Philip R. Abraham Lincolns DNA and
fragments reach the bottom, the detector will Other Adventures in Genetics. Cold Spring Har-
register the colors as they pass. The data are bor, N.Y.: Cold Spring Harbor Laboratory
logged on a computer, which outputs the DNA Press, 2000. A series of brief articles about
sequence. This system has been automated the social and moral implications of uncov-
with robot arms moving the samples into reac- ering DNA information in humans.
tion tubes and loading them into the tube gels Sanger, F., S. Nicklen, and A. R. Coulson. DNA
and computers compiling and comparing the Sequencing with Chain-Terminating Inhibi-
sequence data. An automated sequencer may tors. Proceedings of the National Academy of Sci-
cost more than $250,000 but can generate ences 74 (1977): 5463. The original descrip-
10,000 bp of new sequence data per day. tion of dideoxy termination sequencing.
Smith, Lloyd M., et al. Fluorescence Detection
Future Directions in Automated DNA Sequence Analysis. Na-
Scientists have developed silicon chips that ture 321 (1986): 674. The original descrip-
can bind to DNA and change their electrical tion of automated sequencing techniques.
DNA Structure and Function 237
O- O-
OH OH
NH2 O
Adenine Thymine
CH3
N NH
N
O-
H O-
H N O
N N H
O P O CH2 O O P O CH2 O
O- O-
OH OH
of the geneticist Thomas Hunt Morgan about common cause of lung infections. He was work-
ten years earlier. ing primarily with two different strains of this
However, it was not immediately apparent, bacterium: a strain that was highly virulent
based on this evidence alone, that DNA was the (able to cause disease) and a strain that was
genetic material. In addition to DNA, proteins nonvirulent (not able to cause disease). Grif-
are present in the nucleus of the cell and are an fith noticed that if he heat-killed the virulent
integral part of chromosomes as well. Proteins strain and then mixed its cellular debris with
are also much more complex molecules than the living, nonvirulent strain, the nonvirulent
nucleic acids, having a greater number of strain would be transformed into a virulent
building blocks; there are twenty amino acids strain. He did not know what part of the heat-
that can be used to build proteins, as opposed killed virulent cells was responsible for the
to only four nucleotides for DNA. Moreover, transformation, so he simply called it the
proteins tend to be much more complex than transforming factor to denote its activity in
DNA in terms of their three-dimensional struc- his experiment. Unfortunately, Griffith never
ture as well. Therefore, it was not at all clear in took the next step necessary to reveal the mo-
the minds of many scientists of the time that lecular identity of this transforming factor.
DNA had to be the genetic material, since pro- That critical step was taken by another mi-
teins could not specifically be ruled out. crobiologist, Oswald Avery, and his colleagues
In 1928, the microbiologist Frederick Grif- in 1944. Avery essentially repeated Griffiths
fith supplied some of the first evidence that experiments with two important differences:
eventually led to the identification of DNA as Avery partially purified the heat-killed virulent
the genetic material. Griffiths research in- strain preparation and selectively treated this
volved the bacterium Streptococcus pneumoniae, a preparation with a variety of enzymes to see if
DNA Structure and Function 239
gave Wilkins and Franklin, and later Watson tions in the laboratory, hydrogen bonds in the
and Crick, important clues about the physical double helix can easily be broken just by heat-
structure of DNA. ing a solution of DNA to high temperatures
Another important aspect of Watson and (close to the boiling point).
Cricks double-helix model is the interaction
between the nitrogenous bases in the interior Other Features of the Watson-Crick Model
of the molecule. Important information about Watson and Crick were careful to point out
the nature of this interaction was provided by that their double-helix model of DNA was the
molecular biologist Erwin Chargaff in 1950. first model to immediately suggest a mecha-
Chargaff studied the amounts of each nitroge- nism by which the molecule could be repli-
nous base present in double-stranded DNA cated. They knew that this replication, which
from organisms as diverse as bacteria and hu- must occur before the cell can divide, would be
mans. He found that no matter what the source a necessary characteristic of the genetic mate-
of the DNA, the amount of adenine it contains rial of the cell and that an adequate model of
is always roughly equal to the amount of thy- DNA must help explain how this duplication
mine; there are also equal amounts of guanine could occur. Watson and Crick realized that the
and cytosine in DNA. This information led mechanism of complementary base pairing
Watson and Crick to propose an interaction, or that was an integral part of their model was a
base pairing, between these sets of bases such potential answer to this problem. If the double
that A always base pairs with T (and vice versa) helix is separated into its component single-
and G always base pairs with C. Another name strand molecules, each strand will be able to di-
for this phenomenon is complementary base rect the replacement of the opposite, or com-
pairing: A is said to be the complement of T, plementary, strand by base pairing properly
and so on. with only the correct nucleotides. For example,
The force that holds complementary bases, if a single-strand DNA molecule has the se-
and therefore the two strands of DNA, together quence TTAGTCA, the opposite complemen-
is a weak chemical interaction called a hydro- tary strand will always be AATCAGT; it is as if
gen bond, which is created whenever a hydro- the correct double-stranded structure is built
gen atom in one molecule has an affinity for ni- in to each single strand. Additionally, as each
trogen or oxygen atoms in another molecule. of the single strands in a double-strand DNA
The affinity of the atoms for each other draws molecule goes through this addition of com-
the molecules together in the hydrogen bond. plementary nucleotides, two new DNA double
A-T pairs have two hydrogen bonds between helices are produced where there was only one
them because of the chemical structure of the before. Further, these new DNA molecules are
bases, whereas G-C pairs are connected by three completely identical to each other, barring any
hydrogen bonds, making them slightly stron- mistakes that might have been made in the rep-
ger and more stable than A-T pairs. The entire lication process.
DNA double helix, although it is founded upon A strand of DNA also has a certain direction
the hydrogen bond, one of the weakest bonds built into it; the DNA double helix is often
in nature, is nonetheless an extraordinarily sta- called antiparallel in reference to this aspect
ble structure because of the combined force of of its structure. Antiparallel means that al-
the millions of hydrogen bonds holding most though the two strands of the DNA molecule
DNA molecules together. However, these hy- are essentially side by side, they are oriented in
drogen bonds can be broken under certain different directions relative to the position of
conditions in the cell. This usually occurs as the deoxyribose molecules on the backbone of
part of the process of the replication of the the molecule. To help keep track of the orien-
double helix, in which the two strands of DNA tation of the DNA molecule, scientists often re-
must come apart in order to be duplicated. In fer to a 5 to 3 direction. This designation co-
the cell, the hydrogen bonds are broken with mes from numbering the carbon atoms on the
the help of enzymes. Under artificial condi- deoxyribose molecule (from 1 to 5) and takes
DNA Structure and Function 241
Cell Nucleus
Chromosome
DNA
Genes
Sugar-phosphate
side chain
Guanine
Thymine
Adenine
Cytosine
note of the fact that the deoxyribose molecules one would encounter a 5 carbon atom on a
on the DNA strand are all oriented in the same sugar, then the 3 carbon, and so on all the way
direction in a head-to-tail fashion. If it were pos- down the backbone. If one were walking on the
sible to stand on a DNA molecule and walk other strand, the 3 carbon atom would always
down one of the sugar-phosphate backbones, be encountered before the 5 carbon. The con-
242 DNA Structure and Function
cept of an antiparallel double helix has impor- mechanism by which genetic information can
tant implications for the ways that DNA is pro- be transferred easily from one generation of
duced and used in the cell. Generally, the cells (or organisms) to another.
cellular enzymes that are involved in processes The second role of DNA is to serve as a blue-
concerning DNA are restricted to recognizing print for the ultimate production of proteins in
just one direction. For example, DNA polymer- the cell. This process occurs in two steps. The
ase, the enzyme that is responsible for making first step is the conversion of the genetic infor-
DNA in the cell, can only make DNA in a 5 to 3 mation in a small portion of the DNA molecule,
direction, never the reverse. called a gene, into messenger RNA (mRNA).
Watson and Crick postulated a right-handed This process is called transcription, and here
helix as part of their double-helix model; this the primary role of the DNA molecule is to
means that the strands of DNA turn to the serve as a template for synthesis of the mRNA
right, or in a counterclockwise fashion. This is molecule. The second step, translation, does
now regarded as the biological (B) form of not involve DNA directly; rather, the mRNA
DNA because it is the form present inside the produced during transcription is in turn used
nucleus of the cell and in solutions of DNA. as genetic information to produce a molecule
However, it is not the only possible form of of protein. However, it is important to note that
DNA. In 1979, an additional form of DNA was genetic information originally present in the
discovered by molecular biologist Alexander DNA molecule indirectly guides the synthesis
Rich that exhibited a zigzag, left-handed dou- and final amino acid sequence of the finished
ble helix; he called this form of DNA Z-DNA. protein. Both of these steps, transcription and
Stretches of alternating G and C nucleotides translation, are often called gene expression. A
most commonly give rise to this conformation single DNA molecule in the form of a chromo-
of DNA, and scientists think that this alterna- some may contain thousands of different genes,
tive form of the double helix is important for each providing the information necessary to
certain processes in the cell in which various produce a particular protein. Each one of these
molecules bind to the double helix and affect proteins will then fulfill a particular function
its function. inside or outside the cell.
lowed scientists to investigate the important is- separate disciplines. It may be that this research
sues of genetics on the cellular and molecular will prove to be the seed of another biological
levels. revolution with DNA at its center.
An increased understanding of the role Randall K. Harris
DNA plays in the cell has also provided scien- See also: Ancient DNA; Antisense RNA;
tists with tools and techniques for changing Chromosome Structure; DNA Isolation; DNA
some of the genetic characteristics of cells. This Repair; DNA Replication; Genetic Code; Ge-
is demonstrated by the rapidly expanding field netic Code, Cracking of; Molecular Genetics;
of genetic engineering, in which scientists can Noncoding RNA Molecules; One Gene-One
precisely manipulate DNA and cells on the mo- Enzyme Hypothesis; Protein Structure; Protein
lecular level to achieve a desired result. Addi- Synthesis; Repetitive DNA; RNA Isolation;
tionally, more complete knowledge of how the RNA Structure and Function; RNA Transcrip-
cell uses DNA has opened windows of under- tion and mRNA Processing.
standing into abnormal cellular processes such
as cancer, which is fundamentally a defect in- Further Reading
volving the cells genetic information or the ex- Banaszak, Leonard. Foundations of Structural
pression of that information. Biology. San Diego: Academic Press, 2000.
Through the tools of molecular genetics, Provides visualization skills with three-
many scientists hope to be able to correct al- dimensional imaging to assist students in un-
most any genetic defect that a cell or an organ- derstanding the implications of the three-
ism might have, including cancer or inherited dimensional coordinates for a molecule
genetic defects. The area of molecular biology with several thousand atoms.
that is concerned with using DNA as a way to Bradbury, E. Morton, and Sandor Pongor, eds.
correct cellular defects is called gene therapy. Structural Biology and Functional Genomics.
This is commonly done by inserting a normal Boston: Kluwer Academic, 1999. Topics in-
copy of a gene into cells that have a defective clude DNA repeats in the human genome,
copy of the same gene in the hope that the nor- modeling DNA stretching for physics and bi-
mal copy will take over and eliminate the ef- ology, chromatin control of HIV-1 gene ex-
fects of the defective gene. It is hoped that this pression, and exploring structure space.
sort of technology will eventually be used to Frank-Kamenetskii, Maxim D. Unraveling DNA.
overcome even complex problems such as Alz- Reading, Mass.: Addison-Wesley, 1997.
heimers disease and acquired immunodefi- Melds history, biographical details, and sci-
ciency syndrome (AIDS). ence to provide a general discussion of DNA
One of the most unusual and potentially re- and its basic structure and function.
warding applications of DNA structure was in- McCarty, Maclyn. The Transforming Principle:
troduced by computer scientist Leonard Adle- Discovering That Genes Are Made of DNA. New
man in 1994. Adleman devised a way to use York: W. W. Norton, 1994. Gives an insiders
short pieces of single-stranded DNA in solution view of the circumstances surrounding
as a rudimentary computer to solve a rela- Oswald Averys pivotal experiments.
tively complicated mathematical problem. By Maddox, Brenda. Rosalind Franklin: The Dark
devising a code in which each piece of DNA Lady of DNA. New York: HarperCollins, 2002.
stood for a specific variable in his problem and Tells the other side of the story in the discov-
then allowing these single-stranded DNA ery and structure of DNA, focusing on the
pieces to base pair with each other randomly in often neglected role of Franklin. Illustra-
solution, Adleman obtained an answer to his tions, bibliography, index.
problem in a short amount of time. Soon there- Rosenfield, Israel, et al. DNA for Beginners. New
after, other computer scientists and molecular York: W. W. Norton, 1983. Provides an enter-
biologists began to experiment with other ap- taining, yet factual, cartoon account of basic
plications of this fledgling technology, which DNA structure and function as well as more
represents an exciting synthesis of two formerly advanced topics in molecular biology.
244 Down Syndrome
Modern Understanding of Down which was soon followed by the discovery that
Syndrome the extra chromosome present was a third copy
Although this syndrome was recognized by of chromosome 21.
Down in 1866, true understanding of it dates The modern development of more sophisti-
from the work that Lejeune began in 1953. The cated methods of identifying individual parts
seemingly innocuous characteristic of abnor- of chromosomes has shed much light on the
mal palm prints and fingerprints fostered an possible mechanisms by which the symptoms
important insight for him. Since those prints are caused. Some affected individuals do not
are laid down very early in the childs prenatal have a whole extra chromosome 21; rather,
development, they suggest a profoundly al- they possess a third copy of some part of that
tered embryological course of events. His intu- chromosome. A very tiny strand of DNA, chro-
ition told him that not one or two altered genes mosome 21 contains only about fifteen hun-
but rather a whole chromosomes genes must dred genes. Of these fifteen hundred, only a
be at fault. In 1957, he discovered, by the cul- few hundred are consistently present in those
turing of cells from Down syndrome children who suffer from Down syndrome, namely the
in dishes in the laboratory, that those cells con- genes in the bottom one-third of the chromo-
tained forty-seven chromosomes. This work some. Among those genes are several that
eventually resulted in his 1959 publication, could very likely cause certain symptoms associ-
ated with Down syndrome. A leukemia-
causing gene and a gene for a protein in
the lens of the eye that could trigger cata-
ract formation have both been identi-
fied. A gene for the production of the
chemicals called purines has been lo-
cated. The overabundance of purines
produced when three copies of this gene
are present has been linked to the mental
retardation usually seen. Even the fact
that Down syndrome individuals have a
greatly reduced life expectancy is vali-
Image not available dated by the presence of an extra gene
for the enzyme superoxide dismutase,
which seems involved in the normal ag-
ing process. Like Alzheimers disease pa-
tients, Down syndrome patients who live
past forty years of age have gummy tan-
gles of protein strands called amyloid fi-
bers in their brains. Since one form of in-
herited Alzheimers is caused by a gene
on chromosome 21, scientists continue
to search for links between the impaired
mental functioning characteristic of
both diseases.
Down syndrome is characterized by impaired mental ability and a com-
Other modern research has shed light
plex of physical traits that may include short stature, stubby fingers
and toes, protruding tongue, a single transverse palm crease, slanting
on the long-recognized relationship be-
of the eyes, small nose and ears, abnormal finger orientation, congeni- tween the age of the mother and an in-
tal heart defects, and other traits that vary from individual to individ- creased risk of having a Down syndrome
ual. Despite some or all of these traits, many Down syndrome children, child. Using more and more elaborate
supported by parents and organizations such as the Special Olympics methods of chromosome banding, genet-
and Boy Scouts, engage fully in life. (AP/Wide World Photos) icists can determine whether the extra
Down Syndrome 247
Down syndrome always involves either an extra por- drome do couples discover that one of them is a
tion of or a complete extra copy of chromosome 21. translocation carrier. Carriers can produce (1) non-
There are three mechanisms by which this can occur. carrier, chromosomally normal, children (which usu-
Between 92 and 95 percent of cases result from non- ally happens); (2) carrier children, just like the car-
disjunction during meiosis, in which two copies of rier parent, who are translocation heterozygotes; or
chromosome 21 migrate to the same pole and end (3) children with Down syndrome. Carrier mothers
up in the same daughter cell. This most often hap- produce children with Down syndrome about 12 per-
pens in women, and if an egg with two copies of chro- cent of the time. Carrier fathers produce children
mosome 21 is fertilized, the zygote will have three with Down syndrome about 3 percent of the time.
copies and all cells throughout the developing fetus Why greater risk exists for mothers is not clear.
will have an extra chromosome 21. Though maternal age is the most frequent predis-
The second mechanism, mosaic trisomy 21, in- posing factor for Down syndrome, it is uncorrelated
volves an error in cell division shortly after concep- with familial Down syndrome; translocation trisomy
tion. This error produces two populations or lines of 21 occurs with equal frequency in younger and older
cells, some with 46 chromosomes and some with women. Rarely, a carrier parent will have a transloca-
47the ones that have the additional chromosome tion between both twenty-first chromosomes, a trans-
21. This mechanism occurs in 2 to 4 percent of Down location carrier homozygote. This parent has a 100
syndrome live births. Covert mosaicism in parents percent chance for producing children with Down
used to be suspected as causing familial Down syn- syndrome.
drome but is no longer indicated. Ever since the genes on chromosome 21 were
Between 1 and 4 percent of children with Down fully mapped, pedigree research (family recurrence
syndrome have translocation trisomy 21, which oc- studies) and epidemiological research (studies of
curs when extra genetic material from chromosome chance occurrence among populations) have sup-
21 has been translocated to another chromosome. A ported that these chromosomal abnormalities and
family history of Down syndrome is an indication uneven distributions of genetic material are inher-
that this may be the cause of the defect. The occur- ited, and most often through mothers. Though cryp-
rence of more than one case of Down syndrome in tic parental mosaicism is no longer suspected and
a family is relatively rare, but when it does occur, there is promising research investigating mitochon-
translocation trisomy is often suspected. Carrier par- drial DNA in the form of cytoplasmic inheritance,
ents usually do not display any genetic abnormali- the specific genetic mechanism of familial Down syn-
ties. Not until there is miscarriage of a fetus with drome remains elusive.
Down syndrome or birth of a child with Down syn- Paul Moglia
chromosome 21 came from the mother or the See also: Aging; Amniocentesis and Chori-
father. In 94 percent of children, the egg brings onic Villus Sampling; Congenital Defects; Frag-
the extra chromosome. Since the first steps of ile X Syndrome; Genetic Counseling; Genetic
meiosis to produce her future eggs occur be- Testing; Genetics, Historical Development of;
fore the mothers own birth, the older the Intelligence; Mutation and Mutagenesis; Non-
mother, the longer these egg cells have been disjunction and Aneuploidy; Prenatal Diagno-
exposed to potentially harmful chemicals or ra- sis; Proteomics.
diation. On the other hand, paternal age is not
a factor because all the steps of meiosis in males Further Reading
occur in cells produced in the few weeks before Beighton, Peter. The Person Behind the Syndrome.
conception. The continued study of the age Rev. ed. New York: Springer-Verlag, 1997.
factor as well as new insights from genomics are Biographical details about John Langdon
leading to a greater understanding for all those Down.
affected by Down syndrome. Cohen, William I., Lynn Nadel, and Myra E.
Grace D. Matzen Madnick, eds. Down Syndrome: Visions for the
248 Dwarfism
Twenty-first Century. New York: Wiley-Liss, mental retardation, its causes, and preven-
2002. Reviews findings from a 2000 confer- tion strategies. Topics include parenting is-
ence, providing a comprehensive treatment sues, educational implications, health care
of the current issues of self-determination, needs, employment and economic matters,
education, and advocacy, as well as the most and legal issues. Glossary.
recent research developments.
Hogenboom, Marga. Living with Genetic
Web Sites of Interest
Syndromes Associated with Intellectual Disability.
Dolan DNA Learning Center, Your Genes Your
Philadelphia: Jessica Kingsley, 2001. Ad-
Health. http://www.ygyh.org. Sponsored by
dresses not only Down syndrome but also
the Cold Spring Harbor Laboratory, this site,
Williams, Angelman, and and Prader-Willi
a component of the DNA Interactive Web
syndromes from both a psychological and a
site, offers information on more than a dozen
practical standpoint. Valuable to the genet-
inherited diseases and syndromes, including
ics student for its introductory material on
Down syndrome.
the genetics of these syndromes.
National Down Syndrome Society. http://www
Lubec, G. The Molecular Biology of Down Syn-
.ndss.org. A comprehensive site that includes
drome. New York: Springer, 1999. Twenty-five
information on research into the genetics of
chapters examine different aspects of Down
the syndrome and links to related resources.
syndrome, including neuropathology, mo-
lecular pathology, mechanisms of neuronal
death, oxidative stress, and apoptosis.
_______. Protein Expression in Down Syndrome
Brain. New York: Springer, 2001. Both origi-
nal research and current opinions on Down Dwarfism
syndrome, with an emphasis on the molecu-
Field of study: Diseases and syndromes
lar biology at the protein (rather than the
Significance: Dwarfism in humans is a term used
nucleic acid) level, from studies using fetal
to describe adults who are less than 50 inches (127
brains with Down syndrome.
centimeters) in height. Dwarfism can be caused by
Newton, Richard. The Downs Syndrome Hand-
genetic factors, endocrine malfunction, acquired
book: A Practical Guide for Parents and Care-
conditions, or growth hormone deficiency. Indi-
givers. New York: Arrow Books, 1997. Helpful
viduals with dwarfism usually have normal intel-
advice about the capabilities of affected peo-
ligence and have an average life span. Dwarfism
ple. Combines medical knowledge with sym-
may result in multiple medical problems that can
pathetic common sense, to provide help and
lead to death. Dwarfs who have normal body pro-
advice to caregivers of young Down syn-
portions are referred to as midgets. Dispropor-
drome patients.
tioned human dwarfs are referred to as dwarfs.
Selikowitz, Mark. Down Syndrome: The Facts. 2d
Both scientific terms are socially unacceptable; hu-
ed. New York: Oxford University Press, 1997.
man dwarfs prefer to be referred to as little people.
Covers the entire life span of patients, from
infancy to adulthood, and deals with the de-
velopmental, educational, and social-sexual Key terms
needs of individuals with Down syndrome as allele: one of the different forms of a particu-
well as their medical needs. lar gene (locus)
Shannon, Joyce Brennfleck. Mental Retardation autosomal dominant allele: an allele of a
Sourcebook: Basic Consumer Health Information gene (locus) on one of the nonsex chromo-
About Mental Retardation and Its Causes, In- somes that is always expressed, even if the
cluding Down Syndrome, Fetal Alcohol Syndrome, other allele is normal
Fragile X Syndrome, Genetic Conditions, Injury. autosomal recessive allele: an allele of a
Detroit, Mich.: Omnigraphics, 2000. Provides gene which will be expressed only if there
basic consumer health information about are two identical copies
Dwarfism 249
cusses results of a survey conducted by the Ulijaszek, J. S., Francis E. Johnston, and Mi-
authors. chael A. Preece. Cambridge Encyclopedia of
Krakow, D., et al. Use of Three-Dimensional Human Growth and Development. New York:
Ultrasound Imaging in the Diagnosis of Pre- Cambridge University Press, 1998. Broadly
natal-Onset Skeletal Dysplasias. Ultrasound discusses genetic growth anomalies in rela-
in Obstetrics and Gynecology 21 (2003): 4676- tion to environmental, physiological, social,
4678. Describes in detail the newest ap- economic, and nutritional influences on hu-
proach to prenatal detection of dysplasias. man growth.
Page, Nick. Lord Minimus: The Extraordinary Life Vajo, Zoltan, Clair A. Francomano, and Doug-
of Britains Smallest Man. New York: St. Mar- las J. Wilkin. The Molecular and Genetic
tins Press, 2002. Relates the exciting life led Basis of Fibroblast Growth Factor Receptor 3
by Jeffrey Hudson, a dwarf, in the court of Disorders: The Achondroplasia Family of
King Charles I and Queen Henrietta Maria. Skeletal Dysplasias, Muenke Craniosynosto-
Ranke, M., and G. Gilli. Growth Standards, Bone sis, and Crouzon Syndrome with Acanthosis
Maturation, and Idiopathic Short Stature. Nigricans. Endocrine Reviews 21, no. 1 (2000):
Farmington, Conn.: S. Karger, 1996. KABI 23-39. Aimed at researchers.
International Growth Study to establish Zelzer, Elazar, and Bjorn R. Olsen. The Ge-
global guidelines and standards for diagno- netic Basis for Skeletal Diseases. Nature 423
sis and treatment of growth disorders and (2003): 343-348. Aimed at researchers but
definition of idiopathic short stature (ISS). understandable by a wider audience.
Richardson, John H. In the Little World: A True
Story of Dwarfs, Love, and Trouble. San Fran-
cisco: HarperCollins, 2001. A wide-ranging Web Sites of Interest
look at the world of the little people, as Centralized Dwarfism Resources. http://
many people with dwarfism prefer to be www.dwarfism.org. Offers information on
called. types of dwarfism and links to other informa-
Thorner, M., and R. Smith. Human Growth Hor- tive sites.
mone: Research and Clinical Practice. Vol. 19. National Center for Biotechnology Informa-
Totowa, N.J.: Humana Press, 1999. Exam- tion. Online Mendelian Inheritance in Man.
ines the use of human growth hormone http://www.ncbi.nlm.nih.gov/Omim. A
therapies in the treatment of short stature catalog on genes and genetic disorders, in-
and various diseases. cluding dwarfism, searchable by keyword.
Emerging Diseases Epidemiological Background
Fields of study: Diseases and syndromes; Emerging diseases are new illnesses or old
Viral genetics ailments whose incidence in humans or other
Significance: Pandemics caused by emerging dis- target organisms, such as economically impor-
eases have the potential to sweep the globe and kill tant plants or animals, have increased. The key
millions of persons. These diseases typically arise to an emergent or reemergent disease is that
by evolutionary processesnatural selection or ar- the change in its status is sudden and unex-
tificial selection via the misuse of antibioticsby pected. For example, acquired immunodefi-
swapping of plasmids or other genetic elements, or ciency syndrome (AIDS)caused by the hu-
else they represent pathogens normally found in man immunodeficiency virus (HIV)is an
animals that make the jump into humans. example of a new disease that emerged from an
isolated, mysterious wasting syndrome to a pan-
Key term demic that has killed millions. Tuberculosis,
drug resistance: a phenomenon in which caused by Mycobacterium tuberculosis, is an exam-
pathogens no longer respond to drug thera- ple of an old, more or less controlled condition
pies that used to control them; resistance that has reemerged in an age when many peo-
can arise by recombination, by mutation or ple have compromised immune systems and
by several methods of gene transfer, or by when antibiotic misuse has promoted the de-
misuse of existing drugs velopment of drug-resistant strains.
emerging disease: a disease whose incidence In many cases, emerging diseases are not the
in humans or other target organisms has in- result of genetic changes. They instead gain a
creased foothold in a new species by transmission from
interspecific transmission: when a patho- another host. The probability of interspecific
gen infecting one host infects another host transmission rises as contacts increase between
of a different species species that formerly had few opportunities to
interact. For example, the Ebola virus may have
A Global Scare made the leap into humans as humans en-
Early in 2003, a new virus appeared. The ill- croached upon the forests of central Africa and
ness it caused, severe acute respiratory syn- came into greater contact with the natural hosts
drome (SARS), began with flu-like symptoms of the disease. HIV may have made a similar
fever, chills, headache followed by a dr y leap. Influenza viruses infect humans, swine,
coughbut appeared to be quite deadly. By horses, poultry, and waterfowl. New strains of
mid-April of the year, more than 3,500 persons the virus often emerge in regions, such as south-
around the globe had been diagnosed with ern China, where an agricultural mode of life
SARS. Of those, more than 150 had died. As prevails and humans live in close proximity to
the illness spread from its apparent source in farm animals. The close proximity of several sus-
Guangdong Province, China, individuals in- ceptible hosts makes it easy for mutant strains
fected with or exposed to it were quarantined. to develop in one species and spread to others.
International travel was restricted, damping an
already sluggish global economy. Also by mid- The Mutants
April of that year, the World Heath Organi- In 1997, a new strain of influenza emerged
zation announced that an international team in Hong Kong. The strain (H5N1) leapt from
of researchers had determined that a corona- chickens to humans and was armed with a mu-
virusa type of virus related to those that cause tation that allowed it to disable a part of the
the common coldwas the cause of the syn- immune system. H5N1 killed only six people
drome. However, it was of a type never before but that small number was one-third of the per-
seen. SARS is a prime example of the potential sons infected, a very large proportion. Nor-
threat posed by emerging infectious diseases. mally, the flu virus would be contained within
Emerging Diseases 253
the lungs or intestines of the chicken, but this humans. Other parts resembled those of
particular strain spread to other tissues and strains that normally infected swine. Such
had the potential to kill victims quickly. Subse- swapping of similar genetic sequences is called
quent research traced the change to one gene, recombination. The new combinations may
PB2. The mutation in PB2 gave H5N1 the abil- have arisen as the swine strain infected hu-
ity to infect people. Because of the dangers mans, or as the human strain infected swine
posed by the 1997 strain, Hong Kong authori- or they may have arisen through many infec-
ties ordered the destruction of more than a mil- tions back and forth. While no one is sure how
lion fowl. The mass killing was repeated during the combination of human and swine charac-
another outbreak in 2001 and 2002, during teristics proved so deadlyor how it aroseno
which 4 million fowl were destroyed. one can dispute its lethal effectiveness.
A mutation can affect as little as a single
base pair in a strand of DNA or RNA, or it
can involve much longer segments. The
classes of mutations include substitutions,
deletions, and insertions. Substitutions oc-
cur when a nitrogenous base or a sequence
of bases in a nucleic acid is replaced by an-
other sequence of identical length. Substi-
tutions can be silentthat is, they can have
no effect because the changed sequence
calls for the same amino acid as the origi-
nal. However, substitutions can cause mis-
sense mutations, in which a different
amino acid is called for, or nonsense muta-
tions, which signals the end of a polypep-
tide chain. Deletions occur when a portion
of a gene is cut out and lost. Insertions oc- Image not available
cur when more nucleotides are inserted
into the sequence of an existing gene.
century to define genes that mask the expres- derstanding of the influence of genotype on
sion of other genes. The gene at the initial loca- phenotype.
tion (locus) is termed the epistatic gene. The A gene can influence the expression of
genes at the other loci are hypostatic to the other genes in many different ways. One result
initial gene. In its strictest sense, it describes a of multiple genes is that more phenotypic
nonreciprocal interaction between two or classes can result than can be explained by the
more genes, such that one gene modifies, sup- action of a single pair of alleles. The initial evi-
presses, or otherwise influences the expression dence for this phenomenon came out of the
of another gene affecting the same phenotypic work of Bateson and British geneticist Reginald
(physical) character or process. By this defini- C. Punnett during their investigations on the
tion, simple additive effects of genes affecting a inheritance of comb shape in domesticated
single phenotypic character or process would chickens. The leghorn breed has a single
not be considered an epistatic interaction. Sim- comb, brahmas have pea combs, and wyan-
ilarly, interactions between alternative forms dottes have rose combs. Crosses between brah-
(alleles) of a single gene are governed by domi- mas and wyandottes have walnut combs. Inter-
nance effects and are not epistatic. Epistatic ef- crosses among walnut types show four different
fects are interlocus interactions. Therefore, in types of F2 (second-generation) progeny, in the
terms of the total genetic contribution to phe- ratio 9 walnut: 3 rose: 3 pea: 1 single. This ratio
notype, three factors are involved: dominance of phenotypes is consistent with the classical
effects, additive effects, and epistatic effects. F2 ratio for dihybrid inheritance. The corre-
The analysis of epistatic effects can suggest ways sponding ratio of genotypes, therefore, would
in which the action of genes can control a phe- be 9 A_ B_:3 A_ bb:3 aa B_:1 aa bb, respectively.
notype and thus supply a more complete un- (The underscore is used to indicate that the
White White
CCpp ccPP
Purple
F1 CcPp
CP Cp cP cp
When white-flowered sweet pea plants were crossed, the first-generation progeny (F1 ) all had purple flowers. When these plants were
self-fertilized, the second-generation progeny (F2 ) revealed a ratio of nine purple to seven white. This result can be explained by the
presence of two genes for flower pigmentation, P (dominant) and p (recessive) and C or c. Both dominant forms, P and C, must be
present in order to produce purple flowers.
Epistasis 257
gene phenomenon over an inhibiting epistatic mines the final fitness of an individual, not only
gene interaction. as a sum total of individual genes (additive ef-
fects) or by the interaction between different
Masking Gene Action forms of a gene (dominance effects) but also by
Masking gene action, a form of modifying the interaction between different genes (intra-
gene action, results when one gene is the pri- genomic or epistatic effects). This situation is
mary determinant of the phenotype of the off- something akin to a chorus: Great choruses not
spring. An example of this phenomenon is only have singularly fine voices, but they also
fruit color in summer squash. In this example, perform magnificently as finely tuned and co-
the F2 ratio is 12:3:1, indicating that the first ordinated units. Knowledge of what contrib-
gene in its dominant form results in the first utes to a superior genome would, therefore,
phenotype (white fruit); thus this gene is the lead to a fuller understanding of the inheri-
primary determinant of the phenotype. If the tance of quantitative characters and more di-
first gene is in its recessive form and the second rected approaches to genetic improvement.
gene is in its dominant form, the fruit will be For example, most economically important
yellow. The fruit will be green at maturity only characteristics of agricultural species (such as
when both genes are in their recessive form (1 16 yield, pest and disease resistance, and stress tol-
of the F2 population). erance) are quantitatively inherited, the net re-
sult of many genes and their interactions. Thus
Duplicate Gene Interaction an understanding of the combining ability of
Duplicate gene interaction occurs when two genes and their influence on the final appear-
different genes have the same final result in ance of domesticated breeds and crop varieties
terms of their observable influence on pheno- should lead to more efficient genetic improve-
type. This situation is different from additive ment schemes. In addition, it is thought that
gene action in that either gene may substitute many important human diseases are inherited
for the other in the expression of the final phe- as a complex interplay among many genes.
notype of the individual. It may be argued that Similarly, an understanding of genomic func-
duplicate gene action is not a form of epistasis, tioning should lead to improved screening or
since there may be no interaction between therapies.
genes (if the two genes code for the same pro- Henry R. Owen
tein product), but this situation may be an ex- See also: Chromosome Structure; Chromo-
ample of gene interaction when two genes some Theory of Heredity; Classical Transmis-
code for similar protein products involved in sion Genetics; Complete Dominance; Dihybrid
the same biochemical pathway and their com- Inheritance; Extrachromosomal Inheritance;
bined interaction determines the final pheno- Hybridization and Introgression; Incomplete
type of the individual. An example of this type Dominance; Lamarckianism; Mendelian Ge-
of epistasis is illustrated by seed capsule shape netics; Monohybrid Inheritance; Multiple Al-
in the herb shepherds purse. In this example, leles; Nondisjunction and Aneuploidy; Parthe-
either gene in its dominant form will contrib- nogenesis; Penetrance; Polygenic Inheritance;
ute to the final phenotype of the individual (tri- Quantitative Inheritance.
angular shape). If both genes are in their reces-
sive form, the seed capsule has an ovoid shape. Further Reading
Thus, the phenotypic ratio of the F2 generation Frankel, Wayne N., and Nicholas J. Schork.
is 15:1. Whos Afraid of Epistasis? Nature Genetics
14 (December, 1996). A reexamination of
Impact and Applications the whole concept of epistasis, with statistical
Nonallelic gene interactions have consider- implications.
able influence on the overall functioning of an Russell, Peter J. Fundamentals of Genetics. 2d ed.
individual. In other words, the genome (the San Francisco: Benjamin Cummings, 2000.
entire genetic makeup of an organism) deter- Introduces the three main areas of genetics:
Eugenics 259
studied has often been misinterpreted as inevi- eugenics and the power of good-making traits
tability. In 1907, Galton founded the Eugenics to shape society. Like Galton, he believed that
Education Society of London. He also carefully those in the higher social strata should be pro-
cataloged eminent families in his Hereditary Ge- vided with financial subsidies to counteract the
nius (1869), wherein the Victorian world was resultant sterility caused when upper class in-
assumed to be the ultimate level that society dividuals opt to have fewer children for their
could attain and the cultural transmission of own social advantage.
status, knowledge, and social connections were British embryologist William Bateson, who
discounted. coined the terms genes and genetics, cham-
pioned the Mendelian genetics that finally un-
Early Eugenics in Britain seated the popularity of Galtons ideas in En-
Statistician and social theorist Karl Pearson gland. In a debate that lasted thirty years, those
was Galtons disciple and first Galton Professor that believed in Austrian monk Gregor Men-
of Eugenics at the Galton Laboratory at the dels particulate inheritance argued against
University of London. His Grammar of Science the selection touted by the biometricians, and
(1892) outlined his belief that eugenic man- vice versa. Bateson, who had a deep distrust of
agement of society could prevent genetic dete- eugenics, successfully replicated Mendels ex-
rioration and ensure the existence of intelli- periments. Not recognizing that the two argu-
gent rulers, in part by transferring resources ments were not mutually exclusive, Pearson
from inferior races back into the society. Ac- and Weldon rejected genetics, thus setting up
cording to philosopher David J. Depew and the standoff between the two camps.
biochemist Bruce H. Weber, even attorney Fisher, on the other hand, tried to model the
Thomas Henry Huxley, champion of Darwin- trajectory of genes in a population as if they
ism, balked at this pruning of the human gar- were gas molecules governed by the laws of
den by the administrators of eugenics. For the thermodynamics, with the aim of converting
most part, though, British eugenicists focused natural selection into a universal law. He used
on improving the superior rather than elimi- such genetic atomism to propose that contin-
nating the inferior. uous variation, natural selection, and Mendel-
Another of Galtons followers, comparative ian genetics could all coexist. Fisher also math-
anatomist Walter Frank Weldon, like Galton ematically derived Galtons bell-shaped curves
before him, set out to measure all manner of based on Mendelian principles. Unfortunately,
things, showing that the distribution of many by emulating physics, Fisher underestimated
human traits formed a bell-shaped curve. In a the degree to which environment dictates which
study on crabs, he showed that natural selec- traits are adaptive.
tion can cause the mean of such a curve to shift,
adding fuel to the eugenicists conviction that Early Eugenics in the United States
they could better the human race through arti- While Mendelians and statisticians were de-
ficial selection. bating in Britain, in the United States, Harvard
Population geneticist Ronald A. Fisher was embryologist Charles Davenport and others
Pearsons successor as the Galton Professor of embarked on a mission of meshing early genet-
Eugenics. Fisher cofounded the Cambridge ics with the eugenics movement. In his effort,
Eugenics Society and became close to Charles Davenport created the Laboratory for Experi-
Darwins sons, Leonard and Horace Darwin. In mental Evolution at Cold Springs Harbor, New
a speech made to the Eugenics Education Soci- York. The laboratory was closely linked to his
ety, Fisher called eugenicists the agents of a Eugenics Record Office (ERO), which he es-
new phase of evolution and the new natural tablished in 1910. Davenport raised much of
nobility, with the view that humans were be- the money for these facilities by appealing to
coming responsible for their own evolution. wealthy American families who feared unre-
The second half of his book The Genetical Theory stricted immigration and race degeneration.
of Natural Selection (1930) deals expressly with Though their wealth depended on the availabil-
Eugenics 261
In the first half of the twentieth century, thousands of people in the United States, many of them teenagers thought to be weak or ab-
normal, were sterilized to prevent their genes from passing on to the next generation. Here Sarah Jane Wiley revisits the Virginia
Colony of the Epileptic and Feebleminded in Lynchburg, Virginia, where she and her brother were both sterilized in 1959. (AP/
Wide World Photos)
ity of cheap labor guaranteed by immigration, off. By the late 1920s and early 1930s, eugen-
these American aristocrats feared the cultural ics was a topic in high school biology texts and
impact of a flood of inferior immigrants. college courses across the United States.
Unlike the British, U.S. eugenicists thought Among eugenics supporters was psychologist
of selection as a purifying force and thus fo- Lewis M. Terman, developer of the Stanford-
cused on how to stop the defective from repro- Binet intelligence quotient (IQ) test, and Har-
ducing. Davenport wrongly felt that Mendelian vard psychologist Robert M. Yerkes, developer
genetics supported eugenics by reinforcing the of the Army IQ test, who both believed that IQ
effects of inheritance over the environment. test performance (and hence intelligence) was
He launched a hunt to identify human defects hereditary. The administration of such tests to
and link specific genes (as yet poorly under- immigrants by eugenicist Henry Goddard rep-
stood entities) to specific traits. His primary resented a supposedly objective and quantita-
tool was the family pedigree chart. Unfortu- tive tool for screening immigrants for entry
nately, these charts were usually based on into the United States. Biologist Garland Allen
highly subjective data, such as questionnaires reports that Goddard, in fact, determined that
given to schoolchildren to determine the com- more than 80 percent of the Jewish, Hungar-
parative social traits of various races. ian, Polish, Italian, and Russian immigrants
The Eugenics Research Association was were mentally defective.
founded in 1913 to report the latest findings. Fear that immigrants would take jobs away
In 1918, the Galton Society began meeting reg- from hardworking Americans, supported by
ularly at the American Museum of Natural His- testimony from EROs superintendent, Harry
tory in New York, and in 1923 the American Eu- Laughlin, and the findings of Goddards IQ
genics Society was formed. These efforts paid tests, resulted in the Johnson Act of 1924, which
262 Eugenics
severely restricted immigration. In the end, le- regard to political or ideological lines. Swe-
gal sterilization and immigration restrictions dens Social Democrats forcibly sterilized some
became more widespread in the United States sixty thousand Swedes under a program that
than in any country other than Nazi Germany. lasted from 1935 to 1976 organized by the state-
By 1940, more than thirty states in the United financed Institute for Racial Biology. Grounds
States had enacted compulsory sterilization for sterilization included not only feeblemind-
laws. Most were not repealed until after the edness but also gypsy features, criminality,
1960s. and poor racial quality. The low class or men-
tally slow were institutionalized in the Institutes
Eugenics and the Progressive Era for Misled and Morally Neglected Children
During the Progressive Era, the eugenics and released only if they would agree to be ster-
movement became a common ground for such ilized. Involuntary sterilization policies were
diverse groups as biologists, sociologists, psy- also adopted in countries ranging from Swit-
chologists, militarists, pacifists, socialists, com- zerland and Austria to Belgium and Canada,
munists, liberals, and conservatives. The pro- not to be repealed until the 1970s.
gressive ideology, exemplified by Theodore Hermann Mller, a eugenicist who emi-
Roosevelts Progressive Party, sought the scien- grated to the Soviet Union (and later returned
tific management of all parts of society. Eugen- to the United States), attacked Davenports
ics attracted the same crowd as preventative style of eugenics at the International Eugenics
medicine, since both were seen as methods of Congress in 1932. Mller, a geneticist who won
harnessing science to reduce suffering and the 1946 Nobel Prize for Physiology or Medi-
misfortune. For example, cereal entrepreneur cine for his discovery of the mutagenic power
John Harvey Kellogg founded the Race Better- of X rays, instead favored the style of eugenics
ment Foundation, mixing eugenics with hy- envisioned by English novelist Aldous Huxleys
giene, diet, and exercise. During this period, Brave New World (1932), with state nurseries, ar-
intellectuals of all stripes were attracted by the tificial insemination, and the use of other scien-
promise of the improvement of the human tific techniques to produce a genetically engi-
race by better breeding. The genetics research neered socialist society.
of this time focused on improving agriculture, According to journalist Jonathan Freedland,
and eugenics was seen as the logical counter- the British left, including a large number of so-
part to plant and animal husbandry. cialist intellectuals such as playwright George
Davenport did not hesitate to play on their Bernard Shaw and philosopher Bertrand Rus-
sympathies by making wild claims about the in- sell, was convinced that it knew what was best
heritance of nomadism, shiftlessness, love for society. Concerned with the preservation of
of the sea, and other traits as if they were their higher intellectual capacities, they joined
single Mendelian characteristics. Alcoholism, the fashionable and elitist Eugenics Society in
pauperism, prostitution, rebelliousness, crimi- the 1930s, where they advocated the control of
nality, feeblemindedness, chess expertise, and reproduction, particularly favoring the idea of
industrial sabotage were all claimed to be de- impregnating working-class women with sperm
termined by one or two pairs of Mendelian of men with high IQs.
genes. In particular, the progressives were lured
by the idea of sterilizing the weak minded, es- The American Movement Spreads to
pecially after the publication of articles about Nazi Germany
families in Appalachia and New Jersey that sup- The eugenics movement eventually led to
posedly documented genetic lines cursed by a grave consequences in Nazi Germany. Negative
preponderance of habitual criminal behavior eugenics reached its peak there, with forced
and mental weakness. sterilization, euthanasia or mercy killing, ex-
Having the allure of a social vaccination, perimentation, and ultimately genocide being
the enthusiasm to sterilize the defective used in the name of racial hygiene. Eugeni-
spread rapidly among intellectuals, without cists in the United States and Germany formed
Eugenics 263
close and direct alliances, especially after the himself died childless. This inverse relation-
Nazis came to power in 1933. The EROs Laugh- ship between fertility and social status, coupled
lin gave permission for his article Eugenical with the apparent predatory nature of the up-
Sterilization to be reprinted in German in per class, seemed to doom eugenics to failure.
1928. It soon became the basis of Nazi steriliza- Evolutionary biologist Stephen Jay Gould
tion policy. Davenport even arranged for a claimed that the demise of the eugenics move-
group of German eugenicists to participate in ment in the United States was more a matter of
the three hundredth anniversary of Harvards Adolf Hitlers use of eugenic arguments for
founding in 1936. sterilization and racial purification than it was
Inspired by the U.S. eugenics movement of advances in genetic knowledge. Once the
and spurred by economic hardship that fol- Holocaust and other Nazi atrocities became
lowed World War I, the Nazi Physicians League known, eugenicists distanced themselves from
took a stand that those suffering from incur- the movement. Depew and Weber have written
able disease caused useless waste of medica- that Catholic conservatives opposed to human
tions and, along with the crippled, the feeble- intervention in reproduction and progressives,
minded, the elderly, and the chronic poor, who began to abandon eugenics in favor of be-
posed an economic drain on society. Heredi- haviorism (nurture rather than nature), were
tary defects were considered to be the cause of political forces that began to close down the
such maladies, and these people were dubbed eugenics movement, while Allen points out
lives not worth living. In 1933, the German that the movement had outlived its political
Law on Preventing Hereditarily Diseased Prog- usefulness. Russian geneticist Theodosius Dob-
eny made involuntary sterilization of such peo- zhansky had by this time recognized the prime
ple, including the blind, deaf, epileptic, and importance of context in genetics and conse-
poor, legal. The Nazis set up eugenics courts quently rejected the premise of eugenics, help-
to decide cases of involuntary sterilization. Fred- ing to push it into the realm of phony genetics.
erick Osborn, secretary of the American Eugen-
ics Society, wrote a 1937 report summarizing Implications
the German sterilization programs, indicative The term euphenics is used to describe hu-
of the fascination American eugenicists had for man genetic research that is aimed at improv-
the Nazi agenda and the Nazis ability to move ing the human condition, replacing the tainted
this experiment to a scale never possible in the term eugenics. Euphenics deals primarily with
United States. medical or genetic intervention that is designed
to reduce the impact of defective genotypes on
The Demise of Eugenics individuals (such as gene therapy for those with
With the Great Depression in 1929, the U.S. cystic fibrosis). However, in this age of increas-
eugenics movement lost much of its momen- ing information about human genetics, it is
tum. Geneticist and evolutionary biologist necessary to keep in mind the important role
Sewall Wright, although himself a member of played by environment and the malleability of
the American Eugenics Society, found fault human traits.
with the genetics and the ideology of the move- Allen argues that the eugenics movement
ment: Positive eugenics seems to require . . . may reappear (although probably under a dif-
the setting up of an ideal of society to aim at, ferent name) if economic problems again
and this is just what people do not agree on. make it attractive to eliminate unproductive
He also wrote several articles in the 1930s chal- people. His hope is that a better understanding
lenging the assumptions of Fishers genetic at- of genetics, combined with the lessons of Nazi
omism model. In a speech to the Eugenics Soci- Germany, will deter humans from ever again
ety in New York in 1932, Mller pointed out the going down that path that journalist Jonathan
economic disincentive for middle and upper Freedland calls the foulest idea of the 20th
classes to reproduce, epitomized by the failure century.
of many eugenicists to have children. Galton Lee Anne Martnez
264 Eugenics: Nazi Germany
See also: Artificial Selection; Bioethics; genics movement and the Nazi program of
Bioinformatics; Biological Determinism; Clon- racial hygiene.
ing: Ethical Issues; Eugenics: Nazi Germany; Mazumdar, Pauline Margaret. Eugenics, Human
Evolutionary Biology; Gene Therapy: Ethical Genetics, and Human Failings. London: Rout-
and Economic Issues; Genetic Counseling; Ge- ledge, 1991. A thorough historical approach
netic Engineering: Social and Ethical Issues; that examines the eugenics movement from
Genetic Screening; Genetic Testing: Ethical its origin to its heyday as the source of a sci-
and Economic Issues; Heredity and Environ- ence of human genetics.
ment; Human Genetics; Insurance; Intelli- Pernick, Martin S. Science Misapplied: The
gence; Miscegenation and Antimiscegenation Eugenics Age Revisited. American Journal of
Laws; Natural Selection; Patents on Life- Public Health 87 (November, 1997). A fasci-
Forms; Paternity Tests; Race; Sociobiology; nating exploration of the overlap between
Stem Cells; Sterilization Laws. the goals, values, and concepts of public
health and the eugenics movements in the
Further Reading early twentieth century.
Allen, Garland E. Eugenics and Public Health
in American History. Technology Review 99 Web Sites of Interest
(August/September, 1996). Discusses the Cold Spring Harbor Laboratory, Image Ar-
connection between the eugenics movement chive on the American Eugenics Movement.
and periods of economic or social hardship. http://www.eugenicsarchive.org/eugenics.
Depew, David, and Bruce Weber. Darwinism Comprehensive and extensively illustrated
Evolving: Systems Dynamics and the Genealogy of site that covers the eugenics movement in
Natural Selection. Boston: MIT Press, 1995. the United States, including its scientific his-
Discusses the relationship between eugenics tory and origins, research methods and
and Darwinian evolution and the role played flaws, sterilization laws, and more.
by statistics in the origin of this movement. National Reference Center for Bioethics Lit-
Gillham, Nicholas Wright. A Life of Sir Francis erature. http://www.georgetown.edu/
Galton: From African Exploration to the Birth of research/nrcbl/scopenotes/sn28.html. An
Eugenics. New York: Oxford University Press, introduction to eugenics and a comprehen-
2001. A biography of the founder of the eu- sive annotated bibliography of sources for
genics movement. further study.
Herbert, Wray. The Politics of Biology. U.S.
News and World Report (April, 1997). Con-
siders the fluctuating viewpoint on the valid-
ity and social remedy for the genetics of hu- Eugenics: Nazi Germany
man behavior.
Kevles, Daniel J. In the Name of Eugenics: Genetics Field of study: History of genetics; Human
and the Uses of Human Heredity. Cambridge, genetics and social issues;
Mass.: Harvard University Press, 1995. Traces Significance: Fueled by economic hardship and ra-
the history of eugenics, mainly in the United cial prejudice, the largest-scale application of eu-
States and Britain, from the nineteenth cen- genics occurred in Nazi Germany, where numer-
tury to the late twentieth century. Individ- ous atrocities, including genocide, were committed
uals such as Karl Pearson, C. B. Davenport, in the name of the genetic improvement of the hu-
R. A. Fisher, and J. B. S. Haldane, who have man species. The German example raised world-
been associated with eugenics in various ways, wide awareness of the dangers of eugenics and did
are discussed. much to discredit eugenic theory.
Khl, Stefan. The Nazi Connection: Eugenics,
American Racism, and German National Social- Key terms
ism. New York: Oxford University Press, 2002. Aryan: a race believed by Nazis to have estab-
Exposes the ties between the American eu- lished the civilizations of Europe and India
Eugenics: Nazi Germany 265
euthanasia: the killing of suffering people, law. Between 1934 and 1945, an estimated
sometimes referred to as mercy killing 360,000 people (about 1 percent of the Ger-
Nordic: the northernmost of the Aryan groups man population) who were believed to have he-
of Europe, believed by the Nazis to be the reditary ailments were sterilized. Despite this
highest and purest racial group law, the Nazis did not see eugenics primarily as
a matter of discouraging the reproduction of
Origins of Nazi Eugenic Thought unhealthy individuals and encouraging the re-
Nazi eugenic theory and practice grew out production of healthy individuals. Following
of two traditions: the eugenics movement, the theories of Chamberlain, Adolf Hitler and
founded by British scientist Francis Galton, his followers saw race, not individual health or
and racial theories of human nature. Most his- abilities, as the distinguishing characteristic of
torians trace the origin of modern racial theo- human beings.
ries to French diplomat and writer Joseph- The Schutzstaffel (SS) organization was a
Arthur de Gobineau, who maintained that all key part of Nazi eugenic activities. In January,
great civilizations had been products of the 1929, Heinrich Himmler was put in charge of
Aryan, or Indo-Germanic, race. Through the the SS, a police force aimed at establishing or-
late nineteenth and early twentieth centuries, der among the street fighters who formed a
German thinkers applied Galtons ideas to the large part of the early Nazi Party. In addition
problem of German national progress. The to disciplining rowdy Nazis, the SS quickly
progress of the nation, argued scientists and so- emerged as a racial elite, the spearhead of an
cial thinkers, could be best promoted by improv- intended German eugenic movement. Himm-
ing the German people through government- ler recruited physicians and biologists to help
directed control of human reproduction. This ensure that only those of the purest Nordic her-
type of eugenic thinking became known as itage could serve in his organization. In 1931,
racial hygiene; in 1904, eugenicists and bi- the agriculturalist R. Walther Darre helped
ologists formed the Racial Hygiene Society in Himmler draw up a marriage code for SS men,
Berlin. and Himmler appointed Darre head of an SS
The Aryan mythology of Gobineau also grew Racial Office. Himmler hoped to create the
in popularity. In 1899, an English admirer of seeds of a German super race by directing the
Germany, Houston Stewart Chamberlain, pub- marriages and reproduction of the racially
lished a widely read book entitled The Foun- pure members of the SS.
dations of the Nineteenth Century. Chamberlain, Since the Nazis saw Germans as a master
heavily influenced by Gobineau, maintained race, a race of inherently superior people,
that Europes accomplishments had been the they attempted to improve the human stock by
work of ethnic Germans, members of a healthy encouraging the birth of as many Germans as
and imaginative race. Opposed to the Germans possible and by encouraging those seen as ra-
were the Jews, who were, according to Cham- cially pure to reproduce. The Nazis declared
berlain, impure products of crossbreeding that women should devote themselves to bear-
among the peoples of the Middle East. ing and caring for children. Hitlers mothers
birthday was declared the Day of the German
Basics of Nazi Eugenics Mother. On this day, public ceremonies
The Law to Prevent Hereditarily Sick Off- awarded medals to women with large numbers
spring, requiring sterilization of people with of children. The SS set up and maintained an
hereditary diseases and disabilities, was drafted organization of maternity homes for unmar-
and decreed in Germany in 1933. Before the ried mothers of acceptable racial background
Nazis came to power, many segments of Ger- and orphanages for their children; these insti-
man society had supported sterilization as a tutions were known as the Lebensborn (foun-
way to improve future generations, and Adolf tain of life). There is some evidence that
Hitlers emergence as a national leader pro- young women with desired racial characteris-
vided the pressure to ensure the passage of the tics who were not pregnant were brought to the
266 Eugenics: Nazi Germany
On Wehrmacht Day, 1935, in Nazi Germany (from left): German chancellor Adolf Hitler, head of the air force Hermann Gring,
army commander Wernher von Fritsch, minister of war Werner Eduard Fritz von Blomberg, commander of the navy Erich Raeder,
and other Nazi officials. During the late 1930s and early 1940s, the Nazi government conducted the extreme and brutal form of
eugenics that culminated in the Holocaust and the murder of millions of innocent Jews and other undesirables. (Library of
Congress)
Lebensborn to have children by the SS men to mass murder of the Jews during the Holocaust.
create superior Nordic children. German racial hygienists had long advocated
controlling marriages of non-Jewish Germans
Impact with Jews in order to avoid contaminating the
In addition to encouraging the reproduc- German race. In July, 1941, Nazi leader Her-
tion of those seen as racially pure, the Nazis mann Gring appointed SS officer Reinhard
sought to eliminate the unhealthy and the Heydrich to carry out the final solution of the
racially undesirable. In August, 1939, a com- perceived Jewish problem. At the Wannsee Con-
mittee of physicians and government officials, ference in January, 1942, Hitler and his close
operating under Hitlers authority, issued a associates agreed on a program of extermina-
secret decree under which all doctors and tion. According to conservative estimates, be-
midwives would have to register births of mal- tween four million and five million European
formed or handicapped children. By October Jews died in Nazi extermination camps. When
of that year, Hitler had issued orders for the the murderous activities of the Nazis were re-
mercy killing of these children and all those vealed to the world after the war, eugenics the-
with incurable diseases. This euthanasia move- ory and practice fell into disrepute.
ment expanded from sick and handicapped Carl L. Bankston III
children to those believed to belong to sick See also: Bioethics; Bioinformatics; Biolog-
races. The T4 euthanasia organization, de- ical Determinism; Eugenics; Evolutionary Biol-
signed for efficient and secret killing, experi- ogy; Gene Therapy: Ethical and Economic Is-
mented with lethal injections and killing by in- sues; Genetic Counseling; Genetic Engineering:
jection and became a pilot program for the Social and Ethical Issues; Genetic Screening;
Evolutionary Biology 267
As an example of the need for this perspec- between two species indicates that they are re-
tive, consider three vertebrates of different spe- lated to each other, just as familial similarity
cies, two aquatic (a whale and a fish) and one can be used to identify siblings in a crowd of
terrestrial (a deer). The two aquatic species people. In reality, all traits are somewhere along
share a torpedolike shape and oarlike append- a continuum between these two extremes, but
ages. These two species differ, however, in that this distinction highlights the importance of
one lays eggs and obtains oxygen from the understanding the evolutionary history of or-
water using gills, while the other produces live ganisms and traits. The value of an evolution-
young and must breathe air at the surface. The ary perspective comes from its comparative
terrestrial species has a different, less stream- and historical basis, which allows biologists to
lined, shape and appendages for walking, but it place their snapshot-in-time observations within
too breathes air using lungs and produces live the broader context of the continuous history
young. All three species are the same in having of life.
a bony skeleton typical of vertebrates. In order
to understand why the various organisms display Early Evolutionary Thought
the features they do, it is necessary to consider Underlying evolutionary theory is Mendel-
what forces or historical constraints influence ian genetics, which provides a mechanism
their genotypes and subsequent phenotypes. whereby advantageous traits can be passed on
It is logical to hypothesize that a streamlined to offspring. Both Mendelian genetics and the
shape is beneficial to swimming creatures, as is theory of evolution are at first glance (and in
the structure of their appendages. This state- retrospect) remarkably simple. The theory of
ment is itself an evolutionary hypothesis; it im- evolution, however, is paradoxical in that it
plies that streamlined individuals will be more leads to extremely complex predictions and
successful than less streamlined ones and so thus is often misunderstood, misinterpreted,
will become prevalent. It may initially be diffi- and misapplied.
cult to reconcile the differences between the It is important to distinguish between the
two aquatic forms swimming side-by-side with phenomenon of evolution and the various pro-
the similarities between one of them and the cesses or mechanisms that may lead to evolu-
terrestrial species walking around on dry land. tion. The idea that species might be mutable, or
However, if it is understood that the whale is subject to change over generations, dates back
more closely related to the terrestrial deer than to at least the mid-eighteenth century, when
it is to the fish, much of the confusion disap- the French naturalist Georges-Louis Leclerc,
pears. Using this comparative approach, it is comte de Buffon, the Swiss naturalist Charles
unnecessary, and scientifically unjustified, to Bonnet, and even the Swedish botanist Carolus
construct an elaborate scenario whereby breath- Linnaeus suggested that species (or at least
ing air at the surface is more advantageous to a varieties) might be modified over time by in-
whale than gills would be; the simpler explana- trinsic biological or extrinsic environmental
tion is that the whale breathes air because it factors. Other biologists after that time also
(like the deer) is a mammal, and both species promoted the idea that populations and spe-
inherited this trait from a common ancestor cies could evolve. Nevertheless, with the publi-
sometime in the past. cation of On the Origin of Species by Means of Natu-
Organisms are thus a mixture of two kinds of ral Selection in 1859, Charles Darwin became
traits. Ecological traits are those the particular the first to propose that all species had de-
form of which reflects long-term adaptation to scended from a common ancestor and that
the species habitat. Two species living in the there was a single tree of life. These claims re-
same habitat might then be expected to be sim- garding the history of evolution, however, are
ilar in such features and different from species distinct from the problem of how, or through
in other habitats. Evolutionary characteristics, what mechanisms, evolution occurs.
on the other hand, indicate common ancestry In the first decade of the nineteenth cen-
rather than common ecology. Here, similarity tury, Jean-Baptiste Lamarck promoted the the-
Evolutionary Biology 269
readily explained using Darwinian principles. a population. For example, natural selection
This effort culminated in the 1930s and 1940s may eliminate some individuals while others
in the modern synthesis, a fusion of thought survive and produce a large number of off-
that resulted in the development of the field of spring similar to themselves. As a result, evolu-
population genetics, a discipline in which biol- tion occurs within those populations. A key
ogists seek to describe and predict, quantita- tenet of Darwinian evolution (which distin-
tively, evolutionary changes in populations and guishes it from Lamarckian evolution) is that
higher groups of organisms. populations evolve, but the individual organ-
Since the modern synthesis (also called the isms that constitute that population do not.
neo-Darwinian synthesis), biologists have con- While evolution of populations is certainly the
centrated their efforts on applying the theories most familiar scenario, this is not the only level
of population genetics to understanding the at which evolution occurs.
evolutionary dynamics of particular groups of Richard Dawkins energized the scientific dis-
organisms. More recently, techniques of phylo- cussion of evolution with his book The Selfish
genetic systematics have been developed to Gene, first published in 1976. Dawkins argued
provide a means of reconstructing phylogen- that natural selection could operate on any
etic relationships among species. This effort type of replicator, or unit of biological organi-
has emphasized the need for a comparative zation that displayed a faithful but imperfect
and evolutionary approach to biology, which is mechanism of copying itself and that had dif-
essential to correct interpretation of data. fering rates of survival and reproduction among
In the 1960s, Motoo Kimura proposed the the variant copies. Under this definition, it is
neutral theory of evolution, which challenged possible to view individual genes or strands of
the selectionist view that patterns of genetic DNA as focal points for evolutionary mecha-
and phenotypic variation in most traits are de- nisms such as selection. Dawkins used this
termined by natural selection. The neutralist
view maintains that much genetic variation, es-
pecially that seen in the numerous alleles of
enzyme-coding genes, has little effect on fitness
and therefore must be controlled by mecha-
nisms other than selection. The last remaining
frontier in the quest for a unified model of evo-
lution is the integration of evolutionary theory
with the understanding of the processes of de-
velopment.
Evolutionary Mechanisms
Natural selection as described by Darwin
and Wallace leads to the evolution of adapta-
tions. However, many traits (perhaps the major-
ity) are not adaptations; that is, differences in
the particular form of those traits from one
member of the species to the next do not lead
to differences in fitness among those individu-
als. Such traits cannot evolve through natural
selection, yet they can and do evolve. Thus,
there must be additional mechanisms that lead
to changes in the genetic structure of biologi-
cal systems over time. Alfred Russel Wallace is now considered the co-author of mod-
Evolutionary mechanisms are usually envi- ern evolutionary theory along with Darwin. (National Li-
sioned to act on individual organisms within brary of Medicine)
Evolutionary Biology 271
framework to consider how the existence of ing evolutionary changes when coupled with
DNA selected to maximize its chances of repli- processes of selection or genetic drift that can
cation (or selfish DNA) would influence the quickly change allele frequencies. Recombina-
evolution of social behavior, communication, tion, development, migration, and hybridiza-
and even multicellularity. tion introduce new patterns of genetic variation
Recognizing that biological systems are ar- (initially derived from mutation of individual
ranged in a hierarchical fashion from genes to genes) at the genome, multicellular-organism,
genomes (or cells) to individuals through pop- population, and species levels, respectively.
ulations, species, and communities, Elisabeth
Vrba and Niles Eldredge in 1984 proposed that The Reality of Evolution
evolutionary changes could occur in any col- It is impossible to prove that descent with
lection of entities (such as populations) as a modification from a common ancestor is re-
result of mechanisms acting on the entities sponsible for the diversity of life on earth. In
that make up that collection (individuals). Be- fact, this dilemma of absolute proof exists for
cause each level in the biological hierarchy (at all scientific theories; as a result, science pro-
least above that of genes) has as its building ceeds by constructing and testing potential ex-
blocks the elements of the preceding one, evo- planations, gradually accepting those best sup-
lution may occur within any of them. Vrba and ported by new observations until they are either
Eldredge further argued that evolution could clearly disproved or replaced by another the-
be viewed as resulting from two general kinds ory even more consistent with the data.
of mechanisms: those that introduce genetic Darwins concept of a single tree of life is
variation and those that sort whatever variation supported by vast amounts of scientific evi-
is available. At each level, there are processes dence. In fact, the theory of evolution is among
that introduce and sort variation, though they the most thoroughly tested and best-supported
may have different names depending on the theories in all of science. The view that evolu-
level being discussed. tion has and continues to occur is not debated
Natural selection is a sorting process. Other by biologists; there is simply too much evidence
mechanisms that sort genetic variation include to support its existence, across every biological
sexual selection, whereby certain variants are discipline.
favored based on their ability to enhance repro- On a small scale, it is possible to demon-
ductive success (though not necessarily sur- strate evolutionary changes experimentally or
vival), and genetic drift, which is especially through observation. Spontaneous mutations
important in small populations. While these that introduce genetic variation are well docu-
forces are potentially strong engines for driving mented; the origination and spread of drug-
changes in genetic structure, their action resistant forms of viruses and other pathogens
and therefore the direction and magnitude of is clear evidence of this potential. Agricultural
evolutionary changes that they can causeis breeding programs and other types of artificial
constrained by the types of variation available selection illustrate that the genetic structure of
and the extent to which that variation is geneti- lineages containing heritable variation can be
cally controlled. changed over time. For example, work by John
Processes such as mutation, recombination, Doebley begun in the late 1980s suggested that
development, migration, and hybridization in- the evolution of corn from its wild ancestor teo-
troduce variation at one or more levels in the sinte may have involved changes in as few as five
biological hierarchy. Of these, mutation is ulti- major genes and that this transition likely oc-
mately the most important, as changes in DNA curred as a result of domestication processes
sequences constitute the raw material for evolu- established in Mexico between seven thousand
tion at all levels. Without mutation, there would and ten thousand years ago. The effects of nat-
be no variation and thus no evolution. Never- ural selection can likewise be observed in oper-
theless, mutation alone is a relatively weak evo- ation: Peter Grant and his colleagues demon-
lutionary force, only really significant in driv- strated that during drought periods, when seed
272 Evolutionary Biology
is limited, deep-billed individuals of the Gal- splits, such as reptiles to birds or nonflowering
pagos Island finch Geospiza fortis increase in plants to flowering plants; and (2) paleontolo-
proportion to the general population of the gists have long emphasized that gradualism
species, as only the deep-billed birds can crack that is, evolution by gradual changes, eventually
the large seeds remaining after the supply of producing major changesis not supported by
smaller seeds is exhausted. These and similar the fossil record. The fossil record more often
examples demonstrate that the evolutionary shows a pattern of almost no change over mil-
mechanisms put forward by Darwin and others lions of years, followed by much shorter pe-
do occur and lead to microevolution, or evolu- riods of rapid change. Stephen Jay Gould and
tionary change within single species. Niles Eldredge, both paleontologists, proposed
Attempts to account for larger-scale macro- a new theory called punctuated equilibrium to
evolutionary patterns, such as speciation and explain this discrepancy.
the origin of major groups of organisms, rely Gould and Eldredges theory accepts the
on indirect tests using morphological and ge- fact that the fossil record shows long periods of
netic comparisons among different species, ob- stasis (no change) followed by periods of rapid
served geographic distributions of species, and change and consider this the primary mode for
the fossil record. Such comparative studies rely evolution. Instead of the strict neo-Darwinian
on the concept of homology, the presence of view of gradual changes leading to large
corresponding and similarly constructed fea- changes over time, Gould and Eldredge sug-
tures among species. gest that large changes are the result of a series
At the most basic level, organization of the of larger steps over a much shorter period of
genetic code is remarkably similar across spe- time. Some of the discoveries in developmen-
cies; only minor variations exist among organ- tal biologyof genes that, when mutated, can
isms as diverse as archaea (bacteria found in ex- cause fruit flies (Drosophila melanogaster) to grow
treme environments such as hot springs, salt legs on their heads instead of antennae, or that
lakes, and habitats lacking in oxygen), bacteria, can cause every other body segment to be miss-
and eukaryotes (organisms whose cells contain inghave helped provide some plausible mech-
a true nucleus, including plants, animals, fungi, anisms for rapid change. If genes like those in
and their unicellular counterparts). This ge- the fruit fly, which are master control genes,
netic homology extends as well to the presence undergo mutation, the result could be large
of shared and similarly functioning gene se- changes in a very short time. When first pro-
quences across biological taxa, such as homeo- posed, the punctuated equilibrium theory was
tic genes, common among all eukaryotes. Mor- not readily accepted, but it has gained more ac-
phological homologies are also widespread; the ceptance over time.
limbs of mammals, birds, amphibians, and rep-
tiles, for example, are all built out of the same The Practice of Evolutionary Biology
arrangement of bones (although the particular Contemporary evolutionary biology builds
shapes of these bones can vary greatly among upon the theoretical foundations established
groups). The conclusion that emerges from by Darwin, Wallace, the framers of the modern
this weight of independent evidence is that synthesis, and now Gould and Eldredge. While
structural homologies reflect an underlying evo- the reality of evolution is no longer in doubt,
lutionary homology, or descent from a com- considerable debate remains about the impor-
mon ancestor. tance of the various mechanisms in the history
of particular groups of organisms. Much effort
Punctuated Equilibrium continues to be directed at reconstructing the
Although the order of appearance of organ- particular historical path that life on earth has
isms in the fossil record is consistent with evolu- taken and that has led to the enormous diver-
tionary theory in general, it has been troubling sity of species. Likewise, scientists seek a fuller
in two major ways: (1) there are no unequivocal understanding of how new species arise, as the
transition fossils for the major evolutionary process of splitting lineages represents a water-
Evolutionary Biology 273
experiences of the unsung theorist of evolu- ents, but the site of non-nuclear DNA, the cyto-
tion Alfred Russel Wallace, whose research plasm, is almost always contributed by the female
paralleled that of Charles Darwin. parent. The understanding of this extrachromo-
Singh, Rama S., and Costas B. Krimbas, eds. somal inheritance is crucial, since many impor-
Evolutionary Genetics: From Molecules to Mor- tant traits in plants and animalsas well as mu-
phology. New York: Cambridge University tations implicated in disease and agingdisplay
Press, 2000. Focuses on the necessary role of this type of transmission.
evolutionary genetics in evolutionary biol-
ogy. Published in recognition of Richard Key terms
Lewontins work in evolutionary biology. Il- genome: hereditary material in the nucleus or
lustrations, bibliography, tables, diagrams, organelle of a cell
and index. plasmagene: a self-replicating gene in a cyto-
Weiner, Jonathan. The Beak of the Finch: A Story of plasmic organelle
Evolution in Our Time. New York: Random plasmon: the entire complement of genetic
House, 1995. Describes the work of Peter factors in the cytoplasm of a cell (plasma-
and Rosemary Grant on the evolution of genes or cytogenes); a plastid plasmon is re-
Charles Darwins finches in the Galpagos ferred to as a plastome
Islands. plastid: organelles, including chloroplasts, lo-
cated in the cytoplasm of plant cells which
Web Sites of Interest form the site for metabolic processes such as
Evolutionary Genetics Group, Grningen Uni- photosynthesis
versity. http://www.rug.nl/biologie/onder mitochondria: small structures enclosed by
zoek/onderzoekGroepen/evolutionar y double membranes found in the cytoplasm
Genetics/index. Concerned with how ge- of all higher cells, which produce chemical
netic structure and variation affect evolu- power for the cells and harbor their own
tionary and ecological processes. DNA
Harvard University, Department of Organismic
and Evolutionay Biology. http://www.oeb Discovery of Extrachromosomal
.harvard.edu. Site has a time line of signifi- Inheritance
cant figures in the history of evolutionary bi- Carl Correns, one of the three geneticists
ology and a survey of its foundations. who rediscovered Austrian botanist Gregor
Society for the Study of Evolution. http://www Mendels laws of inheritance in 1900, and
.evolutionandsociety.org. This site offers an Erwin Baur first described, independently, ex-
illustrative guide, Evolution, Science, and trachromosomal inheritance of plastid color
Society and the National Research Agenda, in 1909. However, they did not know then that
which includes discussion of the founda- they were observing the transmission patterns
tions, social effects, and future of evolution- of organelle genes. Correns studied the inheri-
ary biology. tance of plastid color in the albomaculata strain
of four-oclock plants (Mirabilis jalapa), whereas
Baur investigated garden geraniums (Pelargo-
nium zonate). Correns observed that seedlings
Extrachromosomal resembled the maternal parent regardless of the
Inheritance color of the male parent (uniparental-maternal
inheritance). Seeds obtained from plants with
Field of study: Cellular biology three types of brancheswith green leaves,
Significance: Extrachromosomal inheritance refers white leaves, and variegated (a mixture of green
to the transmission of traits that are controlled by and white) leavesprovided interesting results.
genes located in non-nuclear organelles such as Seeds from green-leaved branches produced
chloroplasts and mitochondria. Nuclear or chro- only green-leaved seedlings, and seeds from
mosomal traits are determined equally by both par- white-leaved branches produced only white-
Extrachromosomal Inheritance 275
leaved seedlings. However, seeds from branches (plasmons) can be called nonnuclear or cyto-
with variegated leaves resulted in varying ratios plasmic. The cytoplasm contains, among other
of green-leaved, white-leaved, and variegated- organelles, mitochondria in all higher organ-
leaved offspring. The explanation is that plas- isms and mitochondria and chloroplasts in
tids in egg cells of the green-leaved branches plants. Because cytoplasm is almost always to-
and white-leaved branches were only of one type tally contributed by the female parent, this type
(homoplasmic or homoplastidic)that is, nor- of transmission may also be called maternal or
mal chloroplasts in the green-leaved cells and uniparental inheritance.
white plastids (leukoplasts) in the white-leaved Most chromosomally inherited traits obey
cells. The cells of the variegated branches, on Mendels law of segregation, which states that a
the other hand, contained both chloroplasts and pair of alleles or different forms of a gene sepa-
leukoplasts (heteroplasmic or heteroplastidic) rate from each other during meiosis (the pro-
in varying proportions. Some descendants of cess that halves the chromosome number in ga-
the heteroplastidic cells received only chloro- mete formation). They also follow the law of
plasts, some received only leukoplasts, and some independent assortment, in which two alleles
received a mixture of the two types of plastids in of a gene assort and combine independently
varying proportions in the next generation, with two alleles of another gene. Such traits
hence variegation. may be called Mendelian traits. Extrachromo-
Baur observed similar progeny from recip- somal inheritance is one of the exceptions to
rocal crosses between normal green and white Mendelian inheritance. Thus, it can be called
Pelargonium plants. Progeny in both cases were non-Mendelian inheritance. (Mendel only stud-
of three types: green, white, and variegated, in ied and reported on traits controlled by nuclear
varying ratios. This indicated that cytoplasm genes.) Mendelian heredity is characterized by
was inherited from the male as well as the female regular ratios in segregating generations for
parent; however, the transmission of plastids qualitative trait differences and identical re-
was cytoplasmic. Male transmission of plastids sults from reciprocal crosses. On the contrary,
has also been observed in oenothera, snap- non-Mendelian inheritance is characterized by
dragons, beans (Phaseolus), potatoes, and rye. a lack of regular segregation ratio and non-
Rye is the only member of the grass family that identical results from reciprocal crosses.
exhibits both maternal and paternal inheri- The mitochondria are the sites of aerobic
tance of plastids. respiration (the breaking down of organic sub-
The investigations on plastid inheritance stances to release energy in the presence of oxy-
also clearly established that in plants exhibiting gen) in both plants and animals. They are, like
uniparental-maternal inheritance, a variegated plastids, self-replicating entities and exhibit ge-
maternal parent always produces green, white, netic continuity. The mitochondrial genes do
and variegated progeny in varying proportions not exhibit the Mendelian segregation pattern
because of its heteroplastidic nature. Crosses either. Mitochondrial genetics began around
between green and white plants always yield 1950 with the discovery of petite mutations
green or white progeny, depending upon the in bakers yeast (Saccharomyces cerevisiae). Re-
maternal parent, when the parental plants are searchers observed that one or two out of every
homoplasmic for plastids. one thousand colonies grown on culture me-
dium were smaller than normal colonies. The
Extrachromosomal Inheritance vs. petite colonies bred true (produced only petite
Nuclear Inheritance colonies). The petite mutants were respiration
Extrachromosomal inheritance has been deficient under aerobic conditions. The slow
found in many plants, including barley, maize, growth of the petite colonies was related to the
and rice. Traits are inherited through chloro- loss of a number of respiratory (cytochrome)
plasts, mitochondria, or plasmids (small, self- enzymes that occur in mitochondria. These
replicating structures). Inheritance of traits mitochondrial mutants, termed vegetative pe-
that are controlled by organelle genomes tites, can be induced with acriflavine and re-
276 Extrachromosomal Inheritance
lated dyes. Another type of mutation, called a ilar to that for plastids in the albomaculata vari-
suppressive petite, was found to be caused ety of four oclock plants.
by defective, rapidly replicating mitochondrial The chm mutator gene causes plastid muta-
DNA (mtDNA). Petite mutants that are strictly tions in the plant Arabidopsis, and mutator
under nuclear gene control have also been re- striata in barley causes mutations in both
ported and are called segregational petite mu- plastids and mitochondria. Cases of mutator-
tants. Most respiratory enzymes are under both induced mutations in the plastome have also
nuclear and mitochondrial control, which is in- been reported in rice and catnip.
dicative of collaboration between the two ge-
netic systems. Chloroplast and Mitochondrial DNA
In the fungus Neurospora, mitochondrial in- Plastids contain DNA, have their own DNA
heritance has been demonstrated for mutants polymerase (the enzyme responsible for DNA
referred to as poky (a slow-growth character- replication), and undergo mutation. The chloro-
istic). The mutation resulted from an impaired plast DNA (cpDNA) is a circular, self-replicating
mitochondrial function related to cytochromes system that carries genetic information that is
involved in electron transport. The mating be- transcribed (from DNA to RNA) and translated
tween poky female and normal male yields only (from RNA to protein) in the plastid. It repli-
poky progeny, but when the cross is reversed, cates in a semiconservative mannerthat is, an
the progeny are all normal, confirming mater- original strand of DNA is conserved and serves
nal inheritance for this mutation. as the template for a new strand in a manner
According to a 1970 study, cytoplasmic male similar to replication.
sterility is found in about eighty plant species. The soluble enzyme ribulose biphosphate
The molecular basis of cytoplasmic male steril- carboxylase/oxygenase (Rubisco) is involved
ity in maize through electrophoretic separa- in photosynthetic carbon dioxide fixation. In
tion of restriction-endonuclease-created frag- land plants and green algae, its large subunit is
ments of DNA was traced to mitochondrial a cpDNA product, while its small subunit is con-
DNA. Cytoplasmic male sterility can be over- trolled by a nuclear gene family. Thus, the
come by nuclear genes. The plasmids that reside Rubisco protein is, as are chloroplast ribo-
in mitochondria are also important extrachro- somes, a product of the cooperation between
mosomal DNA molecules that are especially im- the nuclear and chloroplast genes. In all other
portant in antibiotic resistance. Plasmids have algae, both the large and small subunits of
been found to be extremely useful in genetic Rubisco are encoded in cpDNA.
engineering. Mitochondrial DNA (mtDNA) molecules
are also circular and self-replicating. Human,
Mutator Genes yeast, and higher plant mtDNAs are the major
Plastome mutations can be induced by nu- systems that have been studied. The human
clear genes. A gene that increases the mutation mtDNA has a total of 16,569 base pairs. The
rate of another gene is called a mutator. One yeast mtDNA is five times larger than that (84
such gene is the recessive, nuclear iojap (ij) kilobases), and maize mtDNA is much larger
mutation in maize. In the homozygous (ij ij) than the yeast mtDNA. Every base pair of hu-
condition, it induces a plastid mutation. The man mtDNA may be involved in coding for a
name iojap has been derived from Iowa mitochondrial messenger RNA (mRNA) for a
(the maize strain in which the mutation is protein, a mitochondrial ribosomal RNA
found) and japonica (a type of striped variety (rRNA), or a mitochondrial transfer RNA
that the mutation resembles). Once the plastid (tRNA). It is compact, showing no intervening,
gene mutation caused by the ij gene has been noncoding base sequences between genes. It
initiated, the inheritance is non-Mendelian, has only one major promoter (a DNA region to
and it no longer depends on the nuclear ij which an RNA polymerase binds and initiates
gene. As long as the iojap plants are used as fe- transcription) on each strand. Most codons
male parents, the inheritance of the trait is sim- triplets of nucleotides (bases) in messenger
Extrachromosomal Inheritance 277
dependent upon each other. There is much sion of mtDNA in animals can be studied. Nu-
support for this theory. Researchers in 1972 merous deleterious point mutations of mtDNA
showed homology (genetic similarity) between are associated with various types of human dis-
ribosomal RNA from cyanobacteria and DNA orders involving deficiencies in the mitochon-
from the chloroplasts of Euglena gracilis. This drial oxidative phosphorylation (respiration)
provided support for chloroplasts as the de- apparatus. Leigh disease is caused by a point
scendants of cyanobacteria. Mitochondria are mutation in mtDNA. Deletions of mtDNA have
believed to have come from primitive bacteria been associated with diseases such as isolated
and plastids from blue-green algae. Molecular ocular myopathy, chronic progressive external
evidence strongly supports the endosymbiotic ophthalmoplegia, Kearn-Sayre syndrome, and
origin of mitochondria from alpha purple bac- Pearsons syndrome.
teria. The influence of the mitochondrial genome
In 1981, Lynn Margulis summarized evi- and mitochondrial function on nuclear gene
dence for this theory. There are many similari- expression is poorly understood, but progress
ties between prokaryotes and organelles: Both is being made toward understanding why a few
have circular DNA and the same size ribo- genes are still sequestered in the mitochondria
somes, both lack histones and a nuclear mem- and toward developing new tools to manipu-
brane, and both show similar response to anti- late mitochondrial genes.
biotics that inhibit protein synthesis. Both also Manjit S. Kang
show a primitive mode of translation that be- See also: Ancient DNA; Chloroplast Genes;
gins with formulated methionine. The discov- Genetic Code; Human Genetics; Mitochon-
ery of promiscuous DNA (DNA segments that drial Diseases; Mitochondrial Genes; Model
have been transferred between organelles or Organism: Chlamydomonas reinhardtii; RNA
from a mitochondrial genome to the nuclear World.
genome) in eukaryotic cells also lends support
to this theory.
Further Reading
Impact and Applications Attardi, Giuseppe M., and Anne Chomyn, eds.
Genetic investigations have helped tremen- Methods in Enzymology: Mitochondrial Biogenesis
dously in constructing a genetic map of maize and Genetics. Vols. 260, 264. San Diego: Aca-
cpDNA. Important features of the map, includ- demic Press, 1995. One hundred authors
ing two large, inverted, repeat segments con- contribute to thirty-six chapters, presenting
taining several rRNA and tRNA genes, are now a wealth of new methods and data and cover-
known. Detection and quantification of mu- ing the significant developments that have
tant mtDNA are essential for the diagnosis of expanded the scope of enzyme chemistry.
diseases and for providing insights into the mo- Cummings, Michael J. Human Heredity: Princi-
lecular basis of pathogenesis, etiology, and ulti- ples and Issues. 5th ed. Pacific Grove, Calif.:
mately the treatment of diseases. This should Brooks/Cole, 2000. College text that surveys
help enhance the knowledge of mitochondrial topics such as genetics as a human endeavor;
biogenesis. Mitochondrial dysfunction, result- cells, chromosomes, and cell division; trans-
ing partly from mutations in mtDNA, may play mission of genes from generation to genera-
a central role in organismal aging. tion; cytogenics; the source of genetic varia-
A number of human diseases associated with tion; cloning and recombinant DNA; genes
defects in mitochondrial function have been and cancer; genetics of behavior; and genes
identified. Large-scale deletions and tRNA in populations.
point mutations (base changes) in mtDNA are Gillham, Nicholas W. Organelle Genes and Ge-
associated with clinical mitochondrial encepha- nomes. London: Oxford University Press,
lomyopathies. Heteroplasmy (the coexistence 1997. Contains a comprehensive review of
of more than two types of mtDNA) has provided the genetic-molecular aspects of chloroplasts
experimental systems in which the transmis- and mitochondria.
Forensic Genetics and criminal law, especially in court pro-
Field of study: Human genetics and social ceedings
issues
Significance: Forensic genetics uses DNA or the in- Forensic Science and DNA Analysis
herited traits derived from DNA to identify indi- Forensic scientists use genetics for two major
viduals involved in criminal cases. Blood tests legal applications: identifying the source of a
and DNA testing are used to determine the source sample of blood, semen, or other tissue, and es-
of evidence, such as blood stains or semen, left at a tablishing the biological relationship between
crime scene. two people in paternity or maternity suits. Fo-
rensic scientists are frequently called upon to
Key terms testify as expert witnesses in criminal trials.
alleles: alternative versions of genes at a ge- One of the most useful sources of inherited
netic locus that determine an individuals traits for forensic science purposes is blood.
traits Such traits include blood type, proteins found
DNA fingerprinting: a DNA test used by fo- in the plasma, and enzymes found in blood
rensic scientists to aid in the identification of cells. The genes in people that determine such
criminals or to resolve paternity disputes inherited traits have many different forms (al-
forensic science: the application of scientific leles), and the specific combination of alleles
knowledge to analyze evidence used in civil for many of the inherited blood traits can be
A serologist at the Massachusetts State Police Crime Lab displays forms used to collect and identify bloods samples for the states DNA
database of people convicted of certain crimes. In 1998, a group of prisoners brought a suit against the state to overturn a law requir-
ing blood samples from anyone convicted of any of thirty-three different crimes. (AP/Wide World Photos)
280 Forensic Genetics
O. J. Simpson and attorneys discuss strategy for cross-examining a forensic scientist during Simpsons 1995 murder trial. Despite
DNA evidence that blood found near Simpsons home and in his car matched that of the murder victims, Simpson was acquitted by a
jury upon testimony that the evidence might have been contaminated. (AP/Wide World Photos)
used to identify an individual. The number of of criminal cases in which biological materials
useful blood group systems is small, however, are the primary evidence. The likelihood of
which means that a number of individuals false matches ranges from one per million to
might have blood groups identical to those of one per billion. These numbers, however, do
the subject being tested. not include the possibility of mishandling of ev-
The ultimate source of genetic information idence, laboratory errors, or planting of evi-
for identification of individuals is the DNA dence.
found in the chromosomes. Using a class of en-
zymes known as restriction enzymes, techni- Criminal Cases Involving DNA Evidence
cians can cut strands of DNA into segments, On November 6, 1987, serial rapist Tommy
forming bands similar to a supermarket bar Lee Andrews became the first American ever
code that vary with individuals family lines. convicted in a case involving DNA evidence.
The pattern, termed a DNA fingerprint or Samples of semen left at the crime scene by the
profile, is inherited much as are the alleles for rapist and blood taken from Andrews were sent
blood traits. DNA fingerprinting can be used to a New York laboratory for testing. Using the
to establish biological relationships (including techniques of DNA fingerprinting, the labora-
paternity) with great reliability, because a child tory isolated DNA from each sample, com-
cannot have a variation that is not present in pared the patterns, and found a DNA match
one of the parents. Since DNA is stable and can between the semen and the blood. Andrews
be reliably tested in dried blood or semen even was sentenced to twenty-two years in prison for
years after a crime has been committed, DNA rape, aggravated battery, and burglary.
fingerprinting has revolutionized the solution The 1990-1991 United States v. Yee homicide
Forensic Genetics 281
largement is not a result of testosterone levels, The pattern of inheritance for fragile X is
which are normal. Fragile X men are fertile, unusual. Fragile X syndrome increases in sever-
and offspring have been documented, but those ity through successive generations. This is ex-
with significant mental retardation rarely re- plained by a worsening of the defect in the
produce. FMR1 gene as it is passed from mothers to sons.
The intelligence quotient (IQ) of the major- Since males contribute the Y chromosome to
ity of affected males is in the moderate to se- their sons, fathers do not pass the fragile X gene
verely retarded range. Only a few affected males to their sons. They will, however, contribute
have IQs above seventy-five. Fragile X males fre- their X chromosome to their daughters. Be-
quently show delayed speech development and cause these daughters also receive an X chro-
language difficulties. Repetitive speech patterns mosome from their mothers, they generally ap-
may also be present. pear normal or only mildly affected. It is only
when these daughters have a son that the con-
Mode of Inheritance dition is expressed.
In males, any abnormal gene on the X chro- An explanation for this increasing severity
mosome is expressed because males have only through generations was discovered by analyz-
one X chromosome. In females, two copies of ing the DNA sequence of the FMR1 gene. The
the fragile X chromosome must be present for molecules composing DNA are adenine (A),
them to be affected. This is the classic pattern thymine (T), cytosine (C), and guanine (G)
for X-linked, or sex-linked, traits (traits whose and are referred to collectively as bases. In
genes are located on the X chromosome.) fragile X syndrome, a sequence in which the
Seventeen-year-old Jake Porter (wearing Mohawks jersey 45) suffers from fragile X syndrome. Here he is being honored by teammates
during halftime at Motor City Bowl in Detroit on December 26, 2002, for scoring a touchdown during an earlier game in
McDermott, Ohio. (AP/Wide World Photos)
284 Fragile X Syndrome
three bases CGG are repeated over and over extent to which their behavior is determined,
was found. The repetitive sequence is found in the difficulties they face, and the ways in
normal copies of the FMR1 gene, but in individ- which they can achieve independence and
uals with fragile X syndrome there are many fulfillment.
times more copies of the CGG triplet. The lon- Parker, James N., and Philip M. Parker, eds. The
ger repetitive sequence in the FMR1 gene pre- 2002 Official Parents Sourcebook on Fragile X
vents it from being expressed. Individuals not Syndrome. San Diego: ICON Health, 2002.
having the fragile X syndrome have a working Draws from public, academic, government,
FMR1 gene. and peer-reviewed research to guide parents
Linda R. Adkison, updated by Bryan Ness where and how to look for information cov-
See also: Behavior; Chromatin Packaging; ering virtually all topics related to fragile X
Classical Transmission Genetics; Congenital syndrome.
Defects; DNA Replication; Down Syndrome; Schmidt, Michael A. Fragile X Syndrome: Di-
Intelligence; Repetitive DNA. agnosis, Treatment, and Research. Journal
of the American Medical Association 277 (April
Further Reading 9, 1997). Provides a detailed discussion of
Dykens, Elisabeth M., Robert M. Hodapp, and fragile X syndrome.
Brenda M. Finucane. Genetics and Mental Re- Shannon, Joyce Brennfleck, ed. Mental Retarda-
tardation Syndromes: A New Look at Behavior tion Sourcebook: Basic Consumer Health Informa-
and Interventions. Baltimore: Paul H. Brookes, tion About Mental Retardation and Its Causes,
2000. Reviews the genetic and behavioral Including Down Syndrome, Fetal Alcohol Syn-
characteristics of nine mental retardation drome, Fragile X Syndrome, Genetic Conditions,
syndromes, giving in-depth information on Injury, and Environmental Sources. Detroit,
genetic causes, prevalence, and physical and Mich.: Omnigraphics, 2000. Reviews causes,
medical features of Down, Williams, fragile prevention, family life, education, specific
X, and Prader-Willi syndromes, as well as five health care issues, and legal and economic
other less frequently diagnosed syndromes. concerns for health care consumers.
Hagerman, Paul J. Fragile X Syndrome: Diagnosis, Warren, Stephen T. Trinucleotide Repetition
Treatment, and Research. 3d ed. Baltimore: and Fragile X Syndrome. Hospital Practice 32
Johns Hopkins University Press, 2002. Dis- (April 15, 1997). Provides detail about CGG
cusses the clinical approach to diagnosing repeats in fragile X syndrome.
fragile X; the latest research in epidemiol-
ogy, molecular biology, and genetics; and in-
formation on genetic counseling, pharma- Web Sites of Interest
cotherapy, intervention, and gene therapy. Dolan DNA Learning Center, Your Genes Your
Hirsch, David. Fragile X Syndrome. The Ex- Health. http://www.ygyh.org. Sponsored by
ceptional Parent 25 (June, 1995). Answers pa- the Cold Spring Harbor Laboratory, this site,
rental concerns about fragile X syndrome a component of the DNA Interactive Web
genetic testing. site, offers information on more than a dozen
_______. Fragile X Syndrome: Medications for inherited diseases and syndromes, including
Aggressive Behavior? The Exceptional Parent Fragile X syndrome.
26 (October, 1996). Addresses parental con- FRAXA Research Foundation. http://www
cerns about medications for males display- .fraxa.org. The foundation supports research
ing aggressive behavior. aimed at treatment, and this site offers infor-
Hogenboom, Marga. Living with Genetic Syn- mation on managing the syndrome.
dromes Associated with Intellectual Disability. National Fragile X Foundation. Xtraordinary
Philadelphia: Jessica Kingsley, 2001. Gives Accomplishments. http://www.nfxf.org.
an accessible introduction to genetics be- General information about the disorder,
fore detailing the ways in which young peo- with advice for caregivers on testing, medical
ple are affected by genetic conditions: the treatment, education, and life planning.
Gel Electrophoresis the molecule will allow an approximation of its
Field of study: Techniques and relative molecular weight.
methodologies As an analogy, imagine a family with two chil-
Significance: Gel electrophoresis is a laboratory dren picnicking by a thick, brushy forest. Their
technique involving the movement of charged mol- small dog runs into the brush, and the whole
ecules in a buffer solution when an electric field is family runs in after it. The dog, being the small-
applied to the solution. The technique allows scien- est, penetrates into the center of the forest. The
tists to separate DNA, RNA, and proteins accord- six-year-old can duck through many of the
ing to their size. The method is the most widely used branches and manages to get two-thirds of the
way to determine the molecular weight of these mol- way in; the twelve-year-old makes it halfway; the
ecules and can be used to determine the approxi- mother gets tangled up and must stop after
mate size of most DNA molecules and proteins. only a short distance; the father, too large to fit
in anywhere, cannot enter at all. This is what
Key terms happens to molecules moving through a gel:
denaturing: a method of disrupting the nor- Some travel through unimpeded, others are
mal three-dimensional structure of a pro- separated into easily visualized size groups, and
tein or nucleic acid so that it stretches out others cannot even enter the matrix.
more or less linearly
gel: a support matrix formed by interconnect- The Electrophoresis Setup
ing long polymers into a porous, solid mate- The gel is typically composed of a buffer so-
rial that retards the movement of molecules lution containing agarose or acrylamide, two
entrapped in it polymers that easily form a gel-like material at
staining dye: a chemical with a high affinity room temperature. At first the buffer/polymer
for DNA, RNA, or proteins that causes a visi- solution is liquid and is poured into a casting
ble color to develop that allows the detection chamber composed of a special tray or of two
of these molecules in the gel plates of glass with a narrow space between
them. A piece of plastic with alternating inden-
Basic Theory of Electrophoresis tations like an oversized comb is pushed into
Biologists often need to determine the ap- one end of the gel while it is still liquid. When
proximate size of DNA fragments, RNA, or pro- the gel has solidified, the comb is removed,
teins. All of these molecules are much too small leaving small depressions in the matrix (wells)
to visualize using conventional methods. The into which the DNA, RNA, or protein sample is
size of a piece of DNA capable of carrying all applied. The gel is then attached to an appara-
the information needed for a single gene may tus that exposes the ends of the gel to a buffer,
be only 2 microns long and 20 angstroms wide, each chamber of which is attached to an elec-
while the protein encoded by this gene might tric power supply. The buffer allows an even ap-
form into a globular ball only 2.5 to 10 nano- plication of the electric field.
meters in diameter. Therefore, some indirect Since the molecules of interest are so small,
method of seeing the length of these mole- matrices with small pore size must be created. It
cules must be used. The easiest and by far most is important to find a matrix that will properly
common way to do this is by gel electrophoresis. separate the molecules being studied. The key
Electrophoresis is based on the theory that if is to find a material that creates pores large
molecules can be induced to move in the same enough to let DNA or proteins enter but small
direction through a tangled web of material, enough to impede larger molecules. By using
smaller molecules will move farther through different concentrations of agarose or acryla-
the matrix than larger molecules. Thus, the dis- mide, anything from very short pieces of DNA
tance a molecule moves will be related to its that differ only by a single nucleotide to whole
size, and knowing the basic chemical nature of chromosomes can be separated.
286 Gel Electrophoresis
Agarose is composed of long, linear chains The charge on different amino acids varies
of multiple monosaccharides (sugars). At high considerably, and the proportions of the vari-
temperatures, 95 degrees Celsius (203 degrees ous amino acids vary widely from protein to
Fahrenheit), the agarose will melt in a buffer protein. Therefore, the charge on a protein has
solution. As the gel cools to around 50 degrees nothing to do with its length. To correct for
Celsius (122 degrees Fahrenheit), the long this, proteins are mixed with the detergent so-
chains begin to wrap around each other and so- dium dodecyl sulfate, or SDS (the same mate-
lidify into a gel. The concentration of agarose rial that gives most shampoos their suds), be-
determines the pore size, since a larger concen- fore being loaded onto the gel. The detergent
tration will create more of a tangle. Agarose is coats the protein evenly. This has two impor-
usually used with large DNA or RNA molecules. tant effects. The first is that the protein be-
Acrylamide is a short molecule made up of a comes denatured, and the polypeptide chain
core of two carbons connected through a dou- will largely exist as a long strand (rather than
ble bond with a short side-chain with a carboxyl being compactly bunched, as it normally is).
and amino group. When the reactive chemicals This is important because a tightly balled pro-
ammonium persulfate and TEMED are added, tein would more easily pass through the
the carbon ends fuse together to create long polyacrylamide matrix than a linear molecule,
chains of polyacrylamide. If this were the only and proteins with the same molecular weight
reaction, the end result would be much like might appear to be different sizes. More impor-
agarose. However, a small number (usually 5 tant, each SDS molecule has a slight negative
percent or less) of the acrylamides are the re- charge, so the even coating of the protein re-
lated molecule called bis-acrylamide, a two- sults in a negative charge that is directly pro-
headed version of the acrylamide molecule. portional to the size of the protein.
This allows the formation of interconnecting Once the molecules have been subjected to
branch points every twenty to fifty acrylamide the electric field long enough to separate them
residues on the chain, which creates a pattern in the gel, they must be visualized. This is done
more like a net than the tangled strands of by soaking the gel in a solution that contains a
agarose. This results in a narrower pore size dye that stains the molecules. For DNA and
than agarose, which allows the separation of RNA, this dye is usually ethidium bromide, a
much smaller fragments. Acrylamide is used to molecule that has an affinity for nucleic acids
separate proteins and small DNA fragments and slips between the strands or intercalates
and for sequencing gels in which DNA frag- into the helix. The dye, when exposed to ultra-
ments differing in size by only a single nucleo- violet light, glows orange, revealing the loca-
tide must be clearly separated. tion of the nucleic acid in the gel. For pro-
teins, the dye Coomassie blue is usually used, a
Why Nucleic Acids and Proteins stain that readily binds to proteins of most
Move in a Gel types.
DNA and RNA will migrate in an electric J. Aaron Cassill, updated by Bryan Ness
field since every base has a net negative charge. See also: Blotting: Southern, Northern, and
This means that DNA molecules are negatively Western; DNA Fingerprinting; Genetic Testing;
charged and will migrate toward the positive Proteomics; RFLP Analysis; Shotgun Cloning.
pole if placed in an electric field. In fact, since
each base contributes the same charge, the Further Reading
amount of negative charge is directly propor- Dunn, Michael J., ed. From Genome to Proteome:
tional to the length of the DNA. This means Advances in the Practice and Application of Pro-
that the electromotive force on any piece of teomics. New York: Wiley-VCH, 2000. Reviews
DNA or RNA is directly proportional to its advances in proteomics and covers topics
length (and therefore its mass) and that the such as sample preparation and solubiliza-
rate of movement of DNA or RNA molecules of tion, developments in electrophoresis, detec-
the same length should be the same. tion and quantification, mass spectrometry,
Gender Identity 287
may interfere with normal development and physical contact between two individuals of the
differentiation, leading to sexual phenotypes same gender which both recognize as being
that do not correspond to the chromosomal sexual in nature and which ordinarily results in
sex. sexual arousal. Other researchers have under-
One such case is that of hermaphrodites, in- scored the difficulty in defining and measuring
dividuals who possess both ovaries and testes. sexual orientation. Whatever measure is used,
They usually carry both male and female tissue. homosexuality is far more common than trans-
Some of their cells may be of the female chro- sexualism.
mosomal sex (XX), and some may be of the
male chromosomal sex (XY). Such individuals Impact and Applications
are called sex chromosome mosaics, and their Biological and genetic links to gender iden-
resulting phenotype may be related to the tity have been sought for more than a century.
number and location of cells that are XX and Studies on twins indicate a strong genetic com-
those that are XY. Another example is testicular ponent to sexual orientation. There appears to
feminization syndrome, in which a single gene be a greater chance for an identical twin of a
affects sexual differentiation. Individuals with gay person to be gay than for a fraternal twin.
this syndrome have the chromosomal sex of a Heritability averages about 50 percent in the
normal male but have a female phenotype. XY combined twin studies. The fact that heritabil-
males with this gene, located on the X chromo- ity is 50 percent rather than 100 percent, how-
some, exhibit initial development of the testes ever, may indicate that other biological and
and normal production of male hormones. environmental factors play a role. One study us-
However, the mutant gene prevents the hor- ing restriction fragment length polymorphisms
mones from binding to receptor cells; as a re- (RFLPs) to locate a gene on the X chromo-
sult, female characteristics develop. some associated with male homosexual behav-
ior showed a trend of maternal inheritance.
Gender Identity Disorder However, not all homosexual brothers had the
Gender identity disorder, or transsexualism, gene, and some heterosexual brothers shared
is defined by researchers as a persistent feeling the gene, indicating that other factors, whether
of discomfort or inappropriateness concern- genetic or nongenetic, influence sexual orien-
ing ones anatomic sex. The disorder typically tation.
begins in childhood and is manifested in ado- Although some genetic factors have been
lescence or adulthood as cross-dressing. About found to influence sexual orientation, most re-
one in eleven thousand men and one in thirty searchers believe that no single gene causes ho-
thousand women are estimated to display mosexuality. It is also apparent that gender
transsexual behavior. Hormonal and surgical identity and homosexuality are influenced by
sex reassignment are two forms of available complexes of factors dictated by biology, envi-
treatment for those wanting to take on the ronment, and culture. Geneticists and social
physical characteristics of their self-identified scientists alike continue to design studies to de-
gender. Little is known about the causes of gen- fine how the many factors are interrelated.
der identity disorder. In some cases, research Donald J. Nash
shows a strong correlation between children See also: Behavior; Biological Clocks; Her-
who exhibit cross-gender behavior and adult maphrodites; Homosexuality; Human Genet-
homosexual orientation. Adults with gender ics; Metafemales; Pseudohermaphrodites; Ste-
identity disorder and adult homosexuals often roid Hormones; Testicular Feminization
recall feelings of alienation beginning as early Syndrome; X Chromosome Inactivation; XYY
as preschool. Syndrome.
Although some clinical aspects are shared,
however, gender identity disorder is different Further Reading
from homosexuality. One definition for homo- Diamant, L., and R. McAnuity, eds. The Psychol-
sexuality proposed by Paul Gebhard is the ogy of Sexual Orientation, Behavior, and Identity:
Gene Families 289
A Handbook. Westport, Conn.: Greenwood which works to create a world free of shame,
Press, 1995. Draws from biological and psy- secrecy, and unwanted surgery for intersex
chological research to provide a compre- people (individuals born with anatomy or
hensive overview of the major theories about physiology which differs from cultural ideals
sexual orientation; to summarize recent de- of male and female). Includes or links to
velopments in genetic and neuroanatomic information on such conditions as clitoro-
research; to consider the role of social insti- megaly, micropenis, hypospadias, ambigu-
tutions in shaping current beliefs; and to dis- ous genitals, early genital surgery, adrenal
cuss the social construction of gender, sexu- hyperplasia, Klinefelter syndrome, androgen
ality, and sexual identity. insensitivity, and testicular feminization.
Ettore, Elizabeth. Reproductive Genetics, Gender, Johns Hopkins University, Division of Pediatric
and the Body. New York: Routledge, 2002. Fo- Endocrinology, Syndromes of Abnormal
cuses on prenatal screening to explore how Sex Differentiation. http://www.hopkins
the key concepts of gender and the body are medicine.org/pediatricendocrinology. Site
intertwined with the whole process of build- provides a guide to the science and genetics
ing genetic knowledge. of sex differentiation, including a glossary.
Haynes, Felicity, and Tarquam McKenna. Un- Click on patient resources.
seen Genders: Beyond the Binaries. New York:
Peter Lang, 2001. Explores the effects of bi-
nary stereotypes of sex and gender on trans-
sexuals, homosexuals, cross-dressers, and
transgender and intersex people. Gene Families
Money, John. Sex Errors of the Body and Related
Syndromes: A Guide to Counseling Children, Ad- Field of study: Molecular genetics
olescents, and Their Families. 2d ed. Baltimore: Significance: Gene families contain multiple cop-
P. H. Brookes, 1994. Describes numerous ies of structurally and functionally related genes,
gender variations in order to provide a basis derived from duplications of an original gene.
for understanding sexual development Some gene families represent multiple identical
anomalies and to enable appropriate coun- copies of an important gene, while others contain
seling. different versions of a gene with related functions.
Zucker, Kenneth J. Intersexuality and Gender Evolution of gene families can lead some genes to
Identity Differentiation. Annual Review of take on completely new functions, allowing greater
Sex Research 10 (1999). An extensive over- complexity of the genome and perhaps the organ-
view of intersexuality, gender identity forma- ism.
tion, psychosexual differentiation, concerns
about pediatric gender reassignment, her- Key terms
maphroditism and pseudohermaphrodit- concerted evolution: a process in which the
ism, gender socialization, childrearing, and members of a gene family evolve together
more. Includes a discussion of terminology, pseudogenes: nonfunctional segments of DNA
a summary, tables, and a bibliography. that resemble functional genes
repetitive DNA: a DNA sequence that is re-
Web Sites of Interest peated two or more times in a DNA mole-
About Gender. http://www.gender.org.uk. A cule or genome
site that looks at the nature versus nurture
debate in research on gender roles, identity, Evolutionary Origin of Gene Families
and variance, with special emphasis on ge- Gene families are a class of low or moder-
netics. ately repetitive DNA, consisting of structurally
Intersex Society of North America. http:// and functionally related genes resulting from
www.isna.org. The society is a public aware- gene duplication events. Usually, members of
ness, education, and advocacy organization gene families are clustered together on a chro-
290 Gene Families
mosome, but members of a family can be lo- the rate of transcription of many genes, are an-
cated on more than one chromosome. Several other example of clustered repeats of the same
mechanisms can generate tandem copies of set of genes. In this case, there are five histone
genes: chromosome duplication, unequal genes, separated by short, unrelated noncod-
crossing over, and replication slippage. Dupli- ing sequences, repeated several hundred times.
cation of chromosomal segments is often a The repeats are found in tandem in many in-
result of crossing over in inversion heterozy- vertebrate animal genomes but are dispersed
gotes and creates tandem repeated segments. in mammalian genomes.
Unequal crossing over occurs when homolo-
gous segments do not line up correctly dur- Nonidentical Gene Families
ing meiosis and one of the crossover products The human beta-globin gene family is an ex-
has a duplicated segment. Replication slippage ample of a nonidentical gene family, which has
occurs when the DNA polymerase slips dur- functional member genes that serve different,
ing DNA replication and copies part of the but usually related, functions. In this case, the
template strand again. Once there are two cop- different protein products are alternate forms
ies of a gene in tandem, the latter two mecha- of the same type of protein, perhaps expressed
nisms are more likely to generate additional at different times in the organisms develop-
copies. ment. There are five functional genes and one
A member of a gene family may be func- pseudogene clustered together on chromo-
tional or functionless. If the gene was not cop- some 11. One gene is expressed in the human
ied completely or further mutations render it embryo stage, two in the fetus, and two in the
nonfunctional, it is called a pseudogene. Fur- adult. The related alpha-globin gene family,
ther sequence changes in a functional copy with three genes and four pseudogenes, is a
may result in a gene with an altered function, cluster on chromosome 16.
such as producing a similar but different form
of a protein that can serve some biochemical Evolutionary Role of Gene Families
need or a protein that has a much different Gene families serve as an example of how
function than the original. genes may be accidentally duplicated by several
possible processes, and then by mutation and
Identical Gene Families further duplication the various copies can di-
Identical gene families contain functional verge in function. It is known that long-term ge-
member genes that produce proteins that are nomic evolution (with the exceptions of symbi-
identical or very nearly so. These gene families otic and parasitic genomes) usually involves
usually contain genes for protein products that increases in the number of genes. Although
need to be found in abundance in the cell be- there are a number of mechanisms for this, in-
cause of a crucial function. Multiple copies of cluding polyploidization, it is believed that the
the genes allow greater transcription and pro- formation of gene families can be a first step to-
tein production. ward the evolution of new genes. Mutations
For example, in eukaryotes, ribosomal RNA in different members of the gene family cause
(rRNA) genes are repeated in tandem several them to diverge independently, and some may
hundred times. In contrast, there are only evolve to produce completely different pro-
seven copies of rRNA genes in the prokaryote teins. The presence of gene copies still coding
Escherichia coli, and they are dispersed through- for the original protein allows redundant cop-
out its single chromosome. The rRNA products ies to evolve freely without detrimental changes
of these genes make up part of the structure of to cellular physiology.
the ribosome, the organelle responsible for the Although gene family members can evolve
important process of protein synthesis. to be more different, they may also undergo
The genes for eukaryotic histone proteins, concerted evolution, in which the various cop-
which are important in maintaining the struc- ies evolve together. Unequal crossing over not
ture of DNA in chromosomes and in regulating only changes the number of copies of members
Gene Regulation: Bacteria 291
with a plasmid containing the genes of interest. (lacPI) and a single structural gene (lacI). The
Thus, bacteria that are heterozygous at a locus order of the controlling sites and structural
can be produced. When Jacob and Monod pro- genes in the bacterial chromosome is lacPI, lacI,
duced bacteria heterozygous for the lacI gene lacCRP, lacPZYA, lacO, lacZ, lacY, lacA. Transcrip-
(lacI /lacI +), they functioned like normal bac- tion of the regulatory operon proceeds to the
teria (lacI +), indicating that the lacI + allele was right from the promoter site, lacPI. Similarly,
dominant to the lacI allele. Certain alleles of transcription of the L-arabinose operon oc-
the operator site, lacO C, result in the synthesis curs rightward from lacPZYA. A cyclic-adenosine
of lactose-altering enzymes whether or not the monophosphate receptor (CRP) bound by
inducer was present and even when lacI + was cyclic-adenosine monophosphate (cAMP), re-
present. These observations suggested that the ferred to as a CRP-cAMP complex, attaches to
lacI + gene specified a repressor that might bind the lacCRP site.
to lacO + and block transcription of the genes in- The lacI gene specifies the protein subunit
volved in lactose metabolism. Jacob and Monod of the lactose repressor, a tetrameric protein
concluded that inducers interfered with the that binds to the operator site, lacO, and blocks
repressors ability to bind to lacO +. This allowed transcription of the operon. The lacZ gene
transcription and translation of the lactose op- codes for beta-galactosidase, the enzyme that
eron. In their model, the repressor protein is cleaves lactose into galactose plus glucose. This
unable to bind to the altered operator site, enzyme also converts lactose into the effector
lacO C. This explained how certain mutations in molecule allolactose, which actually binds to
the operator caused the enzymes for lactose the repressor inactivating it. The lacY gene
metabolism to be continuously expressed. specifies the enzyme, known as the lactose
Seeing a similarity between the expression permease, that transports lactose across the
of the genes for lactose metabolism, the genes plasma membrane and concentrates it within
for amino acid synthesis, and the genes for the cell. The lacA gene codes for an enzyme
lambda phage proliferation, Jacob and Monod called transacetylase, which adds acetyl groups
proposed that all genes might be under the to lactose.
control of operator sites that are bound by In the absence of lactose, the repressor occa-
repressor proteins. An operon consists of the sionally diffuses from the operator, allowing
genes that the operator controls. Although the RNA polymerase to attach to lacPZYA and make a
vast majority of operons have operators and single RNA transcript. This results in extremely
are regulated by a repressor, there are some low levels of enzymes called the basal level.
operons without operator sites that are not con- With the addition of lactose, a small amount of
trolled by a repressor. Generally, these operons allolactose binding to the repressor induces a
are regulated by an inefficient promoter or conformational change in the repressor so that
by transposition of the promoter site, whereas it no longer binds to lacO. The levels of per-
some are inhibited by attenuation, a more com- mease and beta-galactosidase quickly increase,
plex interaction occurring during transcrip- and within an hour the enzyme levels may be
tion and translation. The only controlling site one thousand times greater than they were be-
absolutely necessary for gene expression is the fore lactose was added.
promoter site, where RNA polymerase binds. Normally, cells do not produce levels of lac-
tose messenger RNA (mRNA) or enzymes that
Lactose Operon: Negatively Controlled are more than one thousand times greater than
Genes basal level because the lactose operon is regu-
The lactose operon (lacZYA) consists of lated by catabolite repression. As cells synthe-
three controlling sites (lacCRP, lacPZYA, and size cellular material at a high rate, lactose
lacO) and three structural genes (lacZ, lacY, and entrance and cAMP synthesis are inhibited,
lacA). The lactose operon is controlled by a whereas cAMP secretion into the environment
neighboring operon, the lactose regulatory is increased. This causes most of the CRP-cAMP
operon, consisting of a single controlling site complex to become CRP. CRP is unable to bind
Gene Regulation: Bacteria 293
to lacCRP and promote transcription from In the absence of L-arabinose, bacteria will
lacPBAD. synthesize only basal levels of the lactose regu-
If lactose is removed from the fully induced latory protein and the enzymes involved in the
operon, repressor quickly binds again to lacO breakdown of L-arabinose. The repressor bind-
and blocks transcription. Within a few hours, ing to araO2 prevents araC transcription begin-
lactose mRNA and proteins return to their ning at araPC from being completed, whereas
basal levels. Since the lactose operon is in- repressor binding to araI1 prevents araBAD
duced and negatively regulated by a repressor transcription beginning at araPBAD.
protein, the operon is classified as an induc- The addition of L-arabinose causes repres-
ible, negatively controlled operon. sor to be converted into activator. Activator
binds to araI1 and araI2 and stimulates araBAD
Arabinose Operon: Positively transcription. Activator is absolutely required
Controlled Genes for the metabolism of L-arabinose since bacte-
The L-arabinose operon (araBAD) has been rial cells with a defective or missing L-arabinose
extensively characterized since the early 1960s regulatory protein, araC , only produce basal
by American researchers Ellis Englesberg, levels of the L-arabinose enzymes. This is in con-
Nancy Lee, and Robert Schleif. This operon trast to what happens to the lactose enzymes
is under the control of a linked regulatory when there is a missing lactose regulatory pro-
operon consisting of (araC, araO2) and (araPC, tein, lacI . Because of the absolute require-
araO1). The parentheses indicate that the re- ment for an activator, the L-arabinose operon
gions overlap: araO2 is an operator site in the is considered an example of a positively con-
middle of araC, whereas araPC and araO1 repre- trolled, inducible operon.
sent a promoter site and an operator site respec- Transcription of the araBAD operon is also
tively, which overlap. The order of the control- dependent upon the cyclic-adenosine mono-
ling sites and genes for the regulatory operon phosphate receptor protein (CRP), which ex-
and the L-arabinose operon is as follows: (araC, ists in two conformations. When excessive ade-
araO2) (araPC, araO1), araCRP, araI1, araI2, nosine triphosphate (ATP) and cellular
araPBAD, araB, araA, araD. RNA polymerase constituents are being synthesized from L-
binding to araPC transcribes araC leftward, arabinose, cAMP levels drop very low in the
whereas RNA polymerase binding to araPBAD cell. This results in CRP-cAMP acquiring the
transcribes araBAD rightward. CRP conformation and dissociating from
The araA gene specifies an isomerase that araCRP. When this occurs, the araBAD operon
converts L-arabinose to L-ribulose, the araB is no longer transcribed. The L-arabinose
gene codes for a kinase that changes L-ribulose operon is controlled by catabolite repression
to L-ribulose-5-phosphate, and the araD gene very much like the lactose operon.
contains the information for an epimerase that
turns L-ribulose-5-phosphate into D-xylulose-5- Tryptophan Operon: Genes Controlled by
phosphate. Further metabolism of D-xylulose- Attenuation
5-phosphate is carried out by enzymes speci- The tryptophan operon (trpLEDCBA) con-
fied by genes in other operons. sists of the controlling sites and the genes that
The araC product is in equilibrium between are involved in the synthesis of the amino acid
two conformations, one having repressor activ- tryptophan. The order of the controlling sites
ity and the other having activator activity. The and genes in the tryptophan operon is as fol-
conformation that functions as an activator is lows: (trpP, trpO), trpL, trpE, trpD, trpC, trpB, trpA.
stabilized by the binding of L-arabinose or by RNA polymerase binds to trpP and initiates
certain mutations (araCC). In the absence of L- transcription at the beginning of trpL.
arabinose, almost all the araC product is in the An inactive protein is specified by an un-
repressor conformation; however, in the pres- linked regulatory gene (trpR). The regulatory
ence of L-arabinose, nearly all the araC product protein is in equilibrium between its inactive
is in the activator conformation. and its repressor conformation, which is stabi-
294 Gene Regulation: Bacteria
lized by tryptophan. Thus, if there is a high con- known as phase variation. The genes for fla-
centration of tryptophan, the repressor binds gellin are in different operons. The first op-
to trpO and shuts off the tryptophan operon. eron consists of a promoter site, an operator
This operon is an example of an operon that is site, and the structural gene for the first flagel-
repressible and negatively regulated. lin (flgPH1, flgO1, flgH1). The first operon is un-
The tryptophan operon is also controlled by der the negative control of a repressor speci-
a process called attenuation, which involves the fied by the second operon. The second operon
mRNA transcribed from the leader region, also specifies the second flagellin and a trans-
trpL. The significance of leader region mRNA posase that causes part of the second operon to
is that it hydrogen-bonds with itself to form a reverse itself. This portion of the operon that
number of hairpinlike structures. Hairpin-III flips is called a transposon. The promoter
interacts with the RNA polymerase, causing it sites for the transposase gene (flgT2), flagellin
to fall off the DNA. Any one of several hairpins gene (flgH2), and repressor gene (flgR2) are lo-
can form, depending upon the level of cated on either side of the transposase gene in
tryptophan in the environment and the cell. sequences called inverted repeats. Transcrip-
When there is no tryptophan in the environ- tion from both promoters in the second op-
ment, the operon is fully expressed so that eron occurs from left to right: flgPT2, flgT2,
tryptophan is synthesized. This is accom- flgPH2R2, flgH2, flgR2.
plished by translation of the leader region right When the second operon is active, the re-
behind the RNA polymerase up to a couple of pressor binds to flgO1, blocking the synthesis of
tryptophan codons, where the ribosomes stall. the first flagellin (flgH1). Consequently, all bac-
The stalled ribosomes cover the beginning of terial flagella will be made of the second fla-
the leader mRNA in such a way that only hair- gellin (flgH2). Occasionally, the transposase
pin-II forms. This hairpin does not interfere will catalyze a recombination event between
with transcription of the rest of the operon and the inverted repeats, which leads to the trans-
so the entire operon is transcribed. poson being reversed. When this occurs, nei-
When there is too much tryptophan, the ther flgH2 nor flgR2 is transcribed. Conse-
operon is turned off to prevent further syn- quently, the first operon is no longer repressed
thesis of tryptophan. This is accomplished by by flgR2, and flgH1 is synthesized. All the new
translation of the leader region up to the end of flagella will consist of flgH1 rather than flgH2.
the leader peptide. Ribosomes synthesizing the
leader peptide cover the leader mRNA in such Impact and Applications
a way that only hairpin-III forms. This hairpin Many of the genetic procedures developed
causes attenuation of transcription. to study gene regulation in bacteria have con-
In some cases, the lack of amino acids other tributed to the development of genetic engi-
than tryptophan can result in attenuation of neering and the production of biosynthetic
the tryptophan operon. In fact, cells starved for consumer goods. One of the first products to
the first four amino acids (N-formylmethionine, be manufactured in bacteria was human insu-
lysine, alanine, and isoleucine) of the leader lin. The genes for the two insulin subunits were
peptide result in attenuation. When these amino spliced to the lactose operon in different popu-
acids are missing, hairpins-I and III both form, lations of bacteria. When induced, each popu-
resulting in attenuation because of hairpin-III. lation produced one of the subunits. The cells
were cracked open, and the subunits were puri-
Flagellin Operons: Operons Controlled by fied and mixed together to produce functional
Transposition human insulin. Many other products have
Some pathogenic bacteria change their fla- been made in bacteria, yeast, and even plants
gella to avoid being recognized and destroyed and animals.
by the hosts immune system. This change in Considerable progress has been made to-
flagella occurs by switching to the synthesis of ward introducing genes into plants and ani-
another flagellar protein. The phenomenon is mals to change them permanently. In most
Gene Regulation: Eukaryotes 295
cases, this is difficult to do because the control- Soisson, Stephen M., et al. Structural Basis of
ling sites and gene regulation are much more Ligand-Regulated Oligomerization of
complicated in higher organisms than in bacte- AraC. Science 276 (April 18, 1997). Explains
ria. Nevertheless, many different species of how two molecules of AraC protein interact
plants have been altered to make them resis- with the inducer, with each other, and with
tant to desiccation, herbicides, insects, and var- controlling sites to regulate the expression
ious plant pathogens. Although curing genetic of the L-arabinose operon.
defects by introducing good genes into animals
and humans has not been very successful, ani-
mals have been transformed so that they pro-
duce a number of medically important pro-
teins in their milk. Goats have been genetically Gene Regulation: Eukaryotes
engineered to release tissue plasminogen acti-
vator, a valuable enzyme used in the treatment Fields of study: Cellular biology; Molecular
of heart attack and stroke victims, into their genetics
milk. Similarly, sheep have been engineered to Significance: Gene regulation refers to the processes
secrete human alpha-1 antitrypsin, useful in whereby the information encoded within a DNA se-
treating emphysema. Cattle that produce more quence is expressed at the required level. For eukar-
than ten times the milk that sheep or goats pro- yotes, this primarily pertains to the selective expres-
duce may potentially function as factories for sion of particular proteins during development or
the synthesis of all types of valuable proteins in specific tissues.
specified by artfully regulated genes.
Jaime S. Colom Key terms
See also: Bacterial Genetics and Cell Struc- antisense technology: use of antisense
ture; Central Dogma of Molecular Biology; oligonucleotides that base pair with mRNA
Gene Regulation: Eukaryotes; Gene Regula- to prevent translation
tion: Lac Operon; Gene Regulation: Viruses; basal transcription factor: protein that is
Model Organism: Escherichia coli; Molecular required for initiation of transcription at all
Genetics; Transposable Elements. promoters
chromatin remodeling: any event that
Further Reading changes the nuclease sensitivity (DNA acces-
Inada, Toshifumi, et al. Mechanism Responsi- sibility) of chromatin
ble for Glucose-Lactose Diauxie in Escheri- core promoters: DNA elements that direct
chia coli: Challenge to the cAMP Model. initiation of transcription by the basal RNA
Genes to Cells 1 (March, 1996). Provides an polymerase machinery
understandable discussion of catabolite re- enhancer: a DNA element that serves to en-
pression with numerous diagrams. hance transcriptional activity above basal
Mller-Hill, Benno. The Lac Operon: A Short His- levels
tory of a Genetic Paradigm. New York: Walter insulator: a DNA element that, when placed
de Gruyter, 1996. Using a unique combina- between an enhancer and a promoter, pre-
tion of personal anecdotes and present-day vents activation of that particular gene
science, describes the history and present RNA interference (RNAi): small, interfering
knowledge of a paradigmatic system, the lac RNAs that cause gene silencing
operon of Escherichia coli. Illustrated. transcription factor: a protein that is in-
Rasooly, Avraham, and Rebekah Sarah Rasooly. volved in initiation of transcription but is not
How Rolling Circle Plasmids Control Their part of the RNA polymerase
Copy Number. Trends in Microbiology 5 (No-
vember, 1997). Illustrates how regulatory Nuclear RNA Polymerases
genes control the rate of synthesis of plas- Three nuclear RNA polymerases share the
mids in bacteria. responsibility of transcribing eukaryotic genes.
296 Gene Regulation: Eukaryotes
RNA polymerase I transcribes genes encoding include the TATA-box, an AT-rich sequence
ribosomal RNA (rRNA), RNA polymerase II that is located about 25 base pairs upstream of
transcribes protein-coding genes and some the transcriptional start, and the region imme-
small nuclear RNA genes, and RNA polymerase diately surrounding the start site, known as the
III transcribes genes encoding transfer RNA initiator. The downstream promoter element,
(tRNA), the 5S rRNA, and some small nuclear DPE, is typically found about 30 base pairs
RNA. DNA elements known as promoters serve downstream of the transcriptional start, and it
to recruit the RNA polymerases to their tran- is mainly found in genes that do not have a
scriptional start sites. The RNA polymerases do TATA-box. The strength of a given promoter, as
not bind their promoters directly. Instead, tran- defined by the level of basal transcription, de-
scription factors bind to the promoter, and the pends on which combination of promoter ele-
RNA polymerases are recruited by binding their ments is present and on their respective se-
cognate transcription factors. Promoters for quences.
RNA polymerases I and III have limited vari- The core promoter elements are recognized
ability and are recognized by a finite set of tran- by basal transcription factors that for RNA poly-
scription factors. In contrast, promoters for merase II are named TFIIX, where X is a letter
RNA polymerase II show significant diversity, that identifies the individual factor. For ex-
and the number of transcription factors in- ample, the TATA-box is bound by the TATA-
volved in recruiting the polymerase is huge. binding protein, which is a subunit of the tran-
For each polymerase, the core promoter ele- scription factor known as TFIID. A subset of
ments are recognized by a set of basal transcrip- TATA-boxes feature a sequence immediately
tion factors which are required for initiation of upstream that serves as a recognition site for
transcription at all promoters. RNA polymerase, TFIIB. TFIIB, in turn, recruits the polymerase.
together with its basal transcription factors, Ultimately, the core promoter is also the target
constitutes the basal transcription apparatus. for the factors that regulate transcriptional ac-
Activated or repressed transcription is mea- tivity.
sured with respect to basal levels.
Transcription can be divided into three Activated Transcription
phases: Initiation, elongation, and termination. Transcription is the key step at which gene
Most regulation occurs at the level of initiation. expression is controlled. Transcriptional initia-
For RNA polymerases I and III, regulation is tion is regulated by enhancers, which are DNA
generally global and involves a repression of elements that function to increase levels of
transcription. For RNA polymerase II, regula- transcription above basal levels. Enhancers may
tion is gene-specific, allowing specific regula- be located on either side of the gene, up to sev-
tion of each of thousands of protein-coding eral thousand base pairs from the transcrip-
genes. RNA polymerase II promoters function tional start. Enhancers are recognized by tran-
only at very low efficiency with the basal tran- scriptional activators that mediate an increase
scription factors, and activation is the common in transcriptional activity. Transcriptional acti-
mode of regulation. This overview will focus on vators show great variability in terms of cell type
regulation of protein-coding genes. and gene specificity, thus allowing unique regu-
lation of individual genes. Activator proteins
Basal Transcription by RNA Polymerase II are modular, containing both a DNA-binding
RNA polymerase II promoters are modular. domain and an activation domain. Some activa-
The core promoter, which directs transcription tors function by directly interacting with com-
by the basal transcription apparatus, typically ponents of the transcription apparatus to stim-
extends about 35 base pairs upstream or down- ulate transcription.
stream of the transcriptional start site. Core Cellular DNA is not naked but packaged into
promoters can vary considerably from gene to highly organized and compacted nucleopro-
gene, and there are no universal core promoter tein structures known as chromatin. Packaging
elements. Common core promoter elements of DNA into chromatin can occlude protein-
Gene Regulation: Eukaryotes 297
binding sitesfor example, interfering with region downstream of the stop codon that ex-
binding of basal transcription factors. Accord- plicitly recruit nuclease complexes that degrade
ingly, activation of transcription may be accom- the RNA. In general, genes that encode house-
plished by relieving the repression caused by keeping proteins produce mRNAs with long
chromatin formation. Indeed, many activators half-lives, whereas genes whose expression must
function by recruiting protein complexes whose be rapidly controlled tend to generate mRNAs
function is to remodel chromatin to increase with short half-lives.
DNA accessibility. Decompaction of chromatin Additional protein diversity may be gener-
at promoters is not always sufficient, as RNA ated by alternative splicing, a process whereby
polymerase II may need to transcribe thousands different combinations of coding sequences,
of base pairs. Efficient transcription, therefore, or exons, are incorporated into the final
may also depend on specific elongation factors spliced mRNA product. In this fashion, multi-
that travel with the RNA polymerase to destabi- ple versions of a protein may be made from a
lize chromatin structure. single gene.
Since enhancers may activate genes that are Finally, the mRNA sequence affects the effi-
located at some distance, mechanisms exist to ciency with which it is translated. For instance,
specify that a certain gene not be the target of a folding of the mRNA region upstream of the
given enhancer. A DNA insulator serves this start codon can interfere with binding of the ri-
function: When placed between the enhancer bosome, and the sequence adjacent to the start
and the promoter, it prevents activation of that codon affects the efficiency of translation initi-
particular gene. Unlike enhancers, insulators ation. Nucleotide sequences in the untrans-
must therefore be located at a specific positions lated regions of mRNA are also recognized by
to work. Recruitment of DNA-binding proteins specific proteins that may anchor the mRNA
to these insulator elements prevents activation to specific cellular structures to ensure their
of a specific gene. translation and accumulation at the appropri-
ate locations.
Post-transcriptional Control
The pre-messenger RNA (pre-mRNA) tran- Changing Gene Expression
script is subject to several types of post-tran- Several techniques exist for modification of
scriptional processing: Intervening sequences gene expression. The principle behind anti-
(introns) are removed by splicing, a cap struc- sense technology is the base pairing of a com-
ture is added to the 5 end, and a polyadenosine plementary oligonucleotide to a target mRNA
(poly-A) tail is added to the 3 end, following that results in the prevention of translation. As
cleavage of the transcript. Although histori- natural oligonucleotides (RNA and DNA) are
cally referred to as post-transcriptional events, rapidly degraded in the cell, more stable, artifi-
this processing occurs during, not after, tran- cial oligonucleotides with modified backbones
scription; the largest RNA polymerase II sub- are typically used. This strategy has great poten-
unit has a carboxy-terminal domain which tial to reduce expression of genes involved in
serves to recruit proteins involved in mRNA disease states.
splicing, polyadenylation, and capping, thus se- RNA interference, or RNAi, also results in
curing a tight association between these pro- sequence-specific gene silencing. The expo-
cesses. sure to double-stranded RNA that matches the
Capping and polyadenylation affect both sta- sequence of coding regions results in loss of the
bility of the mRNA and the efficiency of transla- corresponding mRNA. The double-stranded
tion. Since most intracellular RNA degradation RNA triggers the assembly of a nuclease com-
is in the form of nuclease-mediated degrada- plex that targets the homologous mRNA for
tion from either end, protecting the ends by degradation. In plants, for example, RNAi has
cap-binding proteins and polyA-binding pro- been suggested to play an important role in re-
teins, respectively, prevents degradation. Short- sistance to pathogens. RNAi has also evolved
lived mRNAs often contain elements within the into a powerful tool for probing gene activity
298 Gene Regulation: Lac Operon
The genes involved in using glucose as an en- vented from binding to the promoter when the
ergy source are included in this group. Other repressor is in place. This occurs because the
genes are inducible (expressed only under cer- promoter and operator sequences are overlap-
tain circumstances). The genes for using lac- ping. The lactose (lac) operon is, therefore, un-
tose as an energy source are included in this der negative control. When lactose is present,
group. beta-galactosidase, the enzyme that con- an altered form of the lactose attaches to the
verts lactose into glucose and galactose so that repressor in such a way that the repressor can
the sugar can be easily metabolized by a cell, is no longer bind to the operator. With the opera-
only made in cells when lactose is present. Syn- tor sequence vacant, it is possible for the RNA
thesizing proteins uses a large amount of en- polymerase to begin transcription of the
ergy. In order for the cell to conserve energy, it operon genes at the promoter. Lactose (or its
produces proteins only when they are needed. metabolite) serves as an inducer for transcrip-
There is no need to make beta-galactosidase if tion. Only if it is present are the lactose operon
there is no lactose in the cell, so it is synthesized genes expressed. The lactose operon is, there-
only when lactose is present. fore, an inducible operon under negative con-
As early as the 1940s Franois Jacob, Jacques trol. In 1965, Jacob and Monod were awarded
Monod, and their associates were studying the the Nobel Prize in Physiology or Medicine in
mechanisms by which beta-galactosidase was recognition of their discoveries concerning the
induced in Escherichia coli. They discovered that genetic control of enzyme synthesis.
when there is no lactose in a cell, a repressor
protein binds to the DNA of the operon at the Lac Operon Expression in the Presence
operator site. Under these conditions, tran- of Glucose
scription of genes in the operon cannot occur When a culture of E. coli is given equal
since the RNA polymerase is physically pre- amounts of glucose and lactose for growth and
RP
rnap RP
i p o z y a
RP
rnap
i p o z y a
1. In the absence of lactose, the repressor protein binds to the operator, blocking the movement of RNA polymerase. The genes are
turned off. 2. When lactose is present, it preferentially binds the repressor protein, freeing up the operator and allowing RNA polymer-
ase to move through the operon. The genes are turned on.
300 Gene Regulation: Lac Operon
is compared with cultures given either glucose sion in bacteria. What they learned from study-
alone or lactose alone, the cells given two sug- ing the lac operon has led to a more general un-
ars do not grow twice as fast, but rather show derstanding of gene transcription and the use
two distinct growth cycles. Beta-galactosidase is of mRNA as an information-bearing intermedi-
not synthesized initially; therefore, lactose is ate in the process of gene expression. The
not used until all the glucose has been metabo- operon concept has proven to be a universal
lized. Laboratory observations show that the mechanism by which bacteria organize their
presence of lactose is necessary but not a suffi- genes. Although genes of higher cells (eukary-
cient condition for the lactose (lac) operon to otes) are not usually organized in operons and
be expressed. An activator protein must bind at although negative control of expression is rare
the promoter in order to unravel the DNA dou- in them, similar positive control mechanisms
ble helix so that the RNA polymerase can bind occur in both bacterial and eukaryotic cells.
more efficiently. The activator protein binds Studies of the lac operon have made possible
only when there is little or no glucose in the cell. the understanding of how DNA-binding pro-
If glucose is available, it is preferred over other teins can attach to a promoter to enhance tran-
sugars because it is most easily metabolized to scription.
make energy in the form of adenosine triphos- Linda E. Fisher
phate (ATP). ATP is made through a series of See also: Bacterial Genetics and Cell Struc-
reactions from an intermediate molecule, cyclic ture; Gene Regulation: Bacteria; Gene Regula-
adenosine monophosphate (cAMP). The cAMP tion: Eukaryotes; Gene Regulation: Viruses;
concentration decreases when ATP is being Model Organism: Escherichia coli.
made but builds up when no ATP synthesis oc-
curs. When the glucose has been used, the con-
centration of cAMP rises. The cAMP binds to Further Reading
the activator protein to enable it to bind at the Judson, Horace Freeland. The Eighth Day of Cre-
operons promoter. With the activator bound, ation: Makers of the Revolution in Biology. Rev.
transcription of the genes, including the beta- ed. New York: Cold Spring Harbor, N.Y.:
galactosidase, occurs. Cold Spring Harbor Laboratory Press, 1996.
The activation of a DNA-binding protein A noted text that provides an interesting ac-
by cAMP is a global control mechanism. The count of the personalities behind the discov-
lactose operon is only one of many that are eries that form the basis of modern molecu-
controlled in this way. Global control allows lar biology.
bacteria to prevent or turn on transcription Mller-Hill, Benno. The Lac Operon: A Short His-
of a group of genes in response to a single sig- tory of a Genetic Paradigm. New York: Walter
nal. It ensures that the bacteria always utilize de Gruyter, 1996. Using a unique combina-
the most efficient energy source if more than tion of personal anecdotes and present-day
one is available. This type of global control science, describes the history and present
only occurs, however, when the operon is also knowledge of a paradigmatic system, the lac
under the control of another DNA-binding operon of Escherichia coli. Illustrated.
protein (the lac repressor in the case of the lac Ptashne, Mark, and Walter Gilbert. Genetic
operon), which makes the operon inducible Repressors. Scientific American 222 (June,
or repressible or both. Control of transcrip- 1970). Summarizes repression mechanisms
tion through the binding of an activator pro- that turn genes on and off, using the lac
tein is an example of positive control, since operon and the lambda bacterial virus as
binding of the activator turns on gene expres- models.
sion. Tijan, Robert. Molecular Machines That Con-
trol Genes. Scientific American 271 (Febru-
Impact and Applications ary, 1995). Discusses regulatory proteins
Jacob and Monod developed the concept of that direct transcription of DNA and what
an operon as a functional unit of gene expres- happens when they malfunction.
Gene Regulation: Viruses 301
3 kilobase pairs (3 kbp, or 3,000 base pairs), fection: following infection, the viral genome
enough to encode approximately seven pro- integrates into the host chromosome, becom-
teins. The largest known viruses are the poxvi- ing a prophage in a process known as lysogeny.
ruses, consisting of 200-300 kbp, enough to en- Such phages are known as temperate viruses.
code several hundred proteins. Lambda is Most viruses, including lambda, exhibit a
approximately average in size, with a DNA ge- temporal control of regulation: Gene expres-
nome of 48 kbp, enough to encode approxi- sion is sequential. Three classes of proteins are
mately fifty genes. produced, classified based on when after infec-
tion they are expressed. Immediate early
Lambda as a Model System: The Lytic genes are expressed immediately after infec-
Cycle tion, generally using host machinery and en-
Following infection of the bacterial host, zymes. Early genes are expressed at a later
most bacteriophages replicate, releasing prog- time and generally require proteins expressed
eny as the cell falls apart, or lyses. Lambda phage from early genes. Late genes are expressed
is unusual in that, while it can complete a lytic following genome replication of the virus. The
cycle, it is also capable of a nonproductive in- various temporal classes of gene products may
also be referred to as lambda, beta, and gamma
proteins.
The lytic cycle of lambda represents a proto-
Bacteriophage Structure type of temporal control. Lambda immediate
early gene expression begins following infec-
tion of the host cell, Escherichia coli. Host cell en-
zymes catalyze the process. Transcription of
lambda DNA begins at a site called a promoter,
a region recognized by the host RNA polymer-
ase, which catalyzes transcription. Lambda
DNA is circular after entering the cell, and two
promoters are recognized: One regulates tran-
scription in a leftward direction (PL), while the
other regulates transcription from the oppo-
site strand in a rightward transcription (PR).
Among the immediate early genes ex-
pressed is one encoding the N protein, expres-
sion of which is under the control of PL. Gen-
erally, transcription occurs through a set of
genes and is terminated at a specific point. The
N protein is an example of an antiterminator, a
protein that allows read-through of the stop
signal for transcription and expression of addi-
tional genes. A second protein is encoded by
the cro gene, the product of which plays a vital
role in determining whether the infection is
lytic or becomes lysogenic. Cro gene expression
is controlled through PR, as are several early
Bacteriophages, or phages, are viruses that attach them-
selves to bacteria and inject their genetic material into the cell.
class genes which regulate viral DNA replica-
Sometimes, during the assembly of new viral particles, a piece tion (O and P genes), repressor synthesis (cII),
of the host cells DNA may be enclosed in the viral capsid. When and early gene expression (Q gene).
the virus leaves the host cell and infects a second cell, that piece Both the cro and Q proteins are involved in
of bacterial DNA enters the second cell, thus changing its ge- regulating late genes, those expressed follow-
netic makeup. (Electronic Illustrators Group) ing DNA replication. Like the N protein, the Q
Gene Regulation: Viruses 303
protein is an antitermina-
tor. Late gene products in-
clude those that become the
structural proteins of the vi-
ral capsid. Other late pro-
teins cause cell lysis, releas-
ing progeny phage particles
from the cell. The entire
process is completed in ap-
proximately thirty minutes.
started altering the process of natural selection vancements in routinely available materials
many thousands of years ago, when farmers be- and equipmentincluding fast, efficient, and
gan selectively breeding certain forms of plants affordable laboratory equipment, an explosive
and animals found desirable in a process called proliferation of available biochemicals, and
artificial selection. Artificial selection has been streamlined laboratory procedures. Many key
refined over many thousands of years of suc- laboratory procedures, which once were very
cessful use. In the twentieth century, with the expensive and time-consuming, are now avail-
discovery of DNA as the molecule of inheri- able in reasonably priced and easy-to-use kits,
tance and rapid evolution of laboratory meth- which has greatly increased the speed of bio-
ods to isolate and manipulate DNA, it became medical research. The Human Genome Pro-
possible to change the genetic composition of ject, completed in April, 2003, offers an abun-
living organisms. The lengthy processes of tra- dance of information about the sequence and
ditional breeding could theoretically be by- location of genes within the human genome
passed, and a major barrier of traditional breed- and will be a tremendous boost to future gene
ing, generally limited to breeding only within therapy research.
members of the same phylogenetic family, The simplest and most logical targets for
broke down. gene therapy are hereditary single-gene de-
In the broadest sense, gene therapy offers fects. In these cases, a single faulty gene causes
the potential of replacing defective genes a genetic disease. There are many examples of
within the human genome, be it one or many these single-gene disorders, including certain
genes, with new genetic patches that can types of hemophilia, muscular dystrophy, cystic
counteract the effect of the defective genes. fibrosis, and an immune disorder known as
Additionally, new, beneficial genes that impart severe combined immunodefiency disorder
desirable characteristicssuch as enhanced (SCID). Theoretically, getting a good copy of
life span, cancer resistance, or resistance to the defective gene into people with these disor-
other diseasescan theoretically be inserted ders might cure these types of diseases. In real-
into the human genome even in the absence of ity, however, controlling factorssuch as gene
defective genes. Finally, what makes gene ther- insertion, gene expression, gene targeting, and
apy especially exciting, and simultaneously immune responsepose tremendous techni-
alarming, is the fact that genes from any living cal challenges that researchers are currently
organism, including all animals, bacteria, working to overcome. Gene therapy may also
plants, and even viruses, could potentially be target complex diseases, such as cancer, cardio-
used for gene therapy in humans. No evolu- vascular disease, neurological diseases, and in-
tionary boundaries apply in gene therapy. fectious diseases. It is possible that even these
complex diseases may one day be treated rou-
The Theory of Gene Therapy tinely with gene therapies.
The primary goal of gene therapy is to cor-
rect a genetic disease by replacing defective Key Technologies
genes with functional or supplemental genes Although gene therapy and cloning may be
that will alleviate the disorder. The driving employed together in certain scientific and
forces behind gene therapy are recombinant medical research projects, gene therapy is very
DNA technologies. Recombinant technologies different from cloning. In the process of clon-
allow the extraction, manipulation, and rein- ing, the entire genome of an organism is dupli-
sertion of cellular DNA within and between liv- cated to produce a genetically identical organ-
ing organisms. The development of recombi- ism. In gene therapy, only portions of a
nant DNA technologies began in the 1970s, genome, usually only one or a few genes, are
rapidly evolved through the 1980s and the manipulated at a time, with the goal of correct-
1990s, and is currently at a level where gene ing a specific genetic disorder. Many of the
therapy, at least for some conditions, is techni- same legal and ethical questions do apply to
cally feasible. There have been tremendous ad- both cloning and gene therapy, and both tech-
306 Gene Therapy
nologies do result in the production of a genet- gene therapy, depending on the specific cells
ically modified organism (GMO). or tissues in the body that are being targeted.
Genetic diseases have been studied for many For example, herpesvirus vectors have been
centuries. In many single-gene-defect diseases, used for gene therapy research in cells of the
the faulty gene has been identified, located, nervous system, while oncoretroviruses and
and sequenced. In many cases, the structure lentiviruses have been used for transforming
and function of the gene product is known in cells of the circulatory system and stem cells.
great detail. Through routine molecular biol- In addition to being able to transfer good
ogy techniques, functional copies of the gene, genes into the body, vectors must be genetically
suitable for gene therapy, can be isolated from stable, able to be propagated in cell culture,
normal human tissues in the laboratory. This and able to be purified to a high concentration.
functional gene itself may be altered or put to- After the vector is built, propagated, and puri-
gether with other genes to create an expres- fied, the job is still not complete. A growing
sion cassette. An expression cassette is a syn- number of techniques are used to deliver the
thetic genetic construct that contains the vector to the correct cells and tissues in the
target gene and other DNA elements, which al- body. In most cases, the cells, tissues, or organs
low the gene to be moved about easily and to receive the gene are specifically targeted for
properly expressed in cells. delivery. Targeting can be accomplished either
Once the functional gene is isolated and by exposing certain cells to the vector outside
placed into an expression cassette, the gene is the body (ex vivo), such as in a culture tube, or
still not ready for use in gene therapy. Because by introducing the vector in a targeted way in-
of physical barriers within the human body and side the body (in vivo), such as introducing the
the efficiency of the immune system in defend- vector into an organ through a specific blood
ing the body from pathogens (disease causing vessel. Both in vitro and in vivo targeted deliv-
organisms), delivery and expression of foreign ery methods have been used for human gene
gene constructs in the human body are not easy therapy trials. Targeted delivery appears to be a
to accomplish. To deliver therapeutic genes critical aspect of human gene therapy, in order
into the body, scientists most often harness the to increase efficacy and reduce potential risks.
power of viruses, since they are very adept at The use of potentially dangerous viruses to
getting around the physical and immune de- transfer genes into the human body is one of
fenses of the body. For safety purposes, most the major concerns that surround gene ther-
potentially harmful viral genes that might trig- apy. Even with proper precautions in the de-
ger disease or elicit a severe immune response sign and building of the vector, research and
are removed to produce what is called a dis- human trials are conducted according to strict
armed viral vector. biohazard containment procedures in an at-
tempt to prevent the unintentional spread of
Viral Vectors the gene therapy vector to laboratory and med-
Currently, several classes of virus are used to ical personnel.
produce viral vectors for human gene therapy
trials. These include oncoretroviruses, such as Clinical Trials
the Moloney murine leukemia virus (MLV), a In 1990, the first clinical trial of human gene
virus that causes leukemia in mice; lentiviruses therapy was conducted in children who were af-
(retroviruses), such as human immunodefi- flicted with severe combined immunodefi-
ciency virus (HIV), the virus that causes AIDS ciency disorder (SCID). A single defective gene
in humans; adenoviruses, which are extremely for an enzyme, adenosine deaminase (ADA),
infectious viruses that cause cold or flulike had been linked with this fatal disorder, which
symptoms in humans; and herpesviruses, the prevents the immune system from maturing
family of viruses that cause cold sores, genital and functioning properly, and so it appeared to
herpes, and chickenpox in humans. All of these be an attractive target for human gene therapy.
viruses have different applications in human It was thought that introducing a functional
Gene Therapy 307
as an unqualified success. In September, 2002, tion from environmental toxins, and function as
a three-year-old participant in the SCID-X permanent vaccines against infectious disease.
human gene therapy trials began exhibiting This notion of desirable genes raises the pros-
a leukemia-type lymphoproliferative disorder pect of creating designer humanshumans
(an inappropriate proliferation of white blood with beneficial or targeted genetic traits, even
cells). Subsequently another child from the aesthetic genetic modificationsand all the at-
same SCID-X trial showed signs of the same dis- tendant legal, political, and ethical ramifica-
order. It was determined that this disorder was tions.
most probably due to the nature of the retrovi- Robert A. Sinnott
rus vector used. The vector had apparently in- See also: Bioethics; Bioinformatics; Clon-
serted the therapeutic gene construct into the ing Vectors; Cystic Fibrosis; DNA Structure and
genome of at least one of the stem cells at a Function; Gene Therapy: Ethical and Eco-
place where it inadvertently activated an onco- nomic Issues; Genetic Counseling; Genetic En-
gene (a cancer-causing gene). These cells with gineering: Historical Development; Genetic
an activated oncogene went on to multiply in Engineering: Medical Applications; Genetic
the children and cause their leukemia-type dis- Engineering: Risks; Genetic Engineering: So-
ease. Subsequently, another child in the SCID- cial and Ethical Issues; Genetic Screening; Ge-
X trial tested positive for the same oncogene netic Testing; Genetic Testing: Ethical and
activation, although he did not exhibit the Economic Issues; Human Genetics; Human
leukemia-type disorder. The combination of Genome Project; Inborn Errors of Metabolism;
successes and unforeseen adverse events un- Insurance; Knockout Genetics and Knockout
derscored the fact that human gene therapy is Mice; RNA World; Stem Cells; Transgenic Or-
currently operating in uncharted areas and un- ganisms; Tumor-Suppressor Genes.
doubtedly involves very complex biological fac-
tors, some of which are probably still unknown. Further Reading
Fischer, Alain, Salima Hacein-Bey, and Marina
Future Prospects: Benefits and Risks Cavazzana-Calvo. Gene Therapy of Severe
Future prospects are really limited only by Combined Immunodeficiencies. Nature Re-
imagination and the constraints of currently views (Immunology) 2 (August, 2002): 615-621.
available technology. The Human Genome Review of human gene therapy for severe im-
Project, which maps all the gene sequences as munological disorders, such as severe com-
well as their location in the human genome, bined immunodeficiency disorder (SCID),
will revolutionize the development of human written by the scientists involved in the first
gene therapy. Using these data, scientists will human gene therapy trial in 1990 and the
discover targets for gene therapy that can be ex- first successful human gene therapy inter-
amined in their native context within the hu- ventions, published in 2002.
man genome, which should result in the pro- Habib, Nagy A., ed. Cancer Gene Therapy: Past
duction of much better expression cassettes Achievements and Future Challenges. New York:
and allow targeted insertion of therapeutic Kluwer Academic/Plenum, 2000. Reviews
genes, which in turn should greatly decrease forty-one preclinical and clinical studies in
undesirable side effects such as those seen in cancer gene therapy, organized into sections
the SCID-X trial. Gene therapy may within a on the vectors available to carry genes into
few decades provide physicians with tools to tumors, cell cycle control, apoptosis, tumor-
treat or prevent all sorts of genetic diseases, suppressor genes, antisense and ribozymes,
both simple and complex. immuno-modulation, suicidal genes, angio-
The same technologies developed to correct genesis control, and matrix metallo protein-
defective genes may also give scientists the ase.
power to insert desirable genes, possibly from Thomas, Clare T., Anja Ehrhardt, and Mark A.
other types of living organisms, to increase life Kay. Progress and Problems with the Use of
span, impart cancer resistance, provide protec- Viral Vectors for Gene Therapy. Nature Re-
Gene Therapy: Ethical and Economic Issues 309
herited diseases, including hemophilia, Hun- to their offspring. Eventually, at least in theory,
tingtons disease (Huntingtons chorea), and the genes that cause the disease could be elimi-
cystic fibrosis, and physicians have long recog- nated from the general population.
nized that certain conditions, such as coronary Tempting though it is to see this as a good
artery disease and diabetes, seem to run in thing, ethicists believe that such an approach
some families. It is tempting to consider the could be extremely susceptible to abuse. They
possibility of eliminating these medical condi- view discussions of human germ-line therapy as
tions through germ-line therapies: Not only an attempt to resurrect the failed agenda of the
would the person suffering from the disease be eugenics movement of the 1920s and 1930s. If
cured, but his or her descendants would never scientists are allowed to manipulate human he-
have to worry about passing the condition on redity to eliminate certain characteristics, what
Because of an adverse reactiona leukemia-like dis- cells and then manipulating these cells to develop
order reported in two patients who had undergone into specific tissues or organs would allow the quint-
successful SCID-X gene therapyhuman gene ther- essential degree of targeted gene therapy. While
apy trails are proceeding with caution. The available there is currently no comprehensive ban on the use
data suggest that the retrovirus vector used for the of embryonic stem cells in gene therapy research,
SCID-X gene therapy trials, derived from a cancer- only certain exempted cell lines can be used in feder-
causing mouse virus, may be largely responsible. Ret- ally funded research projects.
rovirus vectors have the ability to insert genes perma- The economics of gene therapy may also affect its
nently into the human genome, which is desirable to actual impact on human health care. The technolo-
obtain long-term results in gene therapy. A problem gies involved in gene therapy are currently very ex-
occurs, however, if a retrovirus inserts the therapeu- pensive and probably will remain so for the foresee-
tic gene near, or in, certain genes called oncogenes able future. Most gene therapy trails are considered
or tumor-suppressor genes: Cancerous mutations experimental procedures and are therefore not cov-
can develop in the transformed cells. When cells ered by health insurance. These and other real eco-
with cancerous mutations replicate over time, can- nomic conditions, particularly in countries with no
cers can develop. That appears to have happened in national health care policy, may make gene therapy
at least two of the patients who participated in the affordable to some and not to others. In this way,
SCID-X trials. In response, an advisory committee gene therapy may increase the disparity in health
that monitors data from gene-therapy trials for the care services available to people of different socio-
U.S. Food and Drug Administration (FDA) recom- economic groups.
mended that gene therapy for SCID-X be moved to a Finally, since the terrorist attacks on the United
second-line treatment, meaning that it should be States of September 11, 2001, any discussion of gene
used only in the absence of other medical treatment therapy must include the possibility that some of the
options, such as a bone marrow transplant from a technologies developed to correct genetic diseases
matched donor. could also be used by people with no moral or legal
These results from the SCID-X trials reinvigo- restraints to cause tremendous human suffering. By
rated the ethical and legal questions surrounding using infectious viral vectors developed for gene
gene therapy. Moral questions originally arose when therapy and incorporating expression cassettes con-
scientists became able to alter the human genome taining harmful or lethal genes, terrorists and others
and were complicated with the rise of research into could develop biological weapons with relative ease
embryonic stem cells (cells obtained from human compared to traditional threats such as nuclear
embryos). Embryonic stem cells are an attractive tar- weapons. The deliberate spread of these malicious
get for researchers in the area of gene therapy be- constructs, especially in densely populated areas,
cause these very young, undifferentiated cells are could have catastrophic results.
the progenitors of all the other cells in the human Robert A. Sinnott
body. Performing gene therapy on embryonic stem
312 Gene Therapy: Ethical and Economic Issues
is to prevent those same scientists from manip- Metabolism; Insurance; Knockout Genetics
ulating the human genome to enhance other and Knockout Mice; RNA World; Stem Cells;
characteristics? Would parents be able to re- Transgenic Organisms; Tumor-Suppressor
quest custom-tailored offspring, children who Genes.
would be tall with predetermined hair color
and eyes? Questions concerning class divisions Further Reading
and racial biases have also been raised. Would Anees, Munawar A. Islam and Biological Futures:
therapies be equally available to all people who Ethics, Gender, and Technology. New York: Con-
requested them, or would such technology tinuum International, 1989. Provides insight
lead to a future in which the wealthy custom- into reproductive biotechnologies from the
tailor their offspring while the poor must rely Islamic perspective.
on conventional biology? Would those poor Becker, Gerhold K., and James P. Buchanan,
people whose parents had been unable to af- eds. Changing Natures Course: The Ethical
ford germ-line therapy then find themselves Challenge of Biotechnology. Hong Kong: Hong
denied access to medical care or employment Kong University Press, 1996. Brings together
based on their inferior or unhealthy ge- articles based on the November, 1993, sym-
netic profiles? posium, Biotechnology and Ethics: Scien-
In addition, many ethicists and scientists raise tific Liberty and Moral Responsibility.
cautionary notes about putting too much faith Topics include environmental and ethical
in new genetic engineering technologies too considerations of genetically engineered
soon. Most scientists concede that not enough plants and foods, clinical and ethical chal-
is known about the interdependency of various lenges of genetic markers for severe human
genes and the roles they play in overall health hereditary disorders, and embryo transfer.
and human evolution to begin a program to Doherty, Peter, and Agneta Sutton, eds. Man-
eliminate so-called bad genes. Genes that in Made Man: Ethical and Legal Issues in Genetics.
one combination may result in a disabling or Dublin: Four Courts Press, 1997. Provides an
life-threatening illness may in another have introduction to advances in the field, with
beneficial effects that are not yet known. Germ- topics that include pre-implantation and pre-
line therapy could eliminate one problem natal testing; carrier testing with a view to re-
while opening the door to a new and possibly productive choice; and somatic gene therapy,
worse condition. Thus, while the economic germ-line gene therapy, and nontherapeutic
benefits of genetic engineering and gene ther- genetic interventions.
apies can be quite tempting, ethicists remind Harpignies, J. P. Double Helix Hubris: Against
us that many questions remain unanswered. Designer Genes. Brooklyn, N.Y.: Cool Grove
Some areas of genetic research, particularly Press, 1996. Examines the moral and ethi-
germ-line therapy, may simply be best left un- cal aspects of genetic engineering and bio-
explored until a clearer understanding of engineering, arguing that these sciences
both the potential social and biological cost will produce shocking changes to sentient
emerges. life.
Nancy Farm Mnnikk, updated by Bryan Ness Resnik, David B., Holly B. Steinkraus, and
See also: Bioethics; Bioinformatics; Clon- Pamela J. Langer. Human Germline Gene Ther-
ing Vectors; Cystic Fibrosis; DNA Structure and apy: Scientific, Moral, and Political Issues. Aus-
Function; Gene Therapy; Genetic Counseling; tin, Tex.: R. G. Landes, 1999. Examines the
Genetic Engineering: Historical Development; medical, ethical, and social aspects of hu-
Genetic Engineering: Medical Applications; man reproductive technology.
Genetic Engineering: Risks; Genetic Engi- Rifkin, Jeremy. The Biotech Century: Harnessing
neering: Social and Ethical Issues; Genetic the Gene and Remaking the World. New York:
Screening; Genetic Testing; Genetic Testing: Jeremy P. Tarcher/Putnam, 1998. Argues
Ethical and Economic Issues; Human Genet- that the information and life sciences are
ics; Human Genome Project; Inborn Errors of fusing into a single powerful technological
Genetic Code 313
The amino acid specified by any codon can be found by looking for the wide row designated by the first base letter of the codon shown
on the left, then the column designated by the second base letter along the top, and finally the narrow row marked on the right, in the
appropriate wide row, by the third letter of the codon. Many amino acids are represented by more than one codon. The codons TAA,
TAG, and TGA do not specify an amino acid but instead signal where a protein chain ends.
The sequence of the nucleotides in the DNA some machinery scans the RNA nucleotide se-
chain provides the information necessary for quence to find signals to start the synthesis of
manufacturing all the proteins required for polypeptides, the molecules of which proteins
survival, but information must be decoded. are made. When the start signals are found, the
DNA contains a variety of codes. For exam- machinery reads the code in the RNA to con-
ple, there are codes for identifying where to vert it into a sequence of amino acids in the
start and where to stop transcribing an RNA polypeptide, a process called translation.
molecule. RNA molecules are nearly identical Translation stops at termination signals. The
in structure to the single strands of DNA mole- term genetic code is sometimes reserved for
cules. In RNA, the nucleotide uracil (U) is used the rules for converting a sequence of nucleo-
in place of T and each nucleotide of RNA con- tides into a sequence of amino acids.
tains a ribose sugar rather than a deoxyribose
sugar. RNA molecules are made using DNA as a The Protein Genetic Code: General
template by a process called transcription. The Characteristics
resulting RNA molecule contains the same in- Experiments in the laboratories of Har
formation as the DNA from which it was made, Gobind Khorana, Heinrich Matthaei, Marshall
but in a complementary form. Some RNAs Nirenberg, and others led to the deciphering
function directly in the structure and activity of of the protein genetic code. They knew that the
cells, but most are used to produce proteins code was more complicated than a simple one-
with the help of ribosomes. This latter type is to-one correspondence between nucleotides
known as messenger RNA (mRNA). The ribo- and amino acids, since there were about twenty
Genetic Code 315
different amino acids in proteins and only four arginine, and serine) are unusual in that each
nucleotides in RNA. They found that three ad- can be specified by any one of six codons.
jacent nucleotides code for each amino acid.
Since each of the three nucleotide positions Punctuation
can be occupied by any one of four different The protein genetic code is often said to be
nucleotides, sixty-four different sets are possi- commaless. The bond connecting two co-
ble. Each set of three nucleotides is called a dons cannot be distinguished from bonds con-
codon. Each codon leads to the insertion of necting nucleotides within codons. There are
one kind of amino acid in the growing polypep- no spaces or commas to identify which three
tide chain. nucleotides constitute a codon. As a result, the
Two of the twenty amino acids (tryptophan choice of which three nucleotides are to be
and methionine) have only a single codon. read as the first codon during translation is very
Nine amino acids are each represented by a important. For example, if EMA is chosen as
pair of codons, differing only at the third posi- the first set of meaningful letters in the follow-
tion. Because of this difference, the third posi- ing string of letters, the result is gibberish:
tion in the codons for these amino acids is of-
ten called the wobble position. For six amino TH EMA NHI TTH EBA TAN DTH EBA TBI
acids, any one of the four nucleotides occupies THI M.
the wobble position. The three codons for iso-
leucine can be considered as belonging to this On the other hand, if THE is chosen as the
class, with the exception that AUG is reserved first set of three letters, the message becomes
for methionine. Three amino acids (leucine, clear:
This figure from the Genome Image Gallery of the Department of Energy makes clear the concept of the reading frame and how the ge-
netic code translates into amino acids and hence proteins. (U.S. Department of Energy Human Genome Program, http://
www.ornl.gov/hgmis)
316 Genetic Code
THE MAN HIT THE BAT AND THE BAT BIT ple, the UGA universal stop codon codes for
HIM. tryptophan in some bacteria and in fungal, in-
sect, and vertebrate mitochondrial DNA
The commaless nature of the code means that (mtDNA). Ciliated protozoans use UAA and
one sequence of nucleotides can be read three UAG, reserved as stop codons in all other or-
different ways, starting at the first, second, or ganisms, for the insertion of glutamine resi-
third letter. Still, the genetic code does have dues. Methionine, which has only one codon in
punctuation. The beginning of each coding the universal genetic code (AUG), is also en-
sequence has a start codon, which is always the coded by AUA in vertebrate and insect mtDNA
AUG. Each coding sequence also has a stop and in some, but not all, fungal mitochondria.
codon, which acts like a period at the end of a Vertebrate mtDNA also uses the universal ar-
sentence, denoting the end of the coding se- ginine codons AGA and AGG as stop codons.
quence. AGA and AGG are serine rather than arginine
These ways of reading are called reading codons in insect mtDNA.
frames. A frame is said to be open if there are
no stop codons for a reasonable distance. In Interpreting the Code
most mRNAs, only one reading frame is open How is the code interpreted? The mRNA
for any appreciable length. However, in some codons organize small RNA molecules called
mRNAs, more than one reading frame is open. transfer RNA (tRNA). There is at least one
Some mRNAs can produce two, rarely three, tRNA for each of the twenty amino acids. They
different polypeptide sequences. are L-shaped molecules. At one end tRNAs
have a set of three nucleotides (the anticodon)
The Near Universality of the Code that can pair with the three nucleotides of
The universal genetic code was discovered themRNA codon. They do not pair with co-
primarily through experiments with extracts dons for other amino acids. At the other end
from the bacterium Escherichia coli and from tRNAs have a site for the attachment of an
rabbit cells. Further work suggested that the amino acid.
code was the same in other organisms. It came Special enzymes called aminoacyl tRNA syn-
to be known as the universal genetic code. The thetases (RS enzymes) attach the correct amino
code was deciphered before scientists knew acids to the correct tRNAs. There is one RS en-
how to determine the sequence of nucleotides zyme for each of the twenty amino acids. Inter-
in DNA efficiently. After nucleotide sequences pretation is possible because each RS enzyme
began to be determined, scientists could, using can bind only one kind of amino acid and only
the universal genetic code, predict the sequence to tRNA that pairs with the codons for that
of amino acids. Comparison with the actual amino acid. The key to this specificity is a spe-
amino acid sequence revealed excellent overall cial code in each tRNA located near where the
agreement. amino acid gets attached. This code is some-
Nevertheless, the universal genetic code as- times referred to as the second genetic code.
signments of codons to amino acids had appar- After binding the correct amino acid and tRNA,
ent exceptions. Some turned out to be caused the RS enzyme attaches the two molecules with
by programmed changes in the mRNA infor- a covalent bond. These charged tRNAs, called
mation. In selected codons of some mRNA, a C aminoacyl-tRNAs, are ready to participate in
is changed to a U. In others, an A is changed so protein synthesis directed by the codons of the
that it acts like a G. Editing of mRNA does not mRNA. Information is stored in RNA in forms
change the code used by the ribosomal ma- other than the triplet code. A special tRNA for
chinery, but it does mean that the use of DNA methionine exists to initiate all peptide chains.
sequences to predict protein sequences has pit- It responds to AUG. However, proteins also
falls. have methionines in the main part of the poly-
Some exceptions to the universal genetic peptide chain. Those methionines are carried
code are true variations in the code. For exam- by a different tRNA that also responds to AUG.
Genetic Code 317
The fidelity of translating codons of messenger RNA near the amino acid attachment site are important.
(mRNA) into amino acids of the protein product re- This is the case for alanine tRNA, where the primary
quires that each transfer RNA (tRNA) be attached to recognition is a G3-U70 base pair. Incorporating this
the proper amino acid. Twenty distinct aminoacyl element into a cysteine tRNA will cause it to accept
tRNA synthetases (RS enzymes) are found in cells; alanine despite the fact that the anticodon remains
each is specific for a particular amino acid which it at- that for cysteine. In other cases, structures in the
taches to an appropriate tRNA. Because some amino middle of the tRNA molecule are important, such as
acids (such as isoleucine and valine) are similar in the variable loop or the D-loop. Usually multiple ele-
structure, some RS enzymes have an editing feature, ments contribute to the recognition and ensure that
which allows them to cleave a mistakenly attached the correct tRNA is recognized by its respective RS
amino acid. The site at which the attachment reac- enzyme.
tion occurs is distinct from the editing site. The end A mutation in the anticodon of a tRNA will usually
result is that fewer than one in ten thousand amino not restrict its being attached to its designated amino
acids is attached to the wrong tRNA. acid. Such a mutation is referred to as a suppressor
Each RS enzyme must also recognize an appropri- mutation if it overrides another mutation that leads
ate tRNA. One might imagine that the anticodon to a chain termination mutation. For example, a
found in the tRNA would be the recognition site. point mutation in the CAG glutamine codon in a
However, only in a few cases is it the major or sole de- gene can convert it to a UAG chain termination
terminant. Because the anticodon is at one end of codon. This would usually be deleterious because
the L-shaped tRNA and the amino acid is attached at the resultant protein would be shorter than normal.
the other end, this is perhaps not surprising. While However, if the normal GUA anticodon on tyrosine
tRNA molecules have the same general shape, they tRNA is mutated to CUA, it would pair with the UAG
typically consist of seventy-six nucleotides, which in the messenger RNA (mRNA) during protein syn-
provide numerous opportunities to distinguish thesis; it would suppress the chain termination mu-
themselves from one another. tation by inserting tyrosine for the original gluta-
The second genetic code is sometimes used to mine in the protein, which may retain its function.
refer to the sequence of the tRNA that ensures that This mutated tRNA would, however, insert a tyrosine
the correct one is recognized by its corresponding for the normal UAG chain termination for other
RS enzyme. Surprisingly, different elements are used genes.
by the various RS enzymes. In some cases, elements James L. Robinson
The ribosome and associated factors must dis- quences additional to UGA are needed for
tinguish an initiating AUG from one for an in- selenocysteine incorporation. Surrounding nu-
ternal methionine. cleotide residues also allow certain termination
Distinction occurs differently in eukaryotes codons to be bypassed. For example, the mRNA
and bacteria. In bacteria, AUG serves as a start from tobacco mosaic virus encodes two poly-
codon only if it is near a sequence that can pair peptides, both starting at the same place; how-
with a section of the RNA in the ribosome. Two ever, one is longer than the other. The exten-
things are required of eukaryotic start (AUG) sion is caused by the reading of a UAG stop
codons: First, they must be in a proper context codon by tRNA charged with tyrosine.
of surrounding nucleotides; second, they must The production of two proteins with identi-
be the first AUG from the mRNA beginning cal beginnings but different ends can also occur
that is in such a context. Context is also impor- by frame shifting. In this mechanism, signals in
tant for the incorporation of the unusual amino the mRNA direct the ribosome machinery to
acid selenocysteine into several proteins. In a advance or backtrack one nucleotide in its read-
limited number of genes, a special UGA stop ing of the mRNA codons. Frame shifting occurs
codon is used as a codon for selenocysteine. Se- at a specific sequence in the RNA. Often the
318 Genetic Code
code for a frame shift includes a string of seven Theory of Heredity; DNA Replication; DNA
or more identical nucleotides and a complex Structure and Function; Evolutionary Biology;
RNA structure (a pseudoknot). Genetic Code, Cracking of; Genetics, Histori-
Further codes are embedded in DNA. The cal Development of; Mendelian Genetics; Mo-
linear sequence of amino acids, derived from lecular Genetics; One Gene-One Enzyme Hy-
DNA, has a code for folding in three-dimen- pothesis; Protein Structure; Protein Synthesis;
sional space, a code for its delivery to the RNA Structure and Function; RNA Transcrip-
proper location, a code for its modification by tion and mRNA Processing; RNA World.
the addition of other chemical groups, and a
code for its degradation. The production of
mRNA requires nucleotide codes for begin- Further Reading
ning RNA synthesis, for stopping its synthesis, Clark, Brian F. C. The Genetic Code and Protein
and for stitching together codon-containing Biosynthesis. 2d ed. Baltimore: E. Arnold,
regions (exons) should these be separated by 1984. Consists of a brief description of the
noncoding regions (introns). RNA also con- genetic code.
tains signals that can tag them for rapid degra- Clark, David, and Lonnie Russell. Molecular Bi-
dation. DNA has a code recognized by protein ology: Made Simple and Fun. 2d ed. Vienna,
complexes for the initiation of DNA replica- Ill.: Cache River Press, 2000. A detailed and
tion and signals recognized by enzymes that accessible account of molecular biology.
catalyze DNA rearrangements. Judson, Horace Freeland. The Eighth Day of Cre-
ation. Rev. ed. Cold Harbor Spring, N.Y.:
Impact and Applications Cold Spring Harbor Laboratory Press, 1997.
A major consequence of the near universal- A noted and fascinating history of molecular
ity of the genetic code is that biotechnologists biology that details the deciphering of the
can move genes from one species into another genetic code.
and they are still expressed correctly. Since the Kay, Lily E. Who Wrote the Book of Life? A History of
code is the same in both organisms, the same the Genetic Code. Stanford, Calif.: Stanford
protein is produced. This has resulted in the University Press, 2000. Brings myriad sources
large-scale production of specific proteins in together to describe research on the genetic
bacteria, yeast, plants, and domestic animals. code between 1953 and 1970, the rise of
These proteins are of immense pharmaceuti- communication technosciences, the inter-
cal, industrial, and research value. section of molecular biology with crypta-
Scientists developed rapid methods for se- nalysis and linguistics, and the social history
quencing nucleotides in DNA in the 1970s. of postwar Europe and the United States.
Since the genetic code was known, it suddenly Trainor, Lynn E. H. The Triplet Genetic Code: The
became easier to predict the amino acid se- Key to Molecular Biology. River Edge, N.J.:
quence of a protein from the nucleotide se- World Scientific, 2001. Intended for nonspe-
quence of its gene than it did to determine the cialists and professionals, surveys the funda-
amino acid sequence of the protein by chemi- mentals of the genetic code and how it has
cal methods. The instant knowledge of the come to revolutionize thinking about living
amino acid sequence of a particular protein systems as a whole, especially regarding the
greatly simplified predictions regarding pro- connection between structure and function.
tein function. This has resulted in the molecu-
lar understanding of many inherited human
diseases and the potential development of Web Site of Interest
rational therapies based on this new knowl- Oak Ridge National Laboratory, The Genetic
edge. Code. http://www.ornl.gov/techresources/
Ulrich Melcher, updated by Bryan Ness human_genome/graphics/slides/images1
See also: Central Dogma of Molecular Biol- .html. Site has link to an image of the genetic
ogy; Chromosome Structure; Chromosome code, with discussion.
Genetic Code, Cracking of 319
tists a valuable genetic tool. Once the amino entific discovery; three chapters are devoted
acid sequence was known for a protein, or for to the genetic code.
even a small portion of a protein, knowledge of Judson, Horace Freeland. The Eighth Day of Cre-
the genetic code allowed scientists to search for ation. Rev. ed. Cold Harbor Spring, N.Y.:
the gene that codes for the protein or, in some Cold Spring Harbor Laboratory Press, 1997.
cases, to design and construct the gene itself. It A noted and fascinating history of molecular
also became possible to predict the sequence of biology that details the deciphering of the
amino acids in a protein if the sequence of nu- genetic code.
cleotide bases in a gene were known. Knowl- Kay, Lily E. Who Wrote the Book of Life? A History of
edge of the genetic code became invaluable in the Genetic Code. Stanford, Calif.: Stanford
understanding the genetic basis of mutation University Press, 2000. Kay brings myriad
and in attempts to correct these mutations by sources together to describe research on the
gene therapy. The discovery of the genetic code genetic code between 1953 and 1970, the
was therefore key to the development of genet- rise of communication technosciences, the
ics in the late twentieth century, perhaps out- intersection of molecular biology with crypta-
shined only by the discovery of DNAs double- nalysis and linguistics, and the social history
helical structure in 1953 and the completion of of postwar Europe and the United States.
the Human Genome Project in 2003. Portugal, Franklin H., and Jack S. Cohn. A Cen-
Barbara Brennessel tury of DNA: A History of the Discovery of the
See also: Central Dogma of Molecular Biol- Structure and Function of the Genetic Substance.
ogy; Chromosome Structure; Chromosome Cambridge, Mass.: MIT Press, 1977. Pro-
Theory of Heredity; DNA Replication; DNA vides a comprehensive historical back-
Structure and Function; Evolutionary Biology; ground and identifies many of the scientists
Genetic Code; Genetics, Historical Develop- who worked to solve the genetic code.
ment of; Human Genome Project; Mendelian Trainor, Lynn E. H. The Triplet Genetic Code: The
Genetics; Molecular Genetics; One Gene-One Key to Molecular Biology. River Edge, N.J.:
Enzyme Hypothesis; Protein Structure; Protein World Scientific, 2001. Intended for nonspe-
Synthesis; RNA Structure and Function; RNA cialists as well as professionals, surveys the
Transcription and mRNA Processing; RNA fundamentals of the genetic code and how it
World. has come to revolutionize thinking about liv-
ing systems as a whole.
Further Reading
Crick, Francis H. C. The Genetic Code III. Sci- Web Site of Interest
entific American 215 (October, 1966). Re- Cracking the Code of Life. http://www.pbs.org/
printed in The Chemical Basis of Life: An Intro- wgbh/nova/genome. The companion Web
duction to Molecular and Cell Biology. San site to the 2001 PBS broadcast of the same
Francisco: W. H. Freeman, 1973. The co- name. Discusses heredity, gene manipula-
discoverer of DNAs double helical structure tion, DNA sequencing, a journey into DNA,
summarizes the story of the genetic code. and more.
_______. The Genetic Code: Yesterday, Today,
and Tomorrow. Cold Spring Harbor Symposia
on Quantitative Biology 31 (1966). Summarizes
how the genetic code was solved and serves
as an introduction to papers presented dur-
Genetic Counseling
ing a symposium on the genetic code. Field of study: Human genetics and social
Edey, Maitland A., and Donald C. Johnson. issues
Blueprints: Solving the Mystery of Evolution. Re- Significance: Genetic counseling involves helping
print. New York: Viking, 1990. Focuses on individuals or families cope with genetic syn-
evolution from the molecular genetic per- dromes or diseases that exist, or could potentially
spective and emphasizes the process of sci- occur, in a family setting. Genetic counselors pro-
322 Genetic Counseling
vide information regarding the occurrence or risk discovered the double-helix structure of DNA,
of occurrence of genetic disorders, discuss avail- the molecule that carries the genetic informa-
able options for dealing with those risks, and help tion in the cells of most living organisms. Three
families determine their best course of action. years later, human cells were found to contain
forty-six chromosomes each.
Key terms These discoveries, along with other develop-
genetic screening: the process of investigat- ments in genetics, periodically generated ef-
ing a specific population of people to detect forts (often misguided) to control the exis-
the presence of genetic defects tence of inferior genes, a concept known as
nondirective counseling: a practice that val- eugenics. Charles F. Dight, a physician influ-
ues patient autonomy and encourages pa- enced by the eugenics movement, left his estate
tients to reach a decision that is right for in 1927 To Promote Biological Race Better-
them based upon their personal beliefs and mentbetterment in Human Brain Structure
values and Mental Endowment and therefor[e] in Be-
pedigree analysis: analysis of a familys his- havior. In 1941 the Dight Institute for Human
tory by listing characteristics such as age, Genetics began to shift their emphasis from eu-
sex, and state of health of family members, genics to genetic studies of individual families.
used to determine the characteristics of a ge- In 1947, Sheldon Reed began working at the
netic disease and the risk of passing it on to Dight Institute as a genetic consultant to indi-
offspring vidual families. Reed believed that his profes-
prenatal diagnosis: the process of detecting sion should put the clients needs before all
a variety of birth defects and inherited disor- other considerations and that it should be sepa-
ders before a baby is born by various imaging rated from the concept of eugenics. He re-
technologies, genetic tests and biochemical jected the older names for his work, such as
assays genetic hygiene, and substituted genetic
counseling to describe the type of social work
The Establishment of Genetic Counseling contributing to the benefit of the family. As a
Historically, people have long understood result, the field of genetic counseling was born
that some physical characteristics are heredi- and separated itself from the direct concern of
tary and that particular defects are often com- its effect upon the state or politics. In fact, Reed
mon among relatives. This concept was widely predicted that genetic counseling would have
accepted by expectant parents and influenced been rejected had it been presented as a form
the thinking of many scientists who experi- of eugenics.
mented with heredity in plants and animals. Genetic counseling developed as a preven-
Many efforts were made to understand, pre- tive tool and became more diagnostic in nature
dict, and control the outcome of reproduction as it moved from academic centers to the major
in humans and other organisms. Gregor Men- medical centers. In 1951, there were ten ge-
dels experiments with garden peas in the mid- netic counseling centers in the United States
1800s led to the understanding of the relation- employing academically affiliated geneticists.
ship between traits in parents and their off- Melissa Richter and Joan Marks were instru-
spring. During the early twentieth century, mental in the development of the first graduate
Walter Sutton proposed that newly discovered program in genetic counseling at Sarah Law-
hereditary factors were physically located on rence College in New York in 1969. By the early
complex structures within the cells of living or- 1970s, there were nearly nine hundred genetic
ganisms. This led to the chromosome theory of counseling centers worldwide. By 2002 there
inheritance, which explains mechanically how were approximately two thousand genetic
genetic information is transmitted from parent counselors in the United States not only work-
to offspring in a regular, orderly manner. In ing with individual families concerning genetic
1953, James Watson and Francis Crick (along conditions but also involved in teaching, re-
with Maurice Wilkins and Rosalind Franklin) search, screening programs, public health, and
Genetic Counseling 323
the coordination of support groups. In 1990, sulted with patients or physicians about specific
the Human Genome Project began as a fifteen- risks of occurrence of genetic diseases. It was
year effort coordinated by the U.S. Depart- not until 1959, when French geneticist Jrme
ment of Energy and the National Institutes of Lejeune discovered that children with Down
Health to map and sequence the entire human syndrome have an extra chromosome 21, that
genome, prepare a model of the mouse ge- human genetics was finally brought to the at-
nome, expand medical technologies, and study tention of ordinary physicians. Rapid growth in
the ethical, legal, and social implications of ge- knowledge of inheritance patterns, improve-
netic research. ments in the ability to detect chromosomal
abnormalities, and the advent of screening pro-
The Training of the Genetic Counselor grams for certain diseases in high-risk popula-
Most genetic counseling students have un- tions all contributed to the increased interest
dergraduate degrees in genetics, nursing, psy- in genetic counseling. Development of the tech-
chology, biology, social work, or public health. nique of amniocentesis, which detects both
Training programs for genetic counselors are chromosomal and biochemical defects in fetal
typically two-year masters-level programs and cells, led to the increased specialization of ge-
include field training in medical genetics and netic counseling. By the 1970s, training of
counseling in addition to a variety of courses fo- genetic counselors focused on addressing pa-
cusing on genetics, psychosocial theory, and tients psychosocial as well as medical needs.
counseling techniques. During the two-year Genetic counseling thus became a voluntary
program, students obtain an in-depth back- social service intended exclusively for the ben-
ground in human genetics and counseling efit of the particular family involved.
through coursework and field training at ge- Genetic counselors provide information
netic centers. Coursework incorporates infor- and support to families who have members
mation on specific aspects of diseases, includ- with genetic disorders, individuals who them-
ing the prognoses, consequences, treatments, selves are affected with a genetic condition,
risks of occurrence, and prevention as they re- and families who may be at risk for a variety of
late to individuals or families. Field training at inherited genetic conditions, including Hun-
genetic centers enables students to develop re- tingtons disease (Huntingtons chorea), cystic
search, analytical, and communication skills fibrosis, and Tay-Sachs disease. The counselor
necessary to meet the needs of individuals at obtains the family medical history and medical
risk for a genetic disease. records in order to interpret information
Many genetic counselors work with M.D. or about the inherited genetic abnormality. Ge-
Ph.D. geneticists and may also be a part of a netic counselors analyze inheritance patterns,
health-care team that may include pediatri- review risks of recurrence, and offer available
cians, cardiologists, psychologists, endocrinol- options for the genetic condition. Other func-
ogists, cytologists, nurses, and social workers. tions of genetic counselors include discussing
Other genetic counselors are in private prac- genetic risks with blood-related couples consid-
tice or are engaged in research activities re- ering marriage, contacting parents during the
lated to the field of medical genetics and ge- crisis following fetal or neonatal death, prepar-
netic counseling. Genetic counseling most ing a community for a genetic population
commonly takes place in medical centers, screening program, and informing couples
where specialists work together in clinical ge- about genetically related causes of their infer-
netics units and have access to diagnostic facili- tility. A pregnant patient is most commonly re-
ties, including genetic laboratories and equip- ferred to a genetic counselor by an obstetrician
ment for prenatal screening. because of her advanced age (thirty-five years
or older).
The Role of the Genetic Counselor In addition to obtaining accurate diagnosis
Prior to the 1960s, most genetic counselors of the genetic abnormality, genetic counselors
were individuals with genetic training who con- strive to explain the genetic information as
324 Genetic Counseling
clearly as possible, making sure that the individ- performed earlier in the pregnancy (during
ual or family understands the information fully the tenth to twelfth weeks of gestation). Fetal
and accurately. The genetic counselor must blood sampling can be performed safely only
evaluate the reliability of the diagnosis and the after eighteen weeks of pregnancy. An ultra-
risk of occurrence of the genetic disease. Be- sound, offered to all pregnant women, uses
cause the reliability of various tests will affect a high-frequency sound waves to create a visual
patients decision about genetic testing and image of the fetus and detects anatomical de-
abortion, the counselor must give the patient a fects such as spina bifida, cleft lip, or certain
realistic understanding of the meaning and in- heart malformations. Pedigree analysis may
herent ambiguity of test results. Most genetic also be used for diagnostic purposes and to de-
counselors practice the principle of nondirec- termine the risk of passing a genetic abnormal-
tiveness and value patient autonomy. They pre- ity on to future generations. A pedigree of the
sent information on the benefits, limitations, family history is constructed, listing the sex,
and risks of diagnostic procedures without rec- age, and state of health of the patients close
ommending a course of action, encouraging relatives; from that, recurrent miscarriages,
patients to reach their own decisions based on stillbirths, and infant deaths are explored.
their personal beliefs and values. This attitude Prenatal diagnostic techniques are used to
reflects the historical shift of genetic counseling identify many structural birth defects, chromo-
away from eugenics toward a focus on the indi- somal abnormalities, and more than five hun-
vidual family. The code of ethics of the National dred specific disorders. Genetic counselors
Society of Genetic Counselors states that its who believe that their client is at risk for passing
members strive to respect their clients beliefs, on a particular disease may suggest several ge-
cultural traditions, inclinations, circumstances, netic tests, depending on the risk the patient
and feelings as well as provide the means for may face. Screening of populations with high
their clients to make informed independent frequencies of certain hereditary conditions,
decisions, free of coercion, by providing or illu- such as Tay-Sachs disease among Ashkenazi
minating the necessary facts and clarifying the Jews, is encouraged so that high-risk couples
alternatives and anticipated consequences. can be identified and their pregnancies moni-
tored for affected fetuses. Pregnant women
Diagnosis of Genetic Abnormalities may also be advised to undergo testing if an ab-
In the latter half of the twentieth century, normality has been found by the doctor, the
discoveries in genetics and developments in re- mother will be thirty-five years of age or older at
productive technology contributed to the ad- the time of delivery, the couple has a family his-
vancements in prenatal diagnosis and genetic tory of a particular genetic abnormality, the
counseling. Prenatal diagnostic procedures mother has a history of stillbirths or miscar-
eventually became an established part of ob- riages, or the mother is a carrier of metabolic
stetrical practice with the development of am- disorders (for example, hemophilia) that can
niocentesis in the 1960s, followed by ultra- be passed from mothers to their sons.
sound, chorionic villus sampling (CVS), and The Human Genome Project is expected to
fetal blood sampling. Amniocentesis, CVS, and have a dramatic impact on presymptomatic
fetal blood sampling are ways to obtain fetal diagnosis of individuals carrying specific dis-
cells for analysis and detection of various types eases, multigene defects involved in common
of diseases. Amniocentesis, a cytogenetic analy- diseases such as heart disease and diabetes, and
sis of the cells within the fluid surrounding the individual susceptibility to environmental fac-
fetus, is performed between the fifteenth and tors that interact with genes to produce dis-
twentieth weeks of gestation and detects possi- eases. The isolation and sequencing of genes
ble chromosomal abnormalities such as Down associated with genetic abnormalities such as
syndrome and trisomy 18. The information ob- cystic fibrosis, kidney disease, Alzheimers dis-
tained from CVS is similar to that obtained ease, and Huntingtons disease (Huntingtons
from amniocentesis, except the testing can be chorea) allow for individuals to be tested for
Genetic Counseling 325
those specific conditions. Many genetic tests the birth of children with genetic defects. Since
have been developed so that the detection of most genetic conditions can be neither treated
genetic conditions can be made earlier and nor modified in pregnancy, abortion is often
with more precision. the preventive measure used. Thus, ethical is-
sues concerning the respect for autonomy of
Ethical Aspects of Genetic Counseling the unborn child must also be considered.
With advancements in human genetics and Jamalynne Stuck and Doug McElroy
reproductive technology, fundamental moral See also: Amniocentesis and Chorionic Vil-
and ethical questions may arise during difficult lus Sampling; Bioethics; Gene Therapy; Gene
decision-making processes involving genetic Therapy: Ethical and Economic Issues; Genetic
abnormalities for which families may be unpre- Screening; Genetic Testing; Genetic Testing:
pared. Diagnosis of a particular genetic disease Ethical and Economic Issues; Hereditary Dis-
may allow individuals or families to make future eases; Human Genetics; In Vitro Fertilization
plans and financial arrangements. However, and Embryo Transfer; Insurance; Linkage
improvements in the capability to diagnose nu- Maps; Pedigree Analysis; Prenatal Diagnosis.
merous hereditary diseases often exceed the
ability to treat such diseases. The awareness Further Reading
that an unborn child is genetically predisposed Leroy, Bonnie, Dianne M. Bartels, and Arthur
toward a disease with no known cure may lead L. Caplan, eds. Prescribing Our Future: Ethical
to traumatic anxiety and depression. The psy- Challenges in Genetic Counseling. New York: Al-
chological aspects of genetic counseling and dine de Gruyter, 1993. Offers ethical insights
genetic centers must therefore continue to be into the implications of genetic counseling,
explored in genetic centers throughout the including the issue of neutrality, the poten-
world. tial impact of the Human Genome Project,
Questions about who should have access to workplace ideology of counselors, and the
the data containing patients genetic makeup role of public policy.
must also be considered as the ability to screen Resta, Robert G., ed. Psyche and Helix: Psychologi-
for genetic diseases increases. Violating pa- cal Aspects of Genetic Counseling. New York:
tients privacy could have devastating conse- Wiley-Liss, 2000. Articles reprinted from
quences, such as genetic discrimination in job myriad sources cover topics pertaining to
hiring and availability of health coverage. Em- the medical, social, psychological, and emo-
ployers and insurance companies have already tional effects of genetic diseases, including
denied individuals such opportunities based the management of guilt and shame, patient
on information found through genetic testing. care, and a detailed analysis of a genetic
Disclosure of genetic information not only con- counseling session.
tributes to acts of discrimination but also may Rothman, Barbara Katz. The Tentative Pregnancy:
result in physical and psychological harm to in- How Amniocentesis Changes the Experience of
dividuals. Motherhood. Rev. ed. New York: Norton, 1993.
With data derived from the Human Genome Provides a discussion of decisions faced by
Project increasing rapidly, problems arising patients who seek genetic counseling.
from the application of new genetic knowledge Schneider, Katherine A. Counseling About Can-
in clinical practice must be addressed. The cer: Strategies for Genetic Counseling. 2d ed.
norm of nondirective counseling will be chal- New York: Wiley-Liss, 2002. A thorough re-
lenged, raising questions of who provides and source to help genetic counselors and other
who receives information and how it is given. health care providers effectively assist pa-
Many believe that genetic counseling is benefi- tients and families in managing hereditary
cial to those faced with genetic abnormalities, cancer. Gives clinical features of thirty can-
while others fear that genetic counseling is a cer syndromes, tables listing major cancer
form of negative eugenics, an attempt to im- syndromes by cancer type, and many case
prove humanity as a whole by discouraging studies.
326 Genetic Engineering
Weil, Jon. Psychosocial Genetic Counseling. New nostic, and therapeutic applications that promise
York: Oxford University Press, 2000. Exam- to help prevent and treat a wide range of genetic
ines the psychosocial components of coun- diseases.
seling interactions, including the role of
emotions such as anxiety and guilt, and the Key terms
complex process of decision making. Illus- biotechnology: the application of recombi-
trated. nant DNA technology to the development of
Wexler, Alice. Mapping Fate: A Memoir of Family, specific products and procedures
Risk, and Genetic Research. Berkeley: Univer- cloning: the process by which large amounts
sity of California Press, 1996. Describes Wex- of a single gene or genome (the entire ge-
lers personal quest to discover the genetic netic content of a cell) are reproduced
basis for Huntingtons disease. complementary base pairing: hydrogen bond
Young, Ian D. Introduction to Risk Calculation in formation that only occurs between adenine
Genetic Counseling. 2d ed. New York: Oxford and thymine or cytosine and guanine
University Press, 1999. Designed for profes- DNA sequence analysis: chemical methods
sionals, but useful to consumers in under- that permit the determination of the order
standing the different types of quantitative of nucleotide bases in a DNA molecule
risk assessment. Illustrated. genomic library: a collection of clones that
includes the entire genome of a single spe-
Web Sites of Interest cies as fragments ligated to vector DNA
American Board of Genetic Counseling. http: probe hybridization: a method that permits
//www.faseb.org/genetics/abgc/abgcmenu the identification of a unique sequence of
.htm. A professional organization that edu- DNA bases using a single-stranded DNA
cates, administers examinations, and certi- segment complementary to the unique se-
fies genetic counselors. quence and carrying a molecular tag allow-
Human Genome Project Information, Genetic ing identification
Counseling. http://www.doegenomes.org. transgenic organism: a species in which the
Site links to genetic counseling information genome has been modified by the insertion
and related resources. of genes obtained from another species
National Society of Genetic Counselors. http:// vector: a segment of DNA, usually derived
www.nsgc.org. Offers a search engine for from viruses, bacteria, or yeast, that contains
locating genetic counselors in the United regulatory sequences that permit the ampli-
States and a newsroom with press releases fication of single genes or genetic segments
and fact sheets about the counseling ser-
vices. Restriction Enzymes
Many of the methods used in genetic engi-
neering represent adaptations of naturally oc-
curring genetic processes. One of the earliest
Genetic Engineering and most significant discoveries was the identi-
fication of a family of DNA enzymes called re-
Field of study: Genetic engineering and striction endonucleases, more commonly
biotechnology called restriction enzymes. Restriction enzymes
Significance: The development of the tools of recom- are DNA-modifying enzymes produced by mi-
binant DNA technology used in genetic engineer- croorganisms as a protection against viral infec-
ing has generated unprecedented inquiry into the tion; their uniqueness and utility in recombi-
nature of the living system and has revolutionized nant DNA technology reside in their ability to
the study of genetics. The implications of this re- cleave DNA at precise recognition sites based
search are far-reaching, ranging from a better on DNA sequence specificity. Several hundred
understanding of basic biological principles and restriction enzymes have been isolated, and
molecular mechanisms to pharmacological, diag- many recognize unique DNA segments and ini-
Genetic Engineering 327
tiate DNA cleavage only at these sites. The site- the host cell, the recombinant plasmid will be
specific cleavages generated by restriction en- replicated by the host cell, along with the hosts
zymes can be used to produce a unique set of own genome. Bacterial cells reproduce rapidly
DNA segments that can be used to map indi- and generate large colonies of cells, each cell
vidual genes and distinguish them from all containing a copy of the recombinant plasmid.
other genes. This type of genetic analysis, based By this process the fragment of DNA in the re-
on differences in the sizes of DNA segments combinant vector is cloned.
from different genes or different individuals The cloned DNA can then be isolated from
when cleaved with restriction enzymes, is re- the bacterial cells and used for other applica-
ferred to as restriction fragment length poly- tions or studies. Plasmids are useful for cloning
morphism (RFLP) analysis. small genes or DNA fragments; larger frag-
If genes or DNA segments from different ments can be cloned using viral vectors such
sources or species are cleaved with the same re- as the bacterial virus (bacteriophage) lambda
striction enzyme, the DNA segments produced, (phage ). This virus can infect bacterial cells
though genetically unrelated, can be mixed to- and reproduce to high copy number. If nones-
gether to produce recombinant DNA. This oc- sential viral genes are removed, recombinant
curs because most restriction enzymes produce viruses containing genes of interest can be pro-
complementary, linear, single-stranded DNA duced. Synthetic recombinant vectors incorpo-
ends that can join together. An additional en- rating bacterial and viral components, called
zyme called DNA ligase is used to seal the link cosmids, have also been developed. In addi-
between the DNA molecules with covalent tion, synthetic minichromosomes called yeast
bonds. This procedure, developed in the 1970s, artificial chromosomes (YACs), which incorpo-
is at the core of recombinant DNA technology rate large segments of chromosomal DNA and
and can be used to analyze the structure and which are capable of replication in bacterial or
function of the genome at the molecular level. eukaryotic systems, have been developed.
Another key development has been the use
of vectors to amplify DNA fragments. Vectors
are specially designed DNA molecules derived DNA Sequence Analysis
from viruses, bacteria, or other microorgan- A further key discovery in genetic engineer-
isms, such as yeast, that contain regulatory se- ing has been the development of chemical
quences permitting the amplification or ex- methods of DNA sequence analysis. These
pression of a DNA fragment or gene. Vectors methods permit a determination of the linear
are available for numerous applications. sequence of nucleotide bases in DNA. DNA se-
quence analysis permits a direct determination
Vectors of gene structure with respect to regulatory
Plasmids are small, circular DNAs that have and protein-coding regions and can be used to
been isolated from many species of bacteria. predict the structure and function of proteins
These naturally occurring molecules often en- encoded by specific genes.
code antibiotic resistance genes that can be There are many important applications of
transferred from one bacterial cell to another the basic principles of genetic engineering. No-
in a process called transformation. In the labo- table examples include the Human Genome
ratory, plasmids can be used as vectors in the Project, the identification and characterization
amplification of genes inserted by restriction of human disease genes, the production of
enzyme treatment of both vector and insert large amounts of proteins for therapeutic or in-
DNA, followed by DNA ligation to produce re- dustrial purposes, the creation of genetically
combinant plasmids. The recombinant DNA is engineered plants that are disease-resistant
then inserted into host bacterial cells by trans- and show higher productivity, the creation of
formation, a routine process in which bacterial genetically engineered microorganisms that
cells are made competent, that is, able to take can help clean up pollution, and the treatment
up DNA from their surroundings. Once inside of genetic disorders using gene therapy.
328 Genetic Engineering
Among less well known genetic engineering projects is the work of Oregon State University professor Steve Strauss and his colleagues,
who are genetically modifying poplar trees to grow larger leaves in order to find genes that affect growth. (AP/Wide World Photos)
Genetic Engineering 329
nology involved the cloning of the human gene guns. This method is particularly useful
insulin gene and its insertion into bacterial ex- for inserting genes into plant cells that are re-
pression vectors. Subsequently, many gene sistant to DNA uptake because of thick cell
products have been produced by genetically walls.
engineered microorganisms, including clotting Genetically engineered transgenic species
factors (used in the treatment of hemophilia), have many biological uses. Transgenic animals
growth factors such as epidermal growth factor have been used to analyze the functions of spe-
(used to accelerate wound healing) and colony- cific genes in development and to generate ani-
stimulating factors (used to stimulate blood mal models of human diseases. For example, a
cell formation in the bone marrow), and inter- transgenic mouse strain incorporating a hu-
ferons (used in the treatment of immune sys- man breast cancer gene has been developed to
tem disorders and certain types of cancer). The explore the mechanisms by which this disease
advantages of using genetically engineered occurs. In addition, transgenic mice have been
products are enormous: Therapeutic proteins used to analyze the normal functions of spe-
or hormones can be produced in much larger cific genes by producing knockout mice,
amounts than could be obtained from tissue whose genomes contain mutated, nonfunc-
isolation, and the genetically engineered prod- tional copies of the genes of interest. This tech-
ucts are free of viruses and other contaminants. nology, developed by Mario Capecchi, uses
Introduction of foreign genes into the fertil- homologous recombination, in which only
ized eggs of host animals is called germ-line complementary nucleotide base pairs carry
transformation and involves the insertion of in- out the genetic exchange within the host chro-
dividual genes into fertilized eggs. After the mosome. Thus, the effects of the inserted gene,
eggs are implanted in foster mothers, the re- or transgene, on development and physiology
sulting transgenic offspring will have the mu- can be examined. Knockout mice lacking a
tated gene in all their cells and will be able to functional adenosine deaminase (ADA) gene,
pass the gene on to their future offspring. for example, show disease characteristics com-
Many of the methods for introducing for- parable to those of humans with severe com-
eign genes into host cells take advantage of the bined immunodeficiency disorder (SCID).
naturally occurring processes facilitated by vi- These mice have been very useful for determin-
ruses. Genetically engineered retroviruses, for ing the efficacy of novel treatments, including
example, can be used to insert a foreign gene the replacement of the faulty gene by gene
into a recipient cell following viral infection. therapy.
Foreign genes may also be incorporated into Transgenic animals have also been devel-
lipid membranes to form liposomes, which oped to produce therapeutic gene products
then can bind to the target cell and insert the in large quantities. For example, transgenic
gene. Chemical methods of gene transfer in- sheep have been developed that secrete the hu-
clude the use of calcium phosphate or dextran man protein alpha-1 antitrypsin (AAT) in their
sulfate to generate pores in the recipient cell milk. AAT is used to treat an inherited form of
membrane through which the foreign DNA en- emphysema. The process involves the microin-
ters the cell. Microinjection involves the use of jection of fertilized sheep eggs with the human
microscopic needles to insert foreign DNA di- AAT gene linked to regulatory sequences that
rectly into the nucleus of the target cell and is allow the gene to be actively expressed in the
often used to insert genetic material into fertil- mammary tissue. Although the process of gen-
ized eggs. Electroporation involves the use of erating transgenic animals is inefficient, indi-
an electric current to open pores in the cell vidual transgenic animals can produce tremen-
membrane, permitting DNA uptake by the re- dous amounts of gene products that can be
cipient cell. Finally, particle bombardment rep- readily purified from the milk. Additional trans-
resents a method of gene transfer in which genic livestock have been engineered to pro-
metal pellets coated with DNA are transferred duce tissue plasminogen activator (used in the
into target cells under high pressure using treatment of blood clots), hemoglobin (used as
330 Genetic Engineering
a blood substitute), erythropoietin (used to killed or attenuated (weakened) live viral vac-
stimulate red blood cell formation in kidney di- cine because of the risk of developing the dis-
alysis patients), human growth hormone (used ease from the vaccination. Genetically engi-
to treat pituitary dwarfism), and factor VIII neered viruses may also be useful in the
(used to treat hemophilia). treatment of diseases such as cancer since they
Transgenic plants have also been produced, could be designed to target specific cells with
using the Ti (tumor-inducing) plasmid. This abnormal cell surface receptors. Recombinant
plasmid is found naturally in the bacterium adenoviruses containing a single gene muta-
Agrobacterium tumefaciens. The Ti plasmid has tion have been engineered that are capable of
been used to transfer a toxin gene from the lethal infection in cancer cells but not in nor-
bacterium Bacillus thuringiensis that kills insect mal tissues of the body.
pests, thereby avoiding the use of pesticides.
Impact and Applications
Genetically Engineered Viruses The methods of recombinant DNA technol-
An additional medical application involves ogy have revolutionized our understanding of
the use of genetically engineered viruses in the the molecular basis of life and have led to a vari-
treatment of genetic diseases. Retroviruses are ety of useful applications. Some of the most im-
the most important group of viruses used for portant discoveries have involved an increased
these purposes, since the life cycle of the virus understanding of the molecular basis of dis-
involves the incorporation of the viral genome ease processes, which has led to new methods
into host chromosomes. Removal of most of of diagnosis and treatment. Genetically engi-
the viruss own structural genes removes its neered animals can be used to produce unlim-
ability to cause disease, while the regulatory ited amounts of therapeutic gene products and
genes are retained and ligated to the therapeu- can also serve as genetic models to enhance un-
tic gene. The recombinant retrovirus then be- derstanding of the physiological basis of dis-
comes harmless; however, it can still enter a cell ease. Plants can be genetically engineered for
and become integrated into the host cell ge- increased productivity and disease resistance.
nome, where it can direct the expression of the Genetically engineered viruses have been de-
therapeutic gene. The first successful clinical veloped as vaccines against infectious disease.
application was the use of genetically engi- The methods of recombinant DNA technology
neered retroviruses in the treatment of severe were originally developed from natural prod-
combined immunodeficiency disorder (SCID). ucts and processes that occur within the living
Viruses with a functional copy of the ADA gene system. The ultimate goals of this research
were able to reverse SCID. However, in 2002 re- must involve applications that preserve the in-
searchers in France and the United States dis- tegrity and continuity of the living system.
covered that this treatment appears to lead to a Sarah Crawford Martinelli,
greatly increased risk of developing leukemia, updated by Bryan Ness
and clinical trials were suspended. See also: Animal Cloning; Biopharmaceuti-
Similar methods have been used to develop cals; Cloning; Cloning: Ethical Issues; Cloning
recombinant vaccines. For example, a recom- Vectors; DNA Replication; DNA Sequencing
binant vaccinia virus has been produced by the Technology; Gene Therapy; Gene Therapy:
insertion of genes from other viruses. During Ethical and Economic Issues; Genetic Engi-
the process of infection, the recombinant vac- neering: Agricultural Applications; Genetic
cinia virus produces proteins from the foreign Engineering: Historical Development; Ge-
genes, which act as antigens which lead to im- netic Engineering: Industrial Applications;
munity following vaccination. This strategy is Genetic Engineering: Medical Applications; Ge-
particularly useful in the development of vac- netic Engineering: Risks; Genetic Engineering:
cines against viruses that are highly pathogenic Social and Ethical Issues; Genetically Modified
such as the human immunodeficiency virus (GM) Foods; High-Yield Crops; Knockout Ge-
(HIV), in which it is not possible to use a whole netics and Knockout Mice; Polymerase Chain
Genetic Engineering 331
Reaction; Restriction Enzymes; Reverse Tran- manipulate genes, and modern applications
scriptase; Shotgun Cloning; Synthetic Genes; of genetic engineering. Illustrated.
Transgenic Organisms; Xenotransplants. Steinberg, Mark, and Sharon D. Cosloy, eds.
The Facts On File Dictionary of Biotechnology and
Further Reading Genetic Engineering. New ed. New York: Check-
Altieri, Miguel A. Genetic Engineering in Agricul- mark Books, 2001. Collects sixteen hundred
ture. Chicago: LPC Group, 2001. Raises seri- medical, chemical, and engineering terms
ous questions about the drive toward geneti- relating to plant and animal biology and mo-
cally engineered crops. lecular genetics and genetic engineering.
Anderson, Luke. Genetic Engineering, Food, and Four appendices cover acronyms and abbre-
Our Environment. White River Junction, Vt.: viations, the genetic code, purine and pyrim-
Chelsea Green, 1999. Introduces issues sur- idine bases, and amino acid side chains.
rounding genetic engineering, including Walker, Mark, and David McKay. Unravelling
the social, environmental, and health impli- Genes: A Laypersons Guide to Genetic Engineer-
cations arising from the commercial use of ing. St. Leonards, N.S.W.: Allen & Unwin,
this technology in food and farming. 2000. Explains the core concepts of genetic
Boylan, Michael, and Kevin E. Brown. Genetic engineering, including the scientific princi-
Engineering: Science and Ethics on the New Fron- ples and technological advances that have
tier. Upper Saddle River, N.J.: Prentice Hall, made gene therapy, cloning, and genetically
2001. Written by a biologist and philoso- modified food products available. Special fo-
pher, this text includes discussions on the cus is given to gene therapy treatments for
professional and practical principles of con- Alzheimers disease, cystic fibrosis, and he-
duct, the biology of genetic therapy, the lim- mophilia.
its of science, somatic gene therapy, en- Williams, J. G., A. Ceccarelli, and A. Wallace.
hancement, cloning, and germ line therapy. Genetic Engineering. 2d ed. New York:
Illustrated. Springer, 2001. Surveys some of the tech-
Drlica, Karl. Understanding DNA and Gene Clon- niques which have made recent advances in
ing: A Guide for the Curious. Rev. ed. New York: genetic engineering possible and shows how
Wiley, 2003. An excellent introduction to they are being applied to clinical problems.
the basic properties of DNA and its modern Yount, Lisa. Biotechnology and Genetic Engineer-
applications. Consists of four sections: basic ing. New York: Facts On File, 2000. Gives
molecular biology, manipulation of DNA, in- background on controversial genetic engi-
sights gained through the use of gene clon- neering technologies and the social, political,
ing (including a chapter on retroviruses), ethical, and legal issues they raise. Includes a
and human genetics. chronology from the birth of agriculture to
Hill, Walter E. Genetic Engineering: A Primer. recent findings.
Newark, N.J.: Harwood Academic, 2000.
Written to help those with little scientific Web Sites of Interest
background become conversant with the Centers for Disease Control, Office of Ge-
area generally called genetic engineering. nomics and Disease Prevention. http://
Illustrations, glossary, index. www.cdc.gov/genomics/default.htm. Of-
Le Vine, Harry, III. Genetic Engineering: A Refer- fers information on the genetic discoveries
ence Handbook. Santa Barbara, Calif.: ABC- and prevention of diseases in humans. In-
CLIO, 1999. Part of the series Contempo- cludes links to related resources.
rary World Issues, covers the basics of ge- U.S. Department of Agriculture, Biotechnol-
netic engineering. Illustrated. ogy: An Information Resource. http://www
Nicholl, Desmond S. T. An Introduction to Ge- .nal.usda.gov/bic. A government site that of-
netic Engineering. 2d ed. New York: Cambridge fers dozens of links to information on ge-
University Press, 2002. Three sections detail netic engineering (biotechnology). glossary,
basic molecular biology, methods used to and an annotated bibliography.
332 Genetic Engineering: Agricultural Applications
facture their own pesticide, which is nontoxic sight. It is estimated in 2003 that about 124 mil-
to humans. lion children in the world lack vitamin A, which
Glyphosate, the most widely used nonselec- puts them at risk of permanent blindness and
tive herbicide, and other broad-spectrum her- other serious diseases. Golden rice could help
bicides are often toxic to crop plants, as well as alleviate the serious problem of vitamin A defi-
the weeds they are intended to kill. A major ciency. Iron deficiency is the worlds worst nu-
thrust is to identify and transfer herbicide resis- trition disorder, causing anemia that affects
tance genes into crop plants. Cotton plants, for 2 billion people worldwide. The scientists have
example, have been genetically engineered to also managed to insert genes into rice to make
be resistant to certain herbicides. it iron-rich.
For improved quality of fruit after harvest,
Improving Crop Yield and Food Quality genetic engineers are inserting genes to slow
Genetic engineering is now being used to the rate of senescence (aging) and thus slow
modify crops, to improve the quality of food spoilage of harvested crops, especially fruits.
taste, fatty acid profile, protein content, sugar For example, scientists at Calgene (Davis, Cali-
composition, and resistance to spoilage. New, fornia) have inserted a gene into tomato plants
useful or attractive horticultural varieties are that blocks the synthesis of the enzyme poly-
also produced, by transforming plants with galacturonase, which causes tomato softening,
new or altered genes. For example, plants have thereby delaying aging (hence rotting) of the
been engineered that have additional genes for fruit.
enzymes that produce anthocyanins, which has Improved tolerance to environmental stress
resulted in flowers with unusual colors and pat- for agricultural plants is also being explored by
terns. biotechnology, especially for drought, saline
Cereals are the staple food and major source conditions, chilling temperatures, high light
of protein for a large percentage of the earths intensities, and extreme heat. Some plants have
population, and contain 10 percent protein in genes that enable them to adapt naturally to
the dry weight. Grains unfortunately lack one harsh environments, and genetic engineers are
or more essential amino acids and
therefore provide incomplete nutri-
tion. There are efforts to engineer
missing amino acids into cereal pro-
tein and to insert genes for higher
yields. The development of a high-
yielding dwarf rice plant so dramati-
cally helped the nutritional status of
millions of people in Southeast Asia
that it has been called the miracle
rice. Image not available
Researchers based at the Swiss Fed-
eral Institute of technology in Zurich
have genetically engineered a more
nutritious type of rice by inserting
three genes into rice that make the
plant produce beta-carotene or pro-
vitamin A. The color that is imparted
to the rice by the vitamin gives it the
name golden rice. Mammals, in-
cluding humans use beta-carotene,
from their food to produce vitamin Tobacco engineered to have no nicotine became economically important to
A, which is necessary for good eye- this Amish farmer during the drought of 2002. (AP/Wide World Photos)
334 Genetic Engineering: Agricultural Applications
A demonstration in Seattle against Starbucks usage of genetically engineered ingredients, dubbed frankenfoods by protesters. Al-
though many in the developed nations of Europe and North American are concerned over unintended consequences, genetic engi-
neering in agriculture has made it possible to breed varieties of desirable crop plants with a wider range of tolerance for climatic and
soil conditions, as well as pests. Such crops offer hope that poorer nations will be able to feed their growing populations. (AP/Wide
World Photos)
using these genes to produce similar effects in terest to everyone because it impacts every as-
crop plants. pect of our daily living, and calls for ideas to be
Biotechnology has produced a marked in- tapped from all sectors of our communities. It
crease in crop productivity worldwide. In 1999, is a modern innovative trend that has become a
about 50 percent of the soybean, 33 percent of major thrust in agriculture by production of ge-
the corn, and 35 percent of the cotton crops in netically modified (GM) foods that are more
the United States and 62 percent of the canola nutritious and better preserved, but raises con-
crop in Canada were planted with genetically cerns as well because of potential dangers of
modified seed. In 1996, genetically engineered microbial infections and chemical hazards.
corn and soybeans were first grown commer- Many nonscientists, and some scientists, are
cially on 1.7 million hectares (4.2 million leery of GM foods, feeling that too little is un-
acres). The land planted in these crops had derstood about the environmental effects of
swelled to 39.9 million hectares (98.8 million growing GM plants and the potential health
acres) by 2003. dangers of eating GM foods. Resistance to GM
foods is widespread in Europe and parts of
Impact and Implications Asia, and a number of environmental groups
The various applications of genetic engi- strongly oppose all GM crops. Some have gone
neering to agriculture have made it possible to so far as to call them frankenfoods. So far
alter genes and modify crops for the benefit of they appear to be safe and successful, holding
humankind, in addition to industrial and med- out great promise to solve the problem of world
ical applications. This should be a subject of in- hunger. They make it possible to breed variet-
Genetic Engineering: Historical Development 335
ies of desirable crop plants with a wider range Wadsworth, 1998. Vital botanical informa-
of tolerance for different climatic and soil con- tion on all aspects of plant biology plus genet-
ditions, offering hope for the promotion of ics. Excellent photographs and illustrations,
global agriculture to feed poorer nations. Ge- summaries, questions, further readings, glos-
netic engineering must be seen as an indispens- sary, and index.
able component of modern scientific advance- Simpson, Beryl Brintnall, and Molly Conner
ment and social development for every nation, Ogorzaly. Economic Botany. 3d ed. Boston,
if handled wisely without exposing living or- New York: McGraw Hill, 2001. Good account
ganisms to harmful microorganisms and toxic of the most important crop plants of the
chemicals in the process. world especially their genetic and agricul-
Samuel V. A. Kisseadoo tural diversities. Useful illustrations, photo-
See also: Animal Cloning; Biofertilizers; Bi- graphs, glossary, additional readings, and in-
ological Weapons; Biopesticides; Biopharma- dex.
ceuticals; Cloning; Cloning: Ethical Issues; Starr, Cecie. Biology: Concepts and Applications.
Cloning Vectors; DNA Replication; DNA Se- 5th ed. United States, Canada: Brooks/Cole,
quencing Technology; Gene Therapy; Gene 2003. Current detailed biological informa-
Therapy: Ethical and Economic Issues; Genetic tion including genetics and evolution. Con-
Engineering; Genetic Engineering: Historical tains excellent photos, illustrations, quizzes,
Development; Genetic Engineering: Industrial appendix, glossary, and index.
Applications; Genetic Engineering: Medical
Applications; Genetic Engineering: Risks; Ge- Web Sites of Interest
netic Engineering: Social and Ethical Issues; Food and Agriculture Organization of the
Genetically Modified (GM) Foods; High-Yield United Nations. Biotechnology in Food and
Crops; Knockout Genetics and Knockout Mice; Agriculture. http://www.fao.org. Addresses
Polymerase Chain Reaction; Restriction En- the role of biotechnology in worldwide food
zymes; Reverse Transcriptase; Shotgun Clon- production.
ing; Synthetic Genes; Transgenic Organisms; National Academic of Sciences. Transgenic
Xenotransplants. Plants and World Agriculture. http://www
.nap.edu/html/transgenic. An online, down-
Further Reading loadable pamphlet, published in July of 2000
Borlaug, Norman E. Ending World Hunger: by a consortium of leading research societies
The Promise of Biotechnology and the around the world, assesses the need to mod-
Threat of Antiscience Zealotry. Plant Physiol- ify crops genetically in order to feed the in-
ogy 124 (2000): 487-490. The father of Green creasing world population and then discusses
Revolution and Nobel Peace Prize winner examples of the technology, safety, effect on
speaks of his unwavering support for GMOs. the environment, funding sources, and in-
Potrykus, Ingo. Golden Rice and Beyond. tellectual property issues.
Plant Physiology 125 (2001): 1157-1161. The
originator of the wonder rice presents scien-
tific, ethical, intellectual, and social chal-
lenges of developing and using the GMOs. Genetic Engineering:
Illuminating and insightful.
Raven, Peter H., et al. Biology of Plants. 6th ed.
Historical Development
New York: W. H. Freeman/Worth, 1999. In- Field of study: Genetic engineering and
cludes discussion of all the essential features biotechnology; History of genetics
and processes in plants, genetic engineer- Significance: Genetic engineering, or biotechnol-
ing, adaptations, and plant uses. Excellent il- ogy, is the use of biology, genetics, and biochemistry
lustrations, colored photos, appendix, glos- to manipulate genes and genetic materials in a
sary, and index. highly controlled fashion. It has led to major ad-
Rost, Thomas L., et al. Plant Biology. New York: vancements in the understanding of the molecular
336 Genetic Engineering: Historical Development
organization, function, and manipulation of rower field of molecular genetics, involving the
genes. The methods have been used to identify manipulation, modification, synthesis, and ar-
causes and solutions to many different human ge- tificial replication of DNA in order to modify
netic diseases and have led to the development of the characteristics of an individual organism or
many new medicines, vaccines, plants, foods, ani- a population of organisms.
mals, and environmental cleanup techniques.
The Development of Genetic Engineering
Key terms Molecular genetics originated during the
clone: a group of genetically identical cells late 1960s and early 1970s in experiments
plasmids: small rings of DNA found naturally with bacteria, viruses, and free-floating rings of
in bacteria and some other organisms DNA found in bacteria known as plasmids. In
recombinant DNA: a DNA molecule made up 1967, the enzyme DNA ligase was isolated. This
of two or more sequences derived from dif- enzyme can join two strands of DNA together,
ferent sources acting like a molecular glue. It is the prerequi-
site for the construction of recombinant DNA
Foundations of Genetic Engineering molecules, which are DNA molecules that are
Microbial genetics, which emerged in the made up of sequences not normally joined to-
mid-1940s, was based upon the principles of gether in nature.
heredity that were originally discovered by The next major step in the development of
Gregor Mendel in the middle of the nine- genetic engineering came in 1970, when re-
teenth century and the resulting elucidation of searchers discovered that bacteria make spe-
the principles of inheritance and genetic map- cial enzymes called restriction endonucleases,
ping during the first forty years of the twentieth more commonly known as restriction enzymes.
century. Between the mid-1940s and the early Restriction enzymes recognize particular se-
1950s, the role of DNA as genetic material be- quences of nucleotides arranged in a specific
came firmly established, and great advances oc- order and cut the DNA only at those specific
curred in understanding the mechanisms of sites, like a pair of molecular scissors. When-
gene transfer between bacteria. A broad base of ever a particular restriction enzyme or set of re-
knowledge accumulated from which later devel- striction enzymes is used on DNA from the
opments in genetic engineering would emerge. same source, the DNA is cut into the same num-
The discovery of the structure of DNA by James ber of pieces of the same length and composi-
Watson and Francis Crick in 1953 provided tion. With a molecular tool kit that included
the stimulus for the development of genetics at isolated enzymes of molecular glue (ligase)
the molecular level, and, for the next few years, and molecular scissors (restriction enzymes), it
a period of intense activity and excitement became possible to remove a piece of DNA
evolved as the main features of the gene and its from one organisms chromosome and insert it
expression were determined. This work culmi- into another organisms chromosome in order
nated with the establishment of the complete to produce new combinations of genes (recom-
genetic code in 1966, which set the stage for ad- binant DNA) that may not exist in nature. For
vancements in genetic engineering. example, a bacterial gene could be inserted
Initially, the term genetic engineering in- into a plant, or a human gene could be inserted
cluded any of a wide range of techniques for into a bacterium.
the manipulation or artificial modification of The first recombinant DNA molecules were
organisms through the processes of heredity generated by Paul Berg at Stanford University
and reproduction, including artificial selec- in 1971, and the methodology was extended in
tion, control of sex type through sperm selec- 1973 when DNA fragments were joined to Es-
tion, extrauterine development of an embryo, cherichia coli (E. coli) plasmids. These recombi-
and development of whole organisms from cul- nant molecules could replicate when intro-
tured cells. However, during the early 1970s, duced into E. coli cells, and a colony of identical
the term came to be used to denote the nar- cells, or clones, could be grown on agar plates.
Genetic Engineering: Historical Development 337
This development marked the beginning of ogists called for a moratorium on recombinant
the technology that has come to be known as DNA experiments in 1974, and the National In-
gene cloning, and the discoveries of 1972 and stitutes of Health (NIH) issued safety guide-
1973 triggered what became known as the lines in 1976 to control laboratory procedures
new genetics. The use of the new technology for gene manipulation.
spread very quickly, and a sense of urgency and In 1977, the pioneer genetic engineering
excitement prevailed. However, because of ris- company Genentech produced the human
ing concerns about the morality of manipulat- brain hormone somatostatin, and, in 1978,
ing the genetic material of living organisms, as Genentech produced human insulin in E. coli
well as the fear that potentially harmful organ- by the plasmid method of recombinant DNA.
isms might accidentally be produced, U.S. biol- Human insulin was the first genetically engi-
Rising concerns related to safety and ethical issues ments. Appropriate safeguards on both physical and
surrounding experiments involving recombinant biological contaminant procedures would have to be
DNA technology led the National Institutes of in effect before recombinant DNA experiments con-
Health (NIH) and the National Institute of Medi- tinued. Within a year, the NIH had developed guide-
cine (NIM) to appoint the Recombinant DNA Advi- lines based upon the recommendations made at the
sory Committee (RAC) to study the matter in 1973. Asilomar Conference.
RAC consisted of twelve experts from the areas of Many positive outcomes resulted from the
molecular biology, genetics, virology, and microbiol- Asilomar Conference. Scientists demonstrated to
ogy. Not only was there adverse public opinion in re- the public their genuine concern for the develop-
action to recombinant DNA (recombinant DNA) ex- ment of safe scientific technology. It marked the first
periments, but many specialists in the field of genetic time in history that scientists themselves halted sci-
engineering were beginning to doubt their own abil- entific research until the potential hazards could be
ity to make important decisions that could impact so- properly assessed. It also became clear that for future
ciety. meetings on recombinant DNA technology it would
In February, 1975, the Asilomar Conference was be wise to include scientists with training in infec-
convened under the direction of the NIH in Pacific tious diseases, epidemiology, and public health, as
Grove, California, to address the relevant issues. A to- well as people from other disciplines, in order to es-
tal of 140 prominent international researchers and tablish a more complete picture of the potential
academicians, including Dr. Phillip Sharp, Nobel problems and solutions. As a result, a variety of scien-
Laureate Professor at the Massachusetts Institute of tists and nonscientists became part of national and
Technologys Center for Cancer Research, met to local review boards on biotechnology.
discuss their opinions about recombinant DNA ex- Conferences that followed focused on worst case
periments. scenarios of recombinant DNA experiments. For
Some of the issues debated at the Asilomar Con- the first time, debate of scientific issues spread be-
ference included whether or not genetically altered yond the scientific community to include the general
microorganisms that posed a health hazard to hu- public. Broad social, ethical, environmental, and
mans and other living things might escape from lab ecological issues became part of conference agendas
facilities, how different genetically tailored recombi- and discussions. The RAC membership was changed
nant DNA organisms should be classified, and what to include experts in epidemiology, infectious dis-
guidelines should be established to regulate recom- eases, botany, tissue culture, and plant pathology, as
binant DNA technology. The scientists concluded well as nonscientists. NIH guidelines for federally
that only safe bacteria and plasmids that could not funded research involving recombinant DNA mole-
escape from the laboratory should be developed. cules were published on June 23, 1976. As recombi-
They called for a moratorium on recombinant DNA nant DNA research continued to progress, appropri-
experiments and demanded that the federal govern- ate modifications to the NIH guidelines were made.
ment establish guidelines regulating these experi- Alvin K. Benson
338 Genetic Engineering: Historical Development
neered product to be approved for human use. organisms, and this action was followed in 1988
By 1979, small quantities of human somato- by the U.S. Patent and Trademark Office issu-
statin, insulin, and interferon were being pro- ing its first patent for a genetically engineered
duced from bacteria by using recombinant higher animal, a mouse that was developed for
DNA methods. Because such research was use in cancer research.
proven to be safe, the NIH gradually relaxed
the guidelines on gene splicing between 1978 Impact and Applications
and 1982. The 1978 Nobel Prize in Physiology The application of genetic engineering to
or Medicine was shared by Hamilton O. Smith, gene therapy (the science of replacing defec-
the discoverer of restriction enzymes, and Dan- tive genes with sound genes to prevent disease)
iel Nathans and Werner Arber, the first people took off in 1990. On September 14 of that year,
to use these enzymes to analyze the genetic ma- genetically engineered cells were infused into
terial of a virus. a four-year-old girl to treat her adenosine de-
By the early 1980s, genetic engineering aminase (ADA) deficiency, an inherited, life-
techniques could be used to produce some threatening immune deficiency called severe
biomolecules on a large scale. In December, combined immunodeficiency disorder (SCID).
1980, the first genetically engineered product In January, 1991, gene therapy was used to treat
was used in medical practice when a diabetic skin cancer in two patients. In 1992, small plants
patient was injected with human insulin gener- were genetically engineered to produce small
ated in bacteria; in 1982, the Food and Drug amounts of a biodegradable plastic, and other
Administration (FDA) approved the general plants were manufactured to produce antibod-
use of insulin produced from bacteria by re- ies for use in medicines.
combinant DNA procedures for the treatment By the end of 1995, mutant genes responsi-
of people with diabetes. During the same time ble for common diseases, including forms of
period, genetically engineered interferon was schizophrenia, Alzheimers disease, breast can-
tested against more than ten different cancers. cer, and prostate cancer, were mapped, and ex-
Methods for adding genes to higher organisms perimental treatments were developed for ei-
were also developed in the early 1980s, and ge- ther replacing the defective genes with working
netic researchers succeeded in inserting a hu- copies or adding genes that allow the cells to
man growth hormone gene into mice, which fight the disease. In February, 1997, a lamb
resulted in the mice growing to twice their nor- named Dolly was cloned from the DNA of an
mal size. By 1982, geneticists had proven that adult sheeps mammary gland cell; it was the
genes can be transferred between plant species first time scientists successfully cloned a fully
to improve nutritional quality, growth, and re- developed mammal. By the end of 1997, ap-
sistance to disease. proximately fifty genetically engineered prod-
In 1985, experimental guidelines were ap- ucts were being sold commercially, including
proved by the NIH for treating hereditary de- human insulin, human growth hormone, al-
fects in humans by using transplanted genes; pha interferon, hepatitis B vaccine, and tissue
the more efficient polymerase chain reaction plasminogen activators for treating heart at-
(PCR) cloning procedure for genes, which pro- tacks. In 1998, strong emphasis was placed on
duces two double helixes in vitro that are iden- research involving gene therapy solutions for
tical in composition to the original DNA sam- specific defects that cause cancer, as well as on a
ple, was also developed. The following year, the genetically engineered hormone that can help
first patent for a plant produced by genetic en- people with damaged hearts grow their own by-
gineering, a variety of corn with increased nu- pass vessels to carry blood around blockages.
tritional value, was granted by the U.S. Patent In spite of the many successes and optimism
and Trademark Office. In 1987, a committee of that prevailed for many years, there have also
the National Academy of Sciences concluded been some serious setbacks. In 1999 a healthy
that no serious environmental hazards were eighteen-year-old participating in a gene ther-
posed by transferring genes between species of apy clinical trial at the University of Pennsylva-
Genetic Engineering: Industrial Applications 339
nia died unexpectedly, casting doubt on the Portugal, Franklin H., and Jack S. Cohn. A Cen-
safety of some types of gene therapy. In another tury of DNA: A History of the Discovery of the
set of clinical trials in France in 2002, involving Structure and Function of the Genetic Substance.
the treatment of children with SCID, two of the Cambridge, Mass.: MIT Press, 1977. Pro-
children developed leukemia, raising doubts vides a comprehensive historical back-
about the safety of yet another gene therapy ground and identifies many of the scientists
protocol. As a result of these events, gene ther- who worked to solve the genetic code.
apy trials of many types were put on hold and Shannon, Thomas A., ed. Genetic Engineering:
extensive discussions and investigations en- A Documentary History. Westport, Conn.:
sued. Still, scientists are hopeful that these Greenwood Press, 1999. A variety of scien-
kinds of obstacles can be overcome, leading to tific, social, and ethical perspectives on ge-
much greater availability of cures for genetic netic engineering.
diseases.
Alvin K. Benson Web Site of Interest
See also: Animal Cloning; Biofertilizers; Bi- National Health Museum, Biotech Chronicles.
ological Weapons; Biopesticides; Biopharma- http://www.accessexcellence.org/ab/bc.
ceuticals; Cloning; Cloning: Ethical Issues; Site discusses the history of biotechnology
Cloning Vectors; DNA Replication; DNA Se- and includes a time line, from 6000 b.c.e. to
quencing Technology; Gene Therapy; Gene the present, with key figures and links.
Therapy: Ethical and Economic Issues; Genetic
Engineering; Genetic Engineering: Agricul-
tural Applications; Genetic Engineering: In-
dustrial Applications; Genetic Engineering:
Medical Applications; Genetic Engineering: Genetic Engineering:
Risks; Genetic Engineering: Social and Ethical Industrial Applications
Issues; Genetically Modified (GM) Foods; High-
Yield Crops; Knockout Genetics and Knockout Field of study: Genetic engineering and
Mice; Polymerase Chain Reaction; Restriction biotechnology
Enzymes; Reverse Transcriptase; Shotgun Clon- Significance: Industrial applications of genetic en-
ing; Synthetic Genes; Transgenic Organisms; gineering include the production of new and better
Xenotransplants. fuels, medicines, products to clean up existing pol-
lution, and tools for recovering natural resources.
Further Reading Associated processes may maximize the use and
Fredrickson, Donald S. The Recombinant DNA production of renewable resources and biodegrad-
Controversy, a Memoir: Science, Politics, and the able materials, while minimizing the generation of
Public Interest, 1974-1981. Washington, D.C.: pollutants during product manufacture and use.
ASM Press, 2001. An overview of the initial
concerns about potential hazards of recom- Key terms
binant DNA cloning. biomass: any material formed either directly
Grace, Eric S. Biotechnology Unzipped: Promises or indirectly by photosynthesis, including
and Reality. Washington, D.C.: National plants, trees, crops, garbage, crop residue,
Academy Press, 1997. Provides a nontechni- and animal waste
cal history and explanation of biotechnol- bioremediation: biologic treatment methods
ogy for general readers. to clean up contaminated water and soils
Judson, Horace Freeland. The Eighth Day of Cre- cloning vector: a DNA molecule that main-
ation. Rev. ed. Cold Harbor Spring, N.Y.: tains and replicates a foreign piece of DNA
Cold Spring Harbor Laboratory Press, 1997. in a cell type of choice, typically the bacte-
A noted and fascinating history of molecular rium Escherichia coli
biology that details the deciphering of the genetic transformation: the transfer of ex-
genetic code. tracellular DNA among and between species
340 Genetic Engineering: Industrial Applications
nanotechnology: development and use of the medical industry include the production of
devices that have a size of only a few bil- new vaccines for use in fighting a variety of dis-
lionths of a meter eases. One approach is to use genetically al-
plasmids: small rings of DNA found naturally tered viruses to insert manufactured vaccines
in bacteria and some other organisms, used directly into the cells of diseased animals and
as cloning vectors humans. In other cases, antigens that invoke
recombinant DNA: a DNA molecule made up immunity to certain diseases are being pro-
of sequences that are not normally joined to- duced from genetically modified viruses, bacte-
gether ria, fungi, and other disease-causing microor-
ganisms.
Foundations in Medical Advancements
Since the 1970s, numerous industrial pro- Cleaning up Waste
cesses have involved applications of genetic Genetic engineering methods are being em-
engineering and biotechnology, ranging from ployed in myriad applications to help clean up
the production of new medicines and foods to waste and pollution worldwide. The idea had
the manufacture of new materials for cleaning its beginning in 1972, when Ananda Chakra-
up the environment and enhancing natural re- barty, a researcher at General Electric (who
source recovery. With these applications, a pri- would later join the college of medicine at the
mary focus has been the development of indus- University of Illinois at Chicago), applied for a
trial processes that reduce or eliminate the patent on a genetically modified bacterium
production of waste products and consume that could partially degrade crude oil. Other
low amounts of energy and nonrenewable re- scientists quickly recognized that toxic wastes
sources. The chemical, plastic, paper, textile, might be cleaned up by pollution-eating micro-
food, farming, and pharmaceutical industries organisms. After a financial downturn for a
are positively impacted by biotechnology. number of years, a resurgence in bioremedia-
The dawn of the age of genetic engineering tion technology occurred in the late 1980s and
was 1971, when Herbert Boyer and Stanley Co- early 1990s, when genetically engineered bac-
hen successfully spliced a toad gene between teria were produced that could accelerate the
two recombined ends of bacterial DNA. After breakdown of oil, as well as a diversity of unnat-
further experimentation and resulting suc- ural and synthetic compounds, such as plastics,
cesses, Boyer and Robert Swanson in 1976 chlorinated insecticides, herbicides, and fungi-
formed Genentech, a company devoted to the cides. In 1987 and 1988, bacterial plasmid trans-
development and promotion of biotechnology fer was used to degrade a variety of hydrocar-
and genetic engineering applications. In 1978, bons found in crude oil. In the 1990s, naturally
Boyer discovered a synthetic version of the hu- occurring and genetically altered bacteria were
man insulin gene and inserted it into Escheri- employed to degrade crude oil spills, such as
chia coli (E. coli) bacteria. The E. coli served as the major spill that occurred in Alaskas Prince
cloning vectors to maintain and replicate large William Sound after the Exxon Valdez accident.
amounts of human insulin. This application of Some genetically altered bacteria have been
recombinant DNA technology to produce hu- designed to concentrate or transform toxic
man insulin for diabetics was a foundation for metals into less toxic or nontoxic forms. In
the future of industrial applications of genetic 1998, a gene from E. coli was successfully trans-
engineering and biotechnology. The Eli Lilly ferred into the bacterium D. radiodurans, allow-
company began manufacturing large quanti- ing this microbe to resist high levels of radioac-
ties of human insulin by vector cloning in 1982. tivity and convert toxic mercury II into less
Growth hormones for children and antibodies toxic elemental mercury. Other altered micro-
for cancer patients were soon being similarly bial genes have been added to this bacterium,
cloned in bacteria. The pharmaceutical indus- allowing it to metabolize the toxic organic
try was revolutionized. chemical toluene, a carcinogenic constituent
Later applications of genetic engineering to of gasoline. Genetically altered plants have
Genetic Engineering: Industrial Applications 341
A genetically engineering enzyme developed from a hybrid poplar tree, shown here by researchers Arun Goyal (left) and Neil Nelson,
could reduce the cost of manufacturing paper by replacing chlorine used for pulp bleaching, and might also become a component of
animal feed and a means of decomposing harmful toxic pollution. (AP/Wide World Photos)
been produced that absorb toxic metals, in- cobs), food industry by-products (cartilage,
cluding lead, arsenic, and mercury, from pol- bones, whey), and products of biomass, such as
luted soils and water. At Michigan State Univer- sugars, starch, and cellulose, into useful prod-
sity, naturally occurring bacteria have been ucts like ethanol, hydrogen gas, and methane.
combined with genetically modified bacteria to Commercial amounts of methane are being
degrade polychlorinated biphenyls (PCBs). A generated from animal manure at cattle, poul-
genetically altered fungus that helps clean up try, and swine feed lots, sewage treatment
toxic substances discharged when paper is plants, and landfills. Biofuels will be cleaner
manufactured also produces methane as a by- and generate less waste than fossil fuels. In a
product, which can be used as a fuel. different application involving fuel technol-
ogy, genetically modified microbes are being
Biomass and Materials Science used to reduce the pollution associated with
Genetically altered microorganisms can fossil fuels by eating the sulfur content from
transform animal and plant wastes into materi- these fuels.
als usable by humans. Bioengineered bacteria In applications involving the generation of
and fungi are being developed to convert bio- new materials, a gene generated in genetically
mass wastes, such as sewage solid wastes (paper, modified cotton can produce a polyester-like
garbage), agricultural wastes (seeds, hulls, corn substance that has the texture of cotton, is even
342 Genetic Engineering: Industrial Applications
warmer, and is biodegradable. Other geneti- metals from seawater. Iron and sulfur-oxidizing
cally engineered biopolymers are being pro- bacteria can also concentrate and release pre-
duced to replace synthetic fibers and fabrics. cious metals from seawater. Genetically modi-
Polyhydroxybutyrate, a feedstock used in pro- fied thermophilic bacteria are being produced
ducing biodegradable plastics, is being manu- to extract precious metals from sands. Some ge-
factured from genetically modified plants and netically altered microorganisms can withstand
microbes. Natural protein polymers, very simi- extreme environments of high salinity, acidity,
lar to spider silk and the adhesives generated by heavy metals, temperature, and/or pressure,
barnacles, are being produced from the fer- like those that exist around hydrothermal vents
mentation of genetically engineered microbes. where precious minerals are present near the
Sugars produced by genetically altered field bottom of the ocean.
corn are being converted into a biodegradable Genetically engineered strains of the bacte-
polyester-type material for use in manufactur- ria Pseudomonas and Bacillus are being pro-
ing packaging materials, clothing, and bed- duced that can extract oil from untapped reser-
ding products. Genetically tailored yeasts can voirs and store it rather than digest it. These
produce a variety of plastics. Such biotechno- bacteria can be extracted and processed to re-
logical advancements will help eliminate the cover the oil. Other strains are being devel-
prevalent use of petroleum-based chemicals oped to absorb oil from the vast supplies of oil
that has been necessary in the creation of plas- shale in North America. The process would in-
tics and polyesters. volve drilling into the oil shale and breaking it
The fields of biotechnology and nanotech- into pieces with chemical explosives. A solution
nology are being merged in some materials sci- of the bioengineered microbes would then be
ence applications. Genetic codes discovered in injected through a well into the rock frag-
microorganisms can be used as codes for nano- ments, where they would grow and absorb the
structures, such as task-specific silicon chips oil. The solution would be pumped back to the
and microtransistors. Nanotech production of surface through another well and the bacteria
bioactive ceramics may provide new ways to pu- processed to remove the oil. Since this process
rify water, since bacteria and viruses stick to would eliminate the need for large, open-pit oil
these ceramic fibers. Recombinant DNA tech- shale mines, as well as the need to store oil shale
nology combined with nanotechnology pro- at the surface, the negative environmental im-
vides the promise for the production of a vari- pact of oil recovery from shale would be greatly
ety of commercially useful polymers. Carbon reduced.
nanotubes possessing great tensile strength may Alvin K. Benson
be used as computer switches and hydrogen en- See also: Animal Cloning; Biofertilizers; Bi-
ergy storage devices for vehicles. When these ological Weapons; Biopesticides; Biopharma-
nanotubes are coated with reaction specific ceuticals; Cloning; Cloning: Ethical Issues;
biocatalysts, many other specialized applica- Cloning Vectors; DNA Replication; DNA Se-
tions are apparent. In the future, DNA frag- quencing Technology; Gene Therapy; Gene
ments themselves may be used as electronic Therapy: Ethical and Economic Issues; Genetic
switching devices. Engineering; Genetic Engineering: Agricul-
tural Applications; Genetic Engineering: His-
Natural Resource Recovery torical Development; Genetic Engineering:
Bioengineered microbes are being devel- Medical Applications; Genetic Engineering:
oped to extract and purify metals from mined Risks; Genetic Engineering: Social and Ethical
ores and from seawater. The microbes obtain Issues; Genetically Modified (GM) Foods;
energy by oxidizing metals, which then come High-Yield Crops; Knockout Genetics and
out of solution. Chemolithotrophic bacteria, Knockout Mice; Polymerase Chain Reaction;
such as Bacillus cereuss, are energized when they Restriction Enzymes; Reverse Transcriptase;
oxidize nickel, cobalt, and gold. They may be Shotgun Cloning; Synthetic Genes; Transgenic
used to filter out and concentrate precious Organisms; Xenotransplants.
Genetic Engineering: Medical Applications 343
DNA microarrays such as the one above can show which genes are expressed in a cancer, knowledge that can be used to design specific
treatment regimens for each subtype of cancer. (Mitch Doktycz, Life Sciences Division, Oak Ridge National Laboratory; U.S.
Department of Energy Human Genome Program, http://www.ornl.gov/hgmis)
346 Genetic Engineering: Medical Applications
for gene therapy, one young man died in 1999 and Disease. Cambridge, England: Cambridge
and two cases of leukemia in children were de- University Press, 2003. Focuses on molecular
tected. These trials used inactivated viruses as biology and clinical information about hu-
vectors, which may have played a role in the man diseases. Includes chapters on genetic
death and leukemia cases. Efforts are therefore engineering, gene knockouts, and gene ther-
focusing on the development of DNA delivery apy. Illustrations, color photographs.
systems that do not use viruses. Langer, Robert. Delivering Genes. Scientific
American 288 (April, 2003): 56. Discusses al-
Future Prospects ternatives to viruses for introducing genes
In the future, stem cells may be used to gen- into cells.
erate tissues to replace defective tissues. Cata- Langridge, William H. R. Edible Vaccines.
lytic RNAs (ribozymes) may be used to repair Scientific American 283 (September, 2000):
genetically defective messenger RNAs. RNA- 66-71. Describes the making of vaccines in
mediated interference may be used to partially plants.
inactivate, rather than knock out, genes to de- Lewis, Ricki. Human Genetics: Concepts and Appli-
termine the genes functions in the cell. With cations. 5th ed. Boston: McGraw-Hill, 2003. A
the completion of the DNA sequence of the hu- well-written introductory text. Includes
man genome, more genes will inevitably be chapters on genetically modified organisms,
identified and their functions determined, gene therapy, and the Human Genome Pro-
leading to many more applications to medical ject. Illustrations, color photos, problems,
diagnosis and therapy. glossary, index. Lists links to Web sites.
Susan J. Karcher Service, Robert F. Recruiting Genes, Proteins
See also: Animal Cloning; Biofertilizers; Bi- for a Revolution in Diagnostics. Science 300
ological Weapons; Biopesticides; Biopharma- (April 11, 2003): 236-239. Overview of the
ceuticals; Cloning; Cloning: Ethical Issues; use of DNA microarrays to diagnose diseases.
Cloning Vectors; DNA Replication; DNA Se- Strachan, Tom, and Andrew P. Read. Human
quencing Technology; Gene Therapy; Gene Molecular Genetics. New York: Wiley-Liss,
Therapy: Ethical and Economic Issues; Genetic 1999. An advanced text with a chapter on
Engineering; Genetic Engineering: Agricul- gene therapy and genetic-based therapeutic
tural Applications; Genetic Engineering: His- approaches to treating diseases. Illustra-
torical Development; Genetic Engineering: In- tions, photos, glossary, index.
dustrial Applications; Genetic Engineering:
Risks; Genetic Engineering: Social and Ethical Web Sites of Interest
Issues; Genetically Modified (GM) Foods; American Medical Association. http://ama-
High-Yield Crops; Knockout Genetics and assn.org. The AMA includes information on
Knockout Mice; Polymerase Chain Reaction; genetic diseases and disorders as well as links
Restriction Enzymes; Reverse Transcriptase; to affiliated professional organizations and
Shotgun Cloning; Synthetic Genes; Transgenic other resources.
Organisms; Xenotransplants. Centers for Disease Control, Office of
Genomics and Disease Prevention. http://
Further Reading www.cdc.gov/genomics/default.htm. Of-
Botstein, David, and Neil Risch. Discovering fers information on the genetic discoveries
Genotypes Underlying Human Phenotypes: and prevention of diseases in humans. In-
Past Successes for Mendelian Disease, Future cludes links to related resources.
Approaches for Complex Disease. Nature Ge- Dolan DNA Learning Center, Your Genes Your
netics, supp. 33 (March 2003): 228-237. Dis- Health. http://www.ygyh.org. Sponsored by
cusses how human genome sequence analy- the Cold Spring Harbor Laboratory, this
sis is helping to identify complex diseases. site, a component of the DNA Interactive
Epstein, Richard J. Human Molecular Biology; Web site, offers information on more than a
An Introduction to the Molecular Basis of Health dozen inherited diseases and syndromes.
Genetic Engineering: Risks 347
National Center for Biotechnology Informa- changes in the behavior, ecology, or fitness of
tion. Online Mendelian Inheritance in Man. transgenic organisms. It is not the process of re-
http://www.ncbi.nlm.nih.gov/Omim. A moving, recombining, or inserting DNA that
catalog of human genes and genetic disor- usually causes problems. Genetically modifying
ders for scientists, offering maps of genes an organism using laboratory techniques cre-
and diseases, statistical summaries, and links ates a plant, animal, or microbe that has DNA
to similar sites devoted to medical literature and RNA that is fundamentally the same as that
and biotechnology. found in nature.
tally friendly means for controlling and pre- ticated species historically has led to adaptation
venting agricultural losses caused by pests. Such in the pest population eventually making the
genes are bred into plants and animals by mat- resistance gene ineffective. Recombinant meth-
ing desirable genotypes to those that carry ods will likely accelerate the loss of resistance
genes for resistance. This method is limited to genes as compared with traditional methods
those species that can interbreed. Biotechnol- because one resistance gene can be expressed
ogy provides breeders with methods for mov- simultaneously in many species, is often contin-
ing resistance genes across species barriers, uously expressed at high levels within the host,
which was not possible prior to the 1980s. Bac- and will more likely be used over large areas be-
teria and viruses, however, have been moving cause of the immediate economic benefits such
bits of DNA in a horizontal fashion (that is, a gene will bring to a grower or producer.
across species and kingdom barriers) since the Hybrid plants carrying genes that increase
beginning of life. The widespread use of an ef- fitness (through, for example, disease resis-
fective, specific host resistance gene in domes- tance or drought tolerance) may decrease the
Crop plants commonly exchange genes with related cally important native plants. For example, in Mex-
wild plants that are growing nearby, in a process ico, which is located in the evolutionary cradle of
known as gene flow. Pollen seems to be the most ef- corn, concerns about the spread of transgenes to an-
fective agent for gene flow, introducing genes of the cient, native corn varieties, which conventional corn
parent plant to the recipient plant through fertiliza- breeders value as genetic reservoirs, led the Mexican
tion of egg cells. Concern has arisen that genes engi- government to outlaw the planting of bioengineered
neered into crop plants, called transgenes, might corn in 1998.
spread to their nondomesticated relatives. As bioen- In addition, wild plants that acquire transgenes
gineered varieties continue to be developed and as for insecticidal properties could harm insects that
farmers grow the resulting transgenic plants on a the crop bioengineers had not targeted. For exam-
commercial scale, the chances of transgenes escap- ple, moth and butterfly species, whose larvae de-
ing both to other crop plants and to nondomesti- pend for food primarily on these wild plants, might
cated, wild relatives will increase. be vulnerable if acquired transgenes endow their
Agriculturally useful traits engineered into crop food plants with insect-killing abilities.
plants include resistance to herbicides, insects, and The potential for transgene flow from crops to
pathogens, and tolerance of harsh environmental wild relatives varies with the crop and the geographic
conditions such as cold, drought, and high salinity. location. Most cultivated plants spontaneously mate
These traits not only give the crops a survival edge with one or more wild cousins somewhere in their ag-
under appropriate conditions but also might do the ricultural distributions. In the United States, some of
same for nearby wild relatives that acquire the trans- the major genetically engineered crops, including
genes. As a result, farmers face the possibility that corn and soybeans, generally have no nearby, wild
wild plants invigorated by transgenes coding for her- relatives. About twenty other U.S. crops (some al-
bicide resistance could turn into superweeds, re- ready having transgenic varieties), however, are
quiring more expensive or more environmentally grown near nondomesticated kin. These crops in-
harmful herbicides. clude rice, sorghum, canola, strawberries, and turf
Further, if transgenes permit a crop to be grown grasses. The hazards from transgene flow to wild rel-
closer to locally rare, wild relatives because it can tol- atives, though, could prove lower than the risks of
erate an environmental stress that it could not toler- crop-to-crop gene flow, because of the prospect that
ate before, the previously isolated species might hy- transgenes for production of pharmaceuticals or
bridize. If hybridization occurs repeatedly, the risk of other industrial chemicals could make their way into
extinction for the wild population increases. food crops.
Another fear is that the spread of transgenes Jane F. Hill
could diminish the genetic diversity of agronomi-
350 Genetic Engineering: Risks
structure of plants tends to lead to a reduction quire more fertilizer and greater amounts of
in the diversity of plant life, making plants less irrigated water than ordinary plants. The tech-
resistant to disease. It could also lead to the nology would therefore serve the interests of
spread of diseases from one plant species to corporate agribusiness at the expense of small-
another, as genes of one species are implanted scale, low-income farmers.
in another. Furthermore, new and unnatural Many of the concerns about the genetic en-
varieties of food plants could have unforeseen gineering of animals are similar to those about
health risks for human beings. the engineering of plants. Loss of biodiversity,
Since genetic engineering is a highly techni- vulnerability to disease, and business control
cal procedure, those who control technology over livestock are all frequently mentioned ob-
have great power over the food supply. Thus, jections to the genetic manipulation of ani-
both corporate power over consumers and the mals. Moral issues tend to become more im-
power of more technologically advanced na- portant, though, when opponents of genetic
tions over less technologically advanced na- engineering discuss its use with animals. Many
tions could be increased as GM foods fill the religious beliefs hold that the order of the
marketplace. In addition, plants that are genet- world, including its division into different types
ically engineered to produce more often re- of creatures, is divinely ordained. From the per-
spective of such beliefs, the relatively common
experimental practice of injecting human
growth genes into mice could be seen as the
sacrilegious creation of monsters. Opponents
of the genetic alteration of animals argue, fur-
ther, that animals will suffer. They point out
that selective breeding, a slow process, has led
to about two hundred diseases of genetic origin
in purebred dogs. Genetic engineering brings
about change much faster than breeding, in-
creasing the probability of genetic diseases.
Engineering of Humans
Some of the greatest ethical and social prob-
Image not available lems with genetic engineering involve its use
on humans. Gene therapy seeks to cure inher-
ited diseases by altering the defective genes
that cause them. Those who favor gene therapy
maintain that it can be a powerful tool to over-
come human misery. Those who oppose this
type of medical procedure usually focus on
three major ethical issues. First, critics main-
tain that this technology raises the problem of
ownership of human life. In the early 1990s,
the National Institutes of Health (NIH) began
filing for patents on human genes, meaning
that the blueprints for human life could actu-
In Battle Creek, Michigan, a demonstration outside the head-
quarters of Kellogg highlights the companys use of genetically
ally be owned. Because all human DNA comes
altered crops without labeling. Those in favor of labeling the from human tissue, the question arises of
use of genetically altered ingredients maintain that the public whether participants in genetic experiments
has a right to know about the use of such ingredients so they own their own DNA or it belongs to the re-
can make informed purchase decisions. (AP/Wide World searchers who have extracted it.
Photos) The second problem involves eugenic impli-
Genetic Engineering: Social and Ethical Issues 353
cations. Eugenics is the practice of trying to See also: Animal Cloning; Biological
produce better humans. If scientists can alter Weapons; Biopharmaceuticals; Cloning: Ethi-
genes to produce humans with more desirable cal Issues; Eugenics; Cloning Vectors; Gene
health characteristics, then scientists can also Therapy; Gene Therapy: Ethical and Eco-
alter genes to produce humans with more de- nomic Issues; Genetic Engineering; Genetic
sirable characteristics of personality or physical Engineering: Agricultural Applications; Ge-
appearance. In this way, genetic engineering netic Engineering: Historical Development;
poses the risk of becoming an extreme and Genetic Engineering: Industrial Applications;
highly technological form of discrimination. Genetic Engineering: Medical Applications;
The third problem is related to both of the first Genetic Engineering: Risks; Genetically Mod-
two: the reduction of humans to objects. When ified (GM) Foods; High-Yield Crops; Knockout
human life becomes something that can be Genetics and Knockout Mice; Organ Trans-
owned and redesigned at will, some ethicists plants and HLA Genes; Paternity Tests; Patents
claim, it will cease to be seen as a sacred mystery on Life-Forms; Shotgun Cloning; Synthetic
and will become simply another piece of bio- Genes; Transgenic Organisms; Xenotrans-
logical machinery. As objects, people will grad- plants.
ually lose the philosophical justification for
their political and moral rights. Further Reading
Boylan, Michael, and Kevin E. Brown. Genetic
Impact and Applications Engineering: Science and Ethics on the New Fron-
Concerns about the social and ethical impli- tier. Upper Saddle River, N.J.: Prentice Hall,
cations of genetic engineering have led to a 2001. Written by a biologist and philoso-
number of attempts to limit or control the tech- pher, text includes discussions on the profes-
nology. The environmental group Greenpeace sional and practical principles of conduct,
has campaigned against GM agricultural prod- the biology of genetic therapy, the limits of
ucts and called for the clear labeling of all foods science, somatic gene therapy, enhance-
produced by genetic manipulation. In Septem- ment, cloning, and germ line therapy. Illus-
ber, 1997, Greenpeace filed a legal petition trated.
against the U.S. Environmental Protection Evans, John Hyde. Playing God? Human Genetic
Agency (EPA), objecting to the EPAs approval Engineering and the Rationalization of Public
of GM plants. Bioethical Debate. Chicago: University of Chi-
Activist Jeremy Rifkin became one of the cago Press, 2002. Chapters include Frame-
most outspoken opponents of all forms of ge- work for Understanding the Thinning of a
netic engineering. Rifkin and his associates Public Debate, The Eugenicists and the
called on the U.S. NIH to stop government- Challenge from the Theologians, Gene
funded transgenic animal research. A num- Therapy, Advisory Commissions, and the
ber of organizations, such as the Boston-based Birth of the Bioethics Profession, and The
Council for Responsible Genetics (CRG), lob- Presidents Commission: The Neutral Tri-
bied to increase the legal regulation of genetic umph of Formal Rationality.
engineering. In 1990, in response to pressure Gonder, Janet C., Ernest D. Prentice, and Lilly-
from critics of genetic engineering, the Federal Marlene Russow, eds. Genetic Engineering and
Republic of Germany enacted a gene law to Animal Welfare: Preparing for the Twenty-first
govern the use of biotechnology. In the United Century. Greenbelt, Md.: Scientists Center
States, the federal government and many state for Animal Welfare, 1999. Covers ethics and
governments considered laws regarding genetic the well-being of animals used in genetic en-
manipulation. A 1995 Oregon law, for example, gineering and xenotransplantation. Illus-
granted ownership of human tissue and ge- trated.
netic information taken from human tissue to Hubbell, Sue. Shrinking the Cat: Genetic Engi-
the person from whom the tissue was taken. neering Before We Knew About Genes. Illustra-
Carl L. Bankston III tions by Liddy Hubbell. Boston: Houghton
354 Genetic Load
Mifflin, 2001. Discusses the way genes have fying plants and animals, altering human
been altered by humans for centuries by fo- genes, and cloning humans.
cusing on corn, silkworms, domestic cats, Veatch, Robert M. The Basics of Bioethics. 2d ed.
and apples and notes some of the mistakes Upper Saddle River, N.J.: Prentice Hall, 2003.
that were made in the quest for improve- In a textbook designed for students, Veatch
ments. presents an overview of the main theories
Kass, Leon R. Life, Liberty, and the Defense of Dig- and policy questions in biomedical ethics.
nity: The Challenge for Bioethics. San Francisco: Includes diagrams, case studies, and defini-
Encounter Books, 2002. Examines genetic tions of key concepts.
research, cloning, and active euthanasia,
and argues that biotechnology has left hu- Web Sites of Interest
manity out of its equation, often debasing American Medical Association. http://ama-
human dignity rather than celebrating it. assn.org. The AMA has posted it guidelines
Lambrecht, Bill. Dinner at the New Gene Cafe: on the ethics of genetic engineering.
How Genetic Engineering Is Changing What We Council for Responsible Genetics. http://
Eat, How We Live, and the Global Politics of Food. www.gene-watch.org. An organization that
New York: Thomas Dunne Books, 2001. encourages debate on issues concerning ge-
Chronicles the growing debate over geneti- netic technologies.
cally altered food in the United States be- National Information Resource on Ethics and
tween corporate profiteers and consumers, Human Genetics. http://www.georgetown
farmers, and environmentalists. Illustrated. .edu/research/nrcbl/nirehg. Site supports
Long, Clarisa, ed. Genetic Testing and the Use of links to databases, annotated bibliographies,
Information. Washington, D.C.: AEI Press, and articles about the ethics of genetic engi-
1999. Chapters include Genetic Privacy, neering and human genetics.
Medical Information Privacy, and the Use of
Human Tissue Specimens in Research,
The Social Implications of the Use of
Stored Tissue Samples: Context, Control, Genetic Load
and Community, and Genetic Discrimina-
tion. Field of study: Population genetics
Reiss, Michael J., and Roger Straughan, eds. Im- Significance: Genetic load is a measure of the num-
proving Nature? The Science and Ethics of Ge- ber of recessive deleterious (lethal or sublethal) al-
netic Engineering. New York: Cambridge Uni- leles in a population. These alleles are maintained
versity Press, 2001. Elucidates the ethical in populations at equilibrium frequencies by mu-
issues surrounding genetic engineering for tation (which introduces new alleles into the gene
the nonbiologist. Chapters examine genetic pool) and selection (which eliminates unfavorable
engineering in microorganisms, plants, ani- alleles from the gene pool). Genetic load is one of
mals, and humans. the causes of inbreeding depression, the reduced
Rifkin, Jeremy. The Biotech Century: Harnessing viability of offspring from closely related individu-
the Gene and Remaking the World. New York: als. For this reason, genetic load is a primary con-
Putnam, 1998. One of the best-known critics cern in the fields of agriculture, animal hus-
of biotechnology warns that procedures bandry, conservation biology, and human health.
such as cloning and genetic engineering
could be disastrous for the gene pool and for Key terms
the natural environment. deleterious alleles: alternative forms of a
Yount, Lisa, ed. The Ethics of Genetic Engineering. gene that, when expressed in the homozy-
San Diego: Greenhaven Press, 2002. Essays gous condition in diploid organisms, may be
written by scientists, science writers, ethi- lethal or sublethalin the latter case typi-
cists, and consumer advocates present the cally resulting in an aberrant phenotype
growing controversy over genetically modi- with low fitness
Genetic Load 355
different genetic background. In other words, tion rates may also increase genetic load. For
some neutral and nonlethal mutations may example, the rate of nucleotide substitution in
have unpredictable remote consequences. mammalian mitochondrial DNA (mtDNA) is
nearly ten times that of nuclear DNA. The ten-
Population Size, Inbreeding, and fold mutation rate difference is postulated to
Genetic Load be due to highly toxic, mutagenic reactive oxy-
As it is used among population geneticists, gen species produced by the mitochondrial
genetic load is most appropriately defined as electron transport chain and/or relatively inef-
the proportionate decrease in the average fit- ficient DNA repair mechanisms. Thus, mito-
ness of a population relative to that of the opti- chondrial genomes accumulate fixed nucleo-
mal genotype. The proportionate decrease in tide changes rapidly via Mllers ratchet.
the average fitness is, of course, due to the Mutation rates and genetic load may also be in-
presence of lethal and deleterious nonlethal al- creased by exposure to harmful environments.
leles that are maintained in equilibrium by mu- For example, an accident on April 25, 1986,
tation and selection. Genetic load within popu- at the Chernobyl nuclear power plant in the
lations may be substantially increased under Ukraine released 5 percent of the radioactive
certain circumstances. Small populations, spe- reactor core into the atmosphere, contaminat-
cies whose mating system involves complete or ing large areas of Belarus, Ukraine, and Russia.
partial inbreeding, and populations with in- Radiation exposure of this kind and toxic
creased mutation rates all are expected to accu- chemicals (such as heavy metals) in watersheds
mulate load at values exceeding that of large pose significant human health risks that, over
outbreeding populations. Small populations time, may be associated with increased genetic
face multiple genetic hazards, including in- loads in affected populations.
breeding depression. J. Craig Bailey
Inbreeding decreases heterozygosity across See also: Consanguinity and Genetic Dis-
loci and, relative to randomly mating popu- ease; Hardy-Weinberg Law; Heredity and Envi-
lations, the fitness of inbred individuals is ronment; Inbreeding and Assortative Mating;
typically depressed. Inbreeding causes rare re- Lateral Gene Transfer; Natural Selection; Pedi-
cessive alleles to occur more frequently in the gree Analysis; Polyploidy; Population Genetics;
homozygous condition, increasing the frequency Punctuated Equilibrium; Quantitative Inheri-
of aberrant phenotypes that are observed. Com- tance; Sociobiology; Speciation.
plete or partial inbreeding (or, in plants, self-
fertilization) leads to the accumulation of dele- Further Reading
terious mutations that increase genetic load. Charlesworth, D., and B. Charlesworth. In-
Paradoxically, continued inbreeding results in breeding Depression and Its Evolutionary
lower equilibrium frequencies of deleterious Consequences. Annual Review of Ecology and
alleles because they are expressed with greater Systematics 18 (1987): 237-268. A review of
frequency in the homozygous state. Thus, in- empirical studies of genetic load and its
breeding populations may eliminate, or purge, short- and long-term affects on the evolu-
some proportion of their genetic load via selec- tionary potentialities of inbred populations.
tion against deleterious recessive alleles. Never- Thornhill, Nancy Wilmsen, ed. The Natural His-
theless it is true that, compared to large ge- tory of Inbreeding and Outbreeding: Theoretical
netically diverse populations, small inbred and Empirical Perspectives. Chicago: Univer-
populations with reduced genetic diversity are sity of Chicago Press, 1993. Several articles in
more likely to go extinct. For these reasons, this book expertly consider the complex re-
population sizes, inbreeding, and genetic load lationship between the costs and benefits as-
are among the primary concerns of conserva- sociated with many different mating systems
tion biologists working to ensure the survival of (totally outbreeding, inbreeding, partial
rare or endangered species. selfing, and haplodiploidy) in relation to to-
As previously mentioned, increased muta- tal genetic load.
Genetic Screening 357
Wallace, Bruce. Genetic Load: Its Biological and lism. The purpose of this kind of screening is to
Conceptual Aspects. Englewood Cliffs, N.J.: provide immediate treatment after birth if a de-
Prentice-Hall, 1970. This 116-page treatise fect is detected, so that the newborn has a
provides an introduction to the concept of chance of having a normal life. A classic exam-
genetic load in individuals and populations ple of neonatal screening in the United States
and discusses how genetic load is calculated. and many countries is the mandatory mass
It also provides a discussion of how the inter- screening of newborn babies for phenylketon-
play among mutation rates, selection, and uria (PKU), a disorder that causes irreversible
inbreeding influences the dynamics of ge- brain damage when not treated. Individuals
netic load within populations. with PKU lack the enzyme phenylalanine hy-
droxylase, which converts the essential amino
acid phenylalanine into the amino acid tyrosine.
PKU results in accumulation of phenylalanine
Genetic Screening in the body, which causes the brain damage.
Newborn babies are screened for PKU using
Field of study: Human genetics and social the Guthrie test, named after its inventor, Rob-
issues ert Guthrie. The Guthrie test detects high lev-
Significance: Genetic screening is a preventive els of phenylalanine in the blood of newborns.
health measure that involves the mandatory or Blood samples are taken from the heels of new-
voluntary testing of certain individuals for the born babies in the hospital nursery, placed on
purpose of detecting genetic disorders or identify-
ing defective genes that can be transmitted to off-
spring. The primary goals of genetic screening in-
clude the prevention and/or treatment of genetic
disorders and the option to make informed and ra-
tional decisions about conception and birth.It has
raised concerns about confidentiality, discrimina-
tion, and the right to privacy.
Key terms
allele: a form of a gene at a locus; each locus
in an individuals chromosomes has two al-
leles, which may be the same or different
carrier: a healthy individual who has one nor- Image not available
mal allele and one defective allele at the
same gene locus
genetic disorder: a disorder caused by a
change in a gene or chromosome
inborn error of metabolism: an inherited
disease caused by a mutation in a gene that
codes for an enzyme important in a meta-
bolic pathway
locus (pl. loci): the actual location of a gene
on a chromosome
Neonatal Screening
The most widespread use of genetic screen- Many states mandate that newborns be screened for phenylke-
ing is the testing of newborn babies, called neo- tonuria (PKU), hypothyroidism, and, in some cases, other in-
natal screening. Every year, millions of newborn born errors of metabolism such as galactosemia. (AP/Wide
babies are tested for inborn errors of metabo- World Photos)
358 Genetic Screening
filter papers as dried spots, and sent off to ap- uals were tested for the presence of distorted or
propriate laboratories for analysis. Newborns sicked-shaped red blood cells caused by the
with positive results can be effectively treated production of abnormal hemoglobin, the mol-
with a diet low in phenylalanine (low-protein ecule that transports oxygen in the body. The
foods). The level of phenylalanine in the blood laws mandating screening were later repealed
is regularly monitored. If treatment is not initi- amid charges of racial discrimination.
ated within the first two months of life, irrevers- After successful identification of the cystic fi-
ible brain damage will occur. brosis gene in 1989, the scientific and medical
In the United States, only one other neona- community began debating the costs and bene-
tal tests is performed routinely in all states: for fits of screening millions of carriers of the gene
hypothyroidism. There is no federal mandate in the United States. Cystic fibrosis is a com-
for which tests must be provided to everyone, mon inherited disorder characterized by accu-
so each state decides independently. Many states mulation of mucus in the lungs and pancreas; it
also screen for galactosemia, an inherited dis- affects Caucasian children and young adults.
order characterized by seizures, mental retar- The proportion of carriers in the population
dation, vomiting, and liver disease, caused by varies by ethnicity. Northern Europeans have
the accumulation of galactose in the blood. the highest proportion of carriers (1 in 22),
Many states also screen for maple syrup urine while African Americans have a much lower pro-
disease, homocystinuria, and biotinidase defi- portion (1 in 65). Some companies have begun
ciency. A majority of states also screen for voluntary screening for the cystic fibrosis gene
sickle-cell disease, an inherited blood disorder in couples with a family history of the disorder.
characterized by anemia, pain in the abdomen
and joints, and damage to organs. Impact and Applications
The benefits of genetic screening include
Carrier Screening early intervention and treatment, detection of
Carrier screening is the voluntary testing of new mutations by researchers, and the educa-
healthy individuals of reproductive age who tion of people about genetic disorders so that
may be carriers of heritable, defective genes, they are able to make informed and responsi-
the purpose being to inform couples of their ble decisions about reproductive issues. How-
risk of having a child with a genetic disorder. In ever, screening for genetic defects has raised
the United States, screening has been limited ethical and social issues over confidentiality,
to some ethnic groups known to have a high in- discrimination, and the right to privacy.
cidence of a specific genetic disorder. In the One example is the sickle-cell screening pro-
1970s, for example, Tay-Sachs screening of gram of the early 1970s. Screening results were
Ashkenazi Jews of reproductive age was success- not kept in strictest confidence; consequently,
fully implemented. Tay-Sachs disease is an in- many healthy African Americans who were car-
herited, progressive disease in infants charac- riers of the sickle-cell gene were stigmatized
terized by a startle response to noise, blindness, and discriminated against in terms of employ-
seizures, paralysis, and death in infancy caused ment and insurance coverage. There were also
by the absence of an enzyme called hexosamini- charges of racial discrimination because carri-
dase A. Tay-Sachs screening measures the level ers were advised against bearing children.
of hexosaminidase A in the blood. People with Although the sickle-cell disease screening
Tay-Sachs disease have no detectable level of programs were unsuccessful, there were some
the enzyme, while carriers have a below-normal successes in other screening programs. For ex-
level of the enzyme. ample, the number of newborns with Tay-Sachs
In the early 1970s, mandatory, large-scale disease has dropped dramatically as a result of
screening of African American couples and carrier screening programs. The screening pro-
some schoolchildren was implemented in an grams succeeded because of the tremendous
effort to identify carriers of the gene for sickle- effort put forth to educate Ashkenazi Jewish
cell disease. Blood samples taken from individ- communities about the disorder and the conse-
Genetic Screening 359
quent acceptance of the programs by these screening in the Ashkenazi Jewish popula-
communities. tion, cystic fibrosis, identifying and manag-
Genetic screening may be even more useful ing hereditary risk of breast and ovarian can-
in the future, when genetic disorders that are cer, and genetic implications for newborn
currently incurable might be treated by gene screening for phenylketonuria.
therapy (the replacement of a defective or miss- Heyman, Bob, and Mette Henriksen. Risk, Age,
ing gene with a normal, functional copy of the and Pregnancy: A Case Study of Prenatal Genetic
gene). The first clinical trials of gene therapy Screening and Testing. New York: Palgrave,
began in 1990 for severe combined immunode- 2001. Provides a detailed case study of a pre-
ficiency disorder (SCID), a lethal genetic disor- natal genetic screening and testing system in
der in which a person has no functional immu- a British hospital, giving perspectives of
nity. Much attention has been focused on gene pregnant women, hospital doctors, and mid-
therapy as a significant treatment option for pa- wives, and elucidating the communication
tients with disorders such as cystic fibrosis. So between women and the hospital doctors
far, gene therapy has garnered mixed results, who advise them.
and much progress will be needed before it be- Pierce, Benjamin A. The Family Genetic Source-
comes possible, much less routinely feasible. book. New York: John Wiley & Sons, 1990. An
However, although it may well be decades or introduction to the principles of heredity
more before that occurs, future generations and a catalog of more than one hundred hu-
may well enjoy the results of todays research. man traits. Topics include heredity, inheri-
Oluwatoyin O. Akinwunmi tance patterns, chromosomes and chromo-
See also: Amniocentesis and Chorionic Vil- somal abnormalities, genetic risks, genetic
lus Sampling; Bioethics; Cystic Fibrosis; Down counseling, and family history. Written for
Syndrome; Gene Therapy; Gene Therapy: Eth- the general reader, with short descriptions,
ical and Economic Issues; Genetic Counseling; and includes suggested readings, appendi-
Genetic Testing; Genetic Testing: Ethical and ces, glossary, and index.
Economic Issues; Hereditary Diseases; Human Roberts, Leslie. To Test or Not to Test? Science
Genetics; In Vitro Fertilization and Embryo 247 (January, 1990). Although a bit dated,
Transfer; Inborn Errors of Metabolism; Insur- outlines well the basic issues surrounding
ance; Linkage Maps; Phenylketonuria (PKU); cystic fibrosis screening.
Prenatal Diagnosis; Sickle-Cell Disease; Tay- Shannon, Joyce Brennfleck, ed. Medical Tests
Sachs Disease. Sourcebook. Detroit, Mich.: Omnigraphics,
1999. As the lengthy subtitle puts it, a guide
Further Reading to basic consumer health information about
Anderson, W. French. Gene Therapy. Scien- medical tests, including periodic health ex-
tific American 273 (September, 1995). Pro- ams, general screening tests, tests you can do
vides an overview for the general reader. at home, findings of the U.S. Preventive Ser-
Chadwick, Ruth, et al., eds. The Ethics of Genetic vices Task Force, X-ray and radiology tests,
Screening. Boston: Kluwer Academic, 1999. electrical tests, tests of blood and other body
Covers three aspects of the topic: ethical fluids and tissues, scope tests, lung tests, ge-
principles that guide genetic screening and netic tests, pregnancy tests, newborn screen-
testing programs, descriptions of genetic ing tests, sexually transmitted disease tests,
screening programs in European nations, and computer aided diagnoses, along with a
and analysis of social and historical condi- section on paying for medical tests, a glos-
tions that influence national programs. sary, and resource listings. Illustrated.
Evans, Mark I., ed. Metabolic and Genetic
Screening. Philadelphia: W. B. Saunders, Web Sites of Interest
2001. Covers principles of screening, screen- American Medical Association. http://ama-
ing for neural tube defects, second-trimester assn.org. The AMAs guidelines on the eth-
biochemical screening, prenatal genetic ics of genetic screening.
360 Genetic Testing
Centers for Disease Control, Genomics and The technique most commonly used for pre-
Disease Prevention. http://www.cdc.gov/ natal diagnosis is amniocentesis. It is per-
genomics/info/reports/program/popula- formed between the sixteenth and eighteenth
tion.htm. A journal article on genetic week of pregnancy. Amniocentesis involves the
screening, entitled Population Screening insertion of a hypodermic needle through the
in the Age of Genomic Medicine. abdomen into the uterus of a pregnant woman.
The insertion of the needle is guided by ultra-
sound, a technique that uses high-frequency
sound waves to locate a developing fetus or in-
Genetic Testing ternal organs and presents a visual image on a
video monitor. A small amount of amniotic
Field of study: Human genetics and social fluid, which surrounds and protects the fetus, is
issues withdrawn. The amniotic fluid contains fetal
Significance: Genetic testing comprises any proce- secretions and cells sloughed off the fetus that
dure used to detect the presence of a genetic disorder are analyzed for genetic abnormalities. Chro-
or a defective gene in a fetus, newborn, or adult. mosomal disorders such as Down syndrome,
The results of genetic tests can be useful in family Edwards syndrome (trisomy 18), and Patau
planning, treatment decisions and medical re- syndrome (trisomy 13) can be detected by ex-
search. Genetic testing has significant implica- amining the chromosome number of the fetal
tions with respect to reproductive choices, privacy, cells. Certain biochemical disorders such as
insurance coverage, and employment. Tay-Sachs disease, a progressive disorder char-
acterized by a startle response to sound, blind-
Key terms ness, paralysis, and death in infancy, can be
genetic disorder: a disorder caused by a mu- determined by testing for the presence or ab-
tation in a gene or chromosome sence of a specific enzyme activity in the amni-
genetic marker: a distinctive DNA sequence otic fluid. Amniocentesis can also determine
that shows variation in the population and the sex of a fetus and detect common birth
can therefore potentially be used for identi- defects such as spina bifida (an open or ex-
fication of individuals and for discovery of posed spinal cord) and anencephaly (partial or
disease genes complete absence of the brain) by measur-
ing levels of alpha fetoprotein in the amni-
Prenatal Diagnosis otic fluid. The limitations of amniocentesis in-
Prenatal diagnosis is the testing of a develop- clude inability to detect most genetic disorders,
ing fetus in the womb, or uterus, for the pres- possible fetal injury or death, infection, and
ence of a genetic disorder. The purpose of this bleeding.
type of genetic testing is to inform a pregnant Chorionic villus sampling (CVS) is another
woman of the chances of having a baby with a technique used for prenatal diagnosis. It is per-
genetic disorder. Prenatal diagnosis is limited formed earlier than amniocentesis (between
to high-risk individuals and is usually recom- the eighth and twelfth week of pregnancy). Un-
mended only if a woman is thirty-five years of der the guidance of ultrasound, a catheter is in-
age or older, if she has had two or more sponta- serted into the uterus via the cervix to obtain a
neous abortions, or if there is a family history of sample of the chorionic villi. The chorionic villi
a genetic disorder. Hundreds of genetic disor- are part of the fetal portion of the placenta, the
ders can be tested in a fetus. One of the most organ that nourishes the fetus. The chorionic
common genetic disorders screened for is villi can be analyzed for chromosomal and bio-
Down syndrome, or trisomy 21, a form of men- chemical disorders but not for congenital birth
tal retardation caused by having an extra copy defects such as spina bifida and anencephaly.
of chromosome 21. The incidence of Down The limitations of this technique are inaccu-
syndrome increases sharply in children born to rate diagnosis and a slightly higher chance of
women over the age of forty. fetal loss than in amniocentesis.
Genetic Testing 361
DNA samples from patients are removed by an eight-needle apparatus and deposited into a tray for genetic testing at Myriad Genetics
in Salt Lake City. (AP/Wide World Photos)
362 Genetic Testing
technique in which geneticists look for consis- like tests for many of the inborn errors of
tent patterns in large families where the mu- metabolism, predictive testing can only give a
tated gene and a genetic marker always appear rough idea of how likely an individual may be to
together in affected individuals and those develop a particular genetic disease. It is not al-
known to be carriers. If a genetic marker lies ways clear how such information should be
close to the defective gene, it is possible to locate used, but at least in some cases lifestyle or thera-
the defective gene by looking for the genetic peutic changes can be instituted to lessen the
marker. The genetic markers used commonly likelihood of developing the disease.
for linkage analysis are restriction fragment
length polymorphisms (RFLPs). When human Impact and Applications
DNA is isolated from a blood sample and di- Genetic testing has had a significant impact
gested at specific sites with special enzymes on families and society at large. It provides ob-
called restriction endonucleases, RFLPs are pro- jective information to families about genetic
duced. RFLPs are found scattered randomly in disorders or birth defects and provides an anal-
human DNA and are of different lengths in dif- ysis of the risks for genetic disorders through
ferent people, except in identical twins. They genetic counseling. Consequently, many pro-
are caused by mutations or the presence of spective parents are able to make informed and
varying numbers of repeated copies of a DNA responsible decisions about conception and
sequence and are inherited. RFLPs are sepa- birth. Some choose not to bear children, some
rated by gel electrophoresis, a technique in terminate pregnancy after prenatal diagnosis,
which DNA fragments of varying lengths are and some take a genetic gamble and hope for a
separated in an electric field according to their normal child. Genetic testing can have a pro-
sizes. The separated DNA fragments are blot- found psychological impact on an individual or
ted onto a nylon membrane, a process known family. A positive genetic test could cause a per-
as Southern blotting. The membrane is probed son to experience depression, while a negative
and then visualized on X-ray film. The charac- test result may eliminate anxiety and distress.
teristic pattern of DNA bands visible on the Questions have been raised in the scientific
film is similar in appearance to the bar codes and medical community about the reliability
on grocery items. and high costs of tests. There is concern about
An early successful example of linkage analy- whether genetic tests are stringent enough to
sis involved the search for the gene that causes ensure that errors are not made. DNA-based di-
Huntingtons disease, an always fatal neurolog- agnosis can lead to errors if DNA samples are
ical disease that typically shows onset after 35 or contaminated. Such errors can be devastating
40 years of age. In 1983, James Gusella, Nancy to families. People at risk for late-onset disor-
Wexler, and Michael Conneally reported a cor- ders such as Huntingtons disease can be tested
relation between one specific RFLP they to determine if they are predisposed to devel-
named G8 and Huntingtons disease (Hunting- oping the disease. There is, however, contro-
tons chorea). After studying numerous RFLPs versy over whether it is ethical to test for dis-
of generations of an extended Venezuelan fam- eases for which there are no known cures or
ily with a history of Huntingtons disease, they preventive therapies. The question of testing
discovered that G8 was present in members af- also creates a dilemma in many families. Unlike
flicted with the genetic disorder and was absent other medical tests, predictive testing involves
in unaffected members. the participation of many members of a family.
High-risk individuals or families can be Some members of a family may wish to know
tested voluntarily for the presence of a mutated their genetic status, while others may not.
gene that may indicate a predisposition to a While there has been great enthusiasm over
late-onset genetic disorder such as Alzheimers genetic testing, there are also social, legal, and
disease or to other conditions such as heredi- ethical issues such as discrimination, confiden-
tary breast, ovarian, and colon cancers. This tiality, reproductive choice, and abuse of ge-
type of testing is called predictive testing. Un- netic information. Insurance companies and
Genetic Testing 363
employers may require prospective customers See also: Amniocentesis and Chorionic Vil-
and employees to submit to genetic testing or lus Sampling; Bioethics; Breast Cancer; Cystic
may inquire about a persons genetic status. In- Fibrosis; DNA Fingerprinting; Down Syn-
dividuals may be denied life and health insur- drome; Gene Therapy; Gene Therapy: Ethical
ance coverage because of their genetic status, and Economic Issues; Genetic Counseling; Ge-
or a prospective customer may be forced to pay netic Screening; Genetic Testing: Ethical and
exorbitant insurance premiums. The potential Economic Issues; Hemophilia; Hereditary Dis-
for discrimination with respect to employment eases; Human Genetics; Huntingtons Disease;
and promotions also exists. For example, as a In Vitro Fertilization and Embryo Transfer; In-
result of the sickle-cell screening programs of born Errors of Metabolism; Insurance; Link-
the early 1970s, many African Americans with age Maps; Paternity Tests; Phenylketonuria
sickle-cell disease were denied employment (PKU); Prenatal Diagnosis; RFLP Analysis;
and insurance coverage and some were denied Sickle-Cell Disease; Tay-Sachs Disease.
entry into the U.S. Air Force. The Americans
with Disabilities Act, signed into federal law in Further Reading
1990, contained provisions safeguarding em- Anderson, W. French. Gene Therapy. Scien-
ployees from genetic discrimination by em- tific American 273 (September, 1995). Pro-
ployers. By 1994, companies with fifteen or vides an overview for the general reader.
more employees had to comply with the law, Genetic Testing for Breast Cancer Risk: Its Your
which prohibits employment discrimination Choice. NIH Publication 99-4252 4008061621.
because of genetic status and also prohibits ge- DHHS Publication 99-4252 4008061622.
netic testing by employers. Washington, D.C.: National Action Plan on
As genetic testing becomes standard prac- Breast Cancer, Public Health Services Office
tice, the potential for misuse of genetic tests on Womens Health, Department of Health
and genetic information will become greater. and Human Services, 1999. Examines the di-
Prospective parents may potentially use prena- agnosis of human chromosome abnormali-
tal diagnosis as a means to ensure the birth of a ties and the genetic aspects of breast and
perfect child. Restriction fragment length ovarian cancer. Illustrated.
polymorphism analysis, used in genetic testing, Heller, Linda. Genetic Testing. Parents 70 (No-
has applications in DNA fingerprinting or DNA vember, 1995). Explores the risks of some
typing. DNA fingerprinting is a powerful tool tests.
for identification of individuals used to gener- Heyman, Bob, and Mette Henriksen. Risk, Age,
ate patterns of DNA fragments unique to each and Pregnancy: A Case Study of Prenatal Genetic
individual based on differences in the sizes of Screening and Testing. New York: Palgrave,
repeated DNA regions in humans. It is used to 2001. Provides a detailed case study of a pre-
establish identity or nonidentity in immigra- natal genetic screening and testing system
tion cases and paternity and maternity dis- in a British hospital, giving perspectives of
putes; it is also used to exonerate the innocent pregnant women, hospital doctors, and mid-
accused of violent crimes and to link a sus- wives, and elucidating the communication
pects DNA to body fluids or hair left at a crime between women and the hospital doctors
scene. Several states in the United States have who advise them.
been collecting blood samples from a variety of Jackson, J. F., H. F. Linskens, and R. B. Inman,
sources, including newborn infants during neo- eds. Testing for Genetic Manipulation in Plants.
natal testing and individuals convicted of vio- New York: Springer, 2002. Surveys the devel-
lent crimes, and have been storing genetic in- oping methods for detecting and character-
formation derived from them in DNA databases izing genetic manipulation in plants and
for future reference. Such information could plant products such as seeds and foods. Fig-
be misused by unauthorized people. ures, tables.
Oluwatoyin O. Akinwunmi, Shannon, Joyce Brennfleck, ed. Medical Tests
updated by Bryan Ness Sourcebook. Detroit, Mich.: Omnigraphics,
364 Genetic Testing: Ethical and Economic Issues
1999. Gives lay readers insight into basic con- more can be determined through genetic test-
sumer health information about a range of ing. Although there are obvious advantages to
medical tests. Topics covered include gen- acquiring this kind of information, there are
eral screening tests, medical imaging tests, also potential ethical problems. For example, if
genetic testing, newborn screenings, and two married people are both found to be carri-
sexually transmitted disease tests, as well as ers of cystic fibrosis, each child born to them
Medicare, Medicaid, and other information will have a 25 percent chance of having cystic
on paying for medical tests. fibrosis. Using this information, they could
choose not to have any children, or, under an
Web Site of Interest oppressive government desiring to improve
National Institutes of Health, National Library the genetics of the population, they could be
of Medicine. http://www.nlm.nih.gov. This forcibly sterilized. Alternatively, they could
site links to comprehensive information on choose to have each child tested prenatally and
genetic testing, research, and more. Also abort any child that tests positive for cystic fi-
available in Spanish. brosis. Ethical dilemmas similar to these are
destined to become increasingly common as
scientists develop tests for more genetic dis-
eases.
Genetic Testing: Ethical and Another dilemma arises in the case of dis-
Economic Issues eases such as Huntingtons disease (Hunting-
tons chorea), which is caused by a single domi-
Field of study: Bioethics; Human genetics nant gene and is always lethal but which does
and social issues not generally cause physical symptoms until
Significance: Using a suite of molecular, biochemi- middle age or later. A parent with such a dis-
cal, and medical techniques, it is now possible to ease has a 50 percent chance of passing it on to
identify carriers of a number of genetic diseases each child. Now that people can be tested, it is
and to diagnose some genetic diseases even before possible for a child to know whether he or she
they display physical symptoms. In addition, nu- has inherited the deadly gene. If a person tests
merous genes that predispose people to particular positive for the disease, he or she can then
diseases such as cancer, alcoholism, and heart dis- choose to remain childless or opt for prenatal
ease have been identified. These technologies raise testing to guard against the possibility of bring-
important ethical questions about who should be ing a child into the world under a death sen-
tested, how the results of tests should be used, who tence.
should have access to the test results, and what Tests for deadly, untreatable genetic diseases
constitutes normality. in offspring have an even darker side. If the test
is negative, the person may be greatly relieved;
Key terms if it is positive, however, doctors can offer no
dominant trait: a genetically determined hope. Is it right to let someone know that they
trait that is expressed when a person receives will die sometime around middle age or shortly
the gene for that trait from either or both thereafter if there is nothing the medical com-
parents munity can do to help them? The psychological
recessive trait: a genetically determined trait trauma associated with such disclosures can
that is expressed only if a person receives the sometimes be severe enough to result in sui-
gene for the trait from both parents cide. Additionally, who should receive informa-
tion about the test, especially if it shows positive
The Dilemmas of Genetic Testing for the disease? If the information is kept confi-
Historically, it was impossible to determine dential, a person with the disease could buy
whether a person was a carrier of a genetic dis- large amounts of life insurance, to the financial
ease or whether a fetus was affected by a genetic advantage of beneficiaries, at the same price as
disease. Now both of these things and much an unaffected person. On the other hand, if
Genetic Testing: Ethical and Economic Issues 365
health and life insurance companies were al- testing information available to employers and
lowed to know the results of such tests, they insurance companies would open the door to
might use the information to refuse insurance discrimination based on the probability that a
coverage of any kind. Finally, none of the ge- prospective employee or client will become a
netic tests is 100 percent accurate. There will be future financial burden. A number of states
occasional false positives and false negatives. have banned insurance companies from using
With so much at stake, how can doctors and ge- genetic testing data for this very reason.
netic counselors help patients understand the
uncertainties? Impact and Applications
The long track record and accuracy of some
How Should Genetic Testing Information tests, such as the tests for cystic fibrosis and Tay-
Be Used? Sachs disease, has led to the suggestion that
Scientists are now able to test for more than they could be used to screen the general popu-
just specific, prominent genetic defects. Ge- lation. Although this would seem to provide
netic tests are now available for determining positive benefits to the population at large,
potential risks for such things as cancer, alco- there is a concern about the cost of testing on
holism, Alzheimers disease, and obesity. A pos- such a broad scale. Would the costs of testing
itive result for the alcoholism gene does not outweigh the benefits? What other medical
mean that a person is doomed to be an alco- needs might not receive funding if such a pro-
holic but rather that they have a genetic ten- gram were started? The medical community
dency toward behavior patterns that lead to al- will have to consider the options carefully be-
coholism or other addictions. Knowing this, a fore more widespread testing takes place.
person can then seek counseling, as needed, to As more genetic tests become available, it
prevent alcoholism and make lifestyle deci- will eventually be possible to develop a fairly
sions to help prevent alcohol abuse. comprehensive genetic profile for each per-
Unfortunately, a positive test for genes that son. Such profiles could be stored on CD-ROMs
predispose people to diseases such as cancer or other storage devices and be used by individ-
may be more ominous. It is believed that people uals, in consultation with their personal physi-
showing a predisposition can largely prevent cians, to make lifestyle decisions that would
the eventual development of cancer with aggres- counteract the effects of some of the defects in
sive early screening (for example, breast exams their genetic profiles. The information could
and colonoscopies) and lifestyle changes. Some also be used to determine a couples genetic
pre-emptive strategies, however, have come un- compatibility before they get married. When a
der fire. For example, some women at risk for woman becomes pregnant, a prenatal genetic
breast cancer have chosen prophylactic mas- profile of the fetus could be produced; if it does
tectomies. In some cases, however, cancer still not match certain minimum standards, it could
develops after a mastectomy, and some studies be aborted. The same genetic profile could be
have shown lumpectomy and other less radical used to shape the childs life and help deter-
treatments to be as effective as mastectomy. mine the childs profession. Although such
Another concern centers on who should comprehensive testing is now prohibitively ex-
have access to the test results. Should employ- pensive, the costs should drop as the tests are
ers be allowed to require genetic testing as a perfected and made more widely available.
screening tool for hiring decisions? Should in- Access to genetic profiles by employers, in-
surance companies have access to the records surance companies, advertisers, and law en-
when making policy decisions? These are espe- forcement agencies could result in consider-
cially disturbing questions considering the fact able economic savings to society, allowing many
that a test for one of the breast cancer genes, decisions to be made with greater accuracy, but
for example, only predicts a significantly higher at what other costs? How should the informa-
probability of developing breast cancer than is tion be used? How should access be limited?
typical for the general population. Making such How much privacy should individuals have with
366 Genetically Modified (GM) Foods
regard to their own genetic profiles? As genetic versity Press, 1997. Focuses on the practical
testing becomes more widespread, these ques- aspects of obtaining genetic information,
tions will need to be answered. Ultimately, the clearly explaining how genetic disorders are
relationship between the good of society and passed along in families.
the rights of the individual will need to be rede-
fined. Web Sites of Interest
Bryan Ness American Medical Association. http://ama-
See also: Amniocentesis and Chorionic Vil- assn.org. The AMAs guidelines on the eth-
lus Sampling; Bioethics; Breast Cancer; Cystic ics of genetic testing and screening of adults
Fibrosis; DNA Fingerprinting; Down Syn- and children and of multiplex testing.
drome; Gene Therapy; Gene Therapy: Ethical National Information Resource on Ethics and
and Economic Issues; Genetic Counseling; Ge- Human Genetics. http://www.georgetown
netic Screening; Genetic Testing; Hemophilia; .edu/research/nrcbl/nirehg. Site supports
Hereditary Diseases; Human Genetics; Hun- links to databases, annotated bibliographies,
tingtons Disease; In Vitro Fertilization and and articles about the ethics of genetic test-
Embryo Transfer; Inborn Errors of Metabo- ing and human genetics.
lism; Insurance; Linkage Maps; Paternity Tests;
Phenylketonuria (PKU); Prenatal Diagnosis;
RFLP Analysis; Sickle-Cell Disease; Tay-Sachs
Disease. Genetically Modified (GM)
Foods
Further Reading
Finger, Anne L. How Would You Handle Field of study: Genetic engineering and
These Ethical Dilemmas? Medical Economics, biotechnology
October 27, 1997. Presents results of a sur- Significance: Genetically modified foods are pro-
vey in which readers were asked to settle two duced through the application of recombinant
ethical dilemmas involving genetic testing. DNA technology to crop breeding, whereby genes
Marteau, Theresa, and Martin Richards, eds. from the same or different species are transferred
The Troubled Helix: Social and Psychological Im- and expressed in crops that do not naturally har-
plications of the New Human Genetics. New bor those genes. While GM crops offer great poten-
York: Cambridge University Press, 1999. Of- tial for food production in agriculture, their re-
fers brief personal narratives of some of the lease has spurred various concerns among the
psychosocial affects of genetic testing for dis- general public.
eases. Illustrations, bibliography, index.
Rennie, John. Grading the Gene Tests. Scien- Key terms
tific American 273 (June, 1994). Not only fo- Bacillus thuringiensis (Bt) toxin: a toxic com-
cuses on the accuracy and implementation pound naturally synthesized by bacterium
of genetic tests but also considers the prob- Bacillus thuringiensis, which kills insects
lems of privacy, discrimination, and eugen- genetic engineering: the manipulation of ge-
ics inherent in genetic testing. netic material for practical purposes; also re-
Rothenberg, Karen, et al. Genetic Informa- ferred to as recombinant DNA technology,
tion and the Workplace: Legislative Ap- gene splicing, or biotechnology
proaches and Policy Challenges. Science 275 genetically modified organisms (GMOs):
(March 21, 1997). Summarizes government genetically modified organisms, created
action designed to protect the privacy of ge- through the use of genetic engineering or
netic test results and outlines suggested biotechnology
guidelines for future legislation. herbicide resistance: a trait acquired by crop
Zallen, Doris Teichler. Does It Run in the Family? plants through recombinant DNA technol-
A Consumers Guide to DNA Testing for Genetic ogy that enables plants to resist chemicals
Disorders. New Brunswick, N.J.: Rutgers Uni- designed to control weeds
Genetically Modified (GM) Foods 367
In 1991, chief executive officer of CalGene Roger Salquist examines genetically modified tomatoes that are able to ripen on the vine be-
fore shipping, instead of having to be picked green. (AP/Wide World Photos)
is the introduction of Bt gene from the bacte- higher vitamin A precursors. This GM rice plays
rium Bacillus thuringiensis to several crops, in- an important role in alleviating vision loss and
cluding corn, cotton, and soybeans. When the blindness caused by vitamin A deficiency among
Bt gene is transferred to plants, the plant cells those who consume rice as their main staple
produce a protein toxic to some insects and food. Attempts are being made to increase ni-
hence become resistant to these insects. The trogen availability, a limiting factor in crop pro-
grains of Bt maize were also found to contain duction, by transferring genes responsible for
low mycotoxin, thus exhibiting better food nitrogen fixation into crops such as wheat and
safety than non-GM corns. Another example is maize. In addition, the reduction in the use of
the successful insertion of a gene resistant to fertilizers, insecticides, and herbicides for GM
the herbicide glyphosate, reducing production crops not only saves billions of dollars in costs
costs and increasing grain purity. but also alleviates the damage to wild organ-
Food quality can be improved in other ways. isms and ecosystems.
Soybeans and canola with reduced saturated
fats (healthier oil) have been developed. Alter- Concerns About GM Foods
ations in the starch content of potatoes and the Like any other technological innovation, ge-
nutritional quality of protein in maize kernels netic engineering in crop breeding and pro-
are being developed. More precise gene trans- duction does not come without risk or contro-
fer is also being used to produce desirable versy. Some of the common questions raised by
products that the plant does not normally consumers include concerns over what plant
make. The potential products include pharma- and animal organisms they are now putting into
ceutical proteins (for example, vaccines), vita- their bodies, whether these are safe, whether
mins, and plastic compounds. Golden rice they have been tested, why they are not labeled
has been engineered to produce significantly as GM foods, and whether GM foods might not
Demonstrators in front of the San Diego Convention Center in 2001, dressed as killer tomatoes, protest the annual conference of the
Biotechnology Industry Organization. (AP/Wide World Photos)
Genetically Modified (GM) Foods 369
As Nobel laureate Norman Borlaug, father subject category, this site offers quality in-
of the Green Revolution, stated, I now say that formation on topics including transgenic
the world has the technology that is either avail- crops.
able or well advanced in the research pipeline Transgenic Crops. http://www.colostate.edu/
to feed a population of 10 billion people. The programs/lifesciences/transgeniccrops.
more pertinent question today is: Will farmers This richly illustrated site provides informa-
and ranchers be permitted to use this new tech- tion on genetically modified (GM) foods, in-
nology? cluding news updates, the history of plant
Ming Y. Zheng breeding, the making of transgenic plants,
See also: Biofertilizers; Biopesticides; Cell government regulations, and risks and con-
Culture: Plant Cells; Cloning; Cloning: Ethical cerns. This site is also available in Spanish.
Issues; Cloning Vectors; Genetic Engineering;
Genetic Engineering: Agricultural Applica-
tions; Genetic Engineering: Historical Devel-
opment; Genetic Engineering: Industrial Ap-
plications; Genetic Engineering: Risks; Genetic Genetics, Historical
Engineering: Social and Ethical Issues; High- Development of
Yield Crops; Hybridization and Introgression;
Lateral Gene Transfer; Transgenic Organisms. Fields of study: Evolutionary biology;
Genetic engineering and biotechnology;
Further Reading History of genetics
Borlaug, Norman E. Ending World Hunger: Significance: Genetics is a relatively new branch of
The Promise of Biotechnology and the biology that explores the mechanisms of heredity. It
Threat of Antiscience Zealotry. Plant Physi- impacts all branches of biology as well as agricul-
ology 124 (2000): 487-490. The father of ture, pharmacology, and medicine. Advances in
Green Revolution and Nobel Peace Prize genetics may one day eliminate a wide variety of
winner speaks of his unwavering support for diseases and disorders and change the way that life
GMOs. is defined.
Fresco, Louise O. Genetically Modified Or-
ganisms in Food and Agriculture: Where Key terms
Are We? Where Are We Going? Keynote Ad- chromosome theory of heredity: the the-
dress, Conference on Crop and Forest Bio- ory put forth by Walter Sutton that genes are
technology for the Future, September, 2001. carried on cellular structures called chro-
Falkenberg, Sweden: Royal Swedish Acad- mosomes
emy of Agriculture and Forestry, 2001. Fasci- Mendelian genetics: genetic theory that
nating and informative perspectives on GM arose from experiments conducted by
foods by an EU scientist. Gregor Mendel in the 1860s, from which he
Potrykus, Ingo. Golden Rice and Beyond. deduced the principles of dominant traits,
Plant Physiology 125 (2001): 1157-1161. The recessive traits, segregation, and indepen-
originator of the wonder rice presents scien- dent assortment
tific, ethical, intellectual, and social chal- model organisms: organisms, from unicellu-
lenges of developing and using the GMOs. lar to mammals, that are suitable for genetic
Illuminating and insightful. research because they are small and easy to
keep alive in a laboratory, reproduce a great
Web Sites of Interest number of offspring, and can produce many
AgBioWorld.org. http://www.agbioworld.org. generations in a relatively short period of
This site advocates the use of biotechnology time
and GM foods. one gene-one enzyme hypothesis: the no-
Agriculture Network Information Center. http: tion that a region of DNA that carries the in-
//www.agnic.org. Searchable by keyword or formation for a gene product codes for a
Genetics, Historical Development of 371
particular enzyme, later refined to the one found himself under attack from religious lead-
gene-one protein hypothesis and then to ers and other prominent scientists. In his subse-
one gene-one polypeptide principle quent works, he further delineated his propos-
als on the emergence of species, including
Charles Darwin man, but was never able to answer the pivotal
The prevailing public attitude of the mid- question that dogged him until his death in
nineteenth century was that all species were the 1882: If species are in fact mutable (capable of
result of a special creation and were immuta- change over long periods of time), by what
ble; that is, they remained unchanged over mechanism is this change possible?
time. The work of Charles Darwin challenged
that attitude. As a young man, Darwin served as Gregor Mendel
a naturalist on the HMS Beagle, a British ship Ironically, it was only six years later that this
that mapped the coastline of South America question was answered, and nobody noticed.
from 1831 to 1836. Darwins observations of Today, Gregor Mendel is considered the fa-
life-forms and their adaptations, especially ther of genetics, but, in 1865, he was an Augus-
those he encountered on the Galpagos Is- tinian monk in a monastery in Brunn, Austria
lands, led him to postulate that living species (now Brno, Czech Republic). From 1856 to
shared common ancestors with extinct species 1863, he conducted a series of experiments us-
and that the pressures of naturethe availabil- ing the sweet pea (Pisum sativum), in which he
ity of food and water, the ratio of predators to cultivated more than twenty-eight thousand
prey, and competitionexerted a strong influ- plants and analyzed seven different physical
ence over which species were best able to ex- traits. These traits included the height of the
ploit a given habitat. Those best able to take plant, the color of the seed pods and flowers,
advantage of an environment would survive, re- and the physical appearance of the seeds. He
produce, and, by reproducing, pass their traits cross-pollinated tall plants with short plants, ex-
on to the next generation. He called this re- pecting the next generation of plants to be of
sponse to the pressures of nature natural se- medium height. Instead, all the plants pro-
lection: Nature selected which species would duced from this cross, which he called the F1
be capable of surviving in any given environ- (first filial) generation, were tall. When he
ment and, by so doing, directed the develop- crossed plants of the F1 generation, the next
ment of species over time. generation of plants (F2) were both tall and
When Darwin returned to England, he short at a 3:1 ratio; that is, 75 percent of the F2
shared his ideas with other eminent scientists generation of plants were tall, while 25 percent
but had no intention of publishing his note- were short. This ratio held true whether he
books, since he knew that his ideas would bring looked at one trait or multiple traits at the same
him into direct conflict with the society in time. He coined two phrases still used in genet-
which he lived. However, in 1858, he received a ics to describe this phenomenon: He called the
letter from a young naturalist named Alfred trait that appeared in the F1 generation domi-
Russel Wallace. Wallace had done the same nant and the trait that vanished in the F1 gen-
type of collecting in Malaysia that Darwin had eration recessive. While he knew absolutely
done in South America, had observed the same nothing about chromosomes or genes, he pos-
phenomena, and had drawn the same conclu- tulated that each visible physical trait, or phe-
sions. Wallaces letter forced Darwin to publish notype, was the result of two factors and that
his findings, and in 1858, a joint paper by both each parent contributed one factor for a given
men on the topic of evolution was presented at trait to its offspring. His research led him to for-
the London meeting of the Linnean Society. In mulate several statements that are now called
1859, Darwin reluctantly published On the Ori- the Mendelian principles of genetics.
gin of Species by Means of Natural Selection. The re- Mendels first principle is called the princi-
sponse was immediate and largely negative. ple of segregation. While all body cells contain
While the book became a best-seller, Darwin two copies of a factor (what are now called
372 Genetics, Historical Development of
genes), gametes contain only one copy. The type. In fact, 1901 was an exciting year in the
factors are segregated into gametes by meiosis, history of genetics: The ABO blood group was
a specialized type of cell division that produces discovered by Karl Landsteiner; the role of the
gametes. The principle of independent assort- X chromosome in determining gender was de-
ment states that this segregation is a random scribed by Clarence McClung; Reginald Pun-
event. One factor will segregate into a gamete nett and William Bateson discovered genetic
independently of other factors contained linkage; and De Vries introduced the term mu-
within the dividing cell. (It is now known that tation to describe spontaneous changes in the
there are exceptions to this rule: Two genes genetic material. Walter Sutton suggested a re-
carried on the same chromosome will not as- lationship between genes and chromosomes in
sort independently.) 1903. Five years later, Archibald Garrod, study-
To make sense of the data he collected from ing a strange clinical condition in some of his
twenty-eight thousand plants, Mendel kept de- patients, determined that their disorder, called
tailed numerical records and subjected his alkaptonuria, was caused by an enzyme defi-
numbers to statistical analysis. In 1865, he pre- ciency. He introduced the concept of inborn
sented his work before the Natural Sciences errors of metabolism as a cause of certain dis-
Society. He received polite but indifferent ap- eases. That same year, two researchers named
plause. Until Mendel, scientists rarely quanti- Godfrey Hardy and Wilhelm Weinberg pub-
fied their findings; as a result, the scientists ei- lished their extrapolations on the principles of
ther did not understand Mendels math or population genetics.
were bored by it. In either case, the scientists From 1910 to 1920, Thomas Hunt Morgan,
completely overlooked the significance of his with his graduate students Alfred Sturtevant,
findings. Mendel published his work in 1866. Calvin Bridges, and Hermann Mller, con-
Unlike Darwins work, it was not a best-seller. ducted a series of experiments with the fruit
Darwin himself died unaware of Mendels work, fly Drosophila melanogaster that confirmed Men-
in spite of the fact that he had an unopened dels principles of heredity and also confirmed
copy of Mendels paper in his possession. Men- the link between genes and chromosomes. The
del died in 1884, two years after Darwin, with mapping of genes to the fruit fly chromosomes
no way of knowing the eventual impact his work was complete by 1920. The use of research or-
was to have on the scientific community. That ganisms such as the fruit fly became standard
impact began in 1900, when three botanists, practice. For an organism to be suitable for this
working in different countries with different type of research, it must be small and easy to
plants, discovered the same principles as had keep alive in a laboratory and must produce a
Mendel. Hugo De Vries, Carl Correns, and great number of offspring. For this reason, bac-
Erich Tschermak von Seysenegg rediscovered teria (such as Escherichia coli), viruses (particu-
Mendels paper, and all three cited it in their larly those that infect bacteria, called bacterio-
work. Sixteen years after his death, Mendels re- phages), certain fungi (such as Neurospora),and
search was given the respect it deserved, and the fruit fly have been used extensively in ge-
the science of genetics was born. netic research.
During the 1920s, Mller found that the
Pivotal Research in Genetics rate at which mutations occur is increased by
In 1877, Walter Fleming identified struc- exposure to X-ray radiation. Frederick Griffith
tures in the nuclei of cells that he called chro- described transformation, a process by which
mosomes; he later described the material of genetic alterations occur in pneumonococci
which chromosomes are composed as chro- bacteria. In the 1940s, Oswald Avery, Maclyn
matin. In 1900, William Bateson introduced McCarty, and Colin MacLeod conducted a se-
the term genetics to the scientific vocabulary. ries of experiments that showed that the trans-
Wilhelm Johannsen expanded the terminol- forming agent Griffith had not been able to
ogy the following year with the introduction identify was, in fact, DNA. George Beadle and
of the terms gene, genotype, and pheno- Edward Tatum proposed the concept of one
Genetics, Historical Development of 373
gene, one enzyme; that is, a gene or a region of tary material in bacteriophages. From that
DNA that carries the information for a gene point, the race was on to discover the structure
product codes for a particular enzyme. This of DNA.
concept was further refined to the one gene, For DNA or any other substance to be able
one protein hypothesis and then to one gene, to carry genetic information, it must be a sta-
one polypeptide. (A polypeptide is a string of ble molecule capable of self-replication. It was
amino acids, which is the primary structure of known that along with a five-carbon sugar and a
all proteins.) phosphate group, DNA contains four different
During the 1940s, it was thought that pro- nitrogenous bases (adenine, thymine, cytosine,
teins were the genetic material. Chromosomes and guanine). Erwin Chargaff described the
are made of chromatin; chromatin is 65 per- ratios of the four nitrogenous bases in what is
cent protein, 30 percent DNA, and 5 percent now called Chargaffs rule: adenine in equal
RNA. It was a logical conclusion that if the chro- concentrations to thymine, and cytosine in
mosomes were the carriers of genetic material, equal concentrations to guanine. What was not
that material would make up the bulk of the known was the manner in which these con-
chromosome structure. By the 1950s, however, stituents bonded to each other and the three-
it was fairly clear that DNA was the genetic ma- dimensional shape of the molecule. Groups of
terial. Alfred Hershey and Martha Chase were scientists all over the world were working on
able to prove in 1952 that DNA is the heredi- the DNA puzzle. A group in Cambridge, En-
James Watson (left) and Francis Crick pose with a model of the double-helical structure of DNA. They won the 1962 Nobel Prize in
Physiology or Medicine, along with Maurice Wilkins. (Hulton Archive)
374 Genetics, Historical Development of
linked. Techniques such as DNA fingerprint- Darwin, Charles. The Variation of Animals and
ing have had a tremendous impact on law en- Plants Under Domestication. Rev. 2d ed. Lon-
forcement. don: J. Murray, 1875. Anticipating discovery
Advances in genetics have also given rise to a of the genetic basis for phenotypic variation,
wide range of ethical questions with which hu- Darwin describes the remarkable variability
mans will be struggling for some time to come. of domesticated plants and animals. Bibliog-
Termination of pregnancies, in vitro fertiliza- raphy, index.
tion, and cloning are just some of the technolo- Edelson, Edward. Gregor Mendel and the Roots of
gies that carry with them serious philosophical Genetics. New York: Oxford University Press,
and ethical problems. There are fears that bio- 1999. Story of Mendels research into the in-
technology will make it possible for humans to heritance of traits in the garden pea. Illustra-
play God and that the use of biotechnology to tions (including botanical drawings), bibli-
manipulate human genes may have unfore- ography, index.
seen consequences for humankind. For all the Fujimura, Joan H. Crafting Science: A Sociohistory
hope that biotechnology offers, it carries with it of the Quest for the Genetics of Cancer. Cam-
possible societal changes that are unpredict- bridge, Mass.: Harvard University Press,
able and potentially limitless. Humans may be 1996. Provides a medical history of how can-
able to direct their own evolution; no other spe- cer research shifted in the 1970s from view-
cies has ever had that capability. How genetic ing cancer as a set of heterogeneous diseases
technology is used and the motives behind its to a disease of human genes.
use will be some of the critical issues of the fu- King, Robert C., and William D. Stansfield. A
ture. Dictionary of Genetics. 6th ed. New York: Ox-
Kate Lapczynski ford University Press, 2001. Organized to
See also: Central Dogma of Molecular Biol- provide a quick understanding to students
ogy; Chromosome Theory of Heredity; Classi- and nonspecialists, including more than
cal Transmission Genetics; DNA Structure and sixty-five hundred definitions of terms and
Function; Evolutionary Biology; Genetic Code, species names relevant to the study of genet-
Cracking of; Genetic Engineering: Historical ics, as well as a chronology that spans four
Development; Genetics in Television and Films; hundred years of genetic study. Extensive
Genomics; Human Genome Project; Lamarck- bibliography.
ianism; Mendelian Genetics; Sociobiology; Bio- Sturtevant, A. H. A History of Genetics. 1965. Re-
graphical Dictionary of Important Geneticists print. Introduction by Edward B. Lewis.
(appendix); Nobel Prizes for Significant Dis- Cold Spring Harbor, N.Y.: Cold Spring Har-
coveries in Genetics (appendix); Time Line of bor Laboratory Press, 2001. Details Thomas
Major Developments in Genetics (appendix). Morgans research, which laid the founda-
tions for modern, chromosomal genetics.
Further Reading Tudge, Colin. The Engineer in the Garden: Genes
Ayala, Francisco J., and Walter M. Fitch, eds. Ge- and Genetics, From the Idea of Heredity to the Cre-
netics and the Origin of Species: From Darwin to ation of Life. New York: Hill and Wang, 1995.
Molecular Biology Sixty Years After Dobzhansky. Provides a historical overview of genetics
Washington, D.C.: National Academies Press, and explores the potential ramifications of
1997. Papers presented on Theodosius Dob- past, present, and future genetic advances.
zhanskys theory of evolution, which argued Illustrations, bibliography, index.
for a genetics perspective on Darwins the- _______. In Mendels Footnotes: An Introduction to
ory of evolution. Illustrations, maps. the Science and Technologies of Genes and Genet-
Corcos, A., and F. Monaghan. Mendels Experi- ics from the Nineteenth Century to the Twenty-
ments on Plant Hybrids: A Guided Study. New Second. London: Jonathan Cape, 2000. In-
Brunswick, N.J.: Rutgers University Press, vestigates the world of biotechnologies,
1993. Covers the seminal work of Gregor including cloning, genomics, and genetic
Mendel, along with a biography. engineering. Bibliography, index.
376 Genetics in Television and Films
Watson, James. The Double Helix. 1968. Reprint. popularized genetics and how it can be applied
New York: Simon and Schuster, 2001. Dis- to transform, extend, and enrich lives. With the
cusses the race to solve the structure of the exception of documentaries such as The DNA
DNA molecule. Revolution (1998), few films and programs fea-
turing genetics are realistic and accurate.
Web Sites of Interest Science-fiction films and television programs
Dolan DNA Learning Center, DNA from the usually depict genetics as a wondrous endeavor
Beginning. http://www.dnaftb.org. Spon- that can abruptly go awry. Genetics is often ap-
sored by the Cold Spring Harbor Labora- propriated to provoke rather than to resolve
tory, an animated site aimed at those looking dilemmas. In film and television, genetic engi-
for a general introduction to DNA, genes, neering is usually equated with powerpower
genetics, and heredity, and their scientific that genetically superior characters occasion-
histories. Organized by key concepts. ally abuse. Plots frequently contrast extremes,
Electronic Scholarly Publishing Project, Classic such as good and evil scientists pitted against
Genetics: Foundations. http://www.esp.org. each other or combating corrupt administra-
A collection of classic papers marking the tors and greedy entrepreneurs. Many depic-
development of genetics. Includes a time tions of genetics perpetuate stereotypes such as
line. mad scientists isolated in laboratories and un-
accountable to humankind for their research
and creations. A host of biotechnological mon-
sters and mutants populate films.
Genetics in Television and
Films
DNA and Identity
Field of study: History of Genetics; Human CSI: Crime Scene Investigation, a television se-
genetics and social issues ries that first aired in 2000, is representative of
Significance: Popular culture expresses attitudes crime-based television shows that became pop-
regarding genetics. Films and television programs ular in the late 1990s, in part because of pub-
present biotechnology in extremes of either pro- lic fascination with the O. J. Simpson murder
moting genetics as a valuable investigative and trial and other high-profile cases in which DNA
reproductive tool or demeaning it as a dangerous evidence was showcased in the media. Both
science which is hazardous to people and environ- episodic drama programming and true-crime
ments. Most genetic depictions in these media are shows such as Cold Case Files rely on sets that are
more entertaining than accurate. filled with genetic tools. Scenes depict charac-
ters collecting DNA samples from crime scenes
Key terms and evaluating the tissues in laboratories to
eugenics: the selective application of genetics identify victims, prove criminals guilt, or exon-
to produce superior offspring erate the falsely accused.
genetic determinism: how genes might influ- Soap-opera writers often appropriate genet-
ence behavioral characteristics ics as a plot device. Characters test DNA to con-
firm paternity, establish identity, or prove a per-
Science Fiction sons presence at a crime scene. These daytime
In the 1950s, science-fiction films and televi- serials usually restrict access to DNA knowledge
sion programming gradually incorporated ref- to medical and police personnel. Some charac-
erences to genetics. The expansion of biotech- ters manipulate DNA evidence by switching
nology research in the 1970s inspired fictional samples or tampering with laboratory records.
plots that focused on genetics to amuse audi- In 2002, Days of Our Lives introduced a story
ences more than educate them. Box-office suc- line involving the genetically engineered Gem-
cesses such as Jurassic Park (1993) and hit televi- ini Twins, who displayed previously undocu-
sion series, including The X-Files (1993-2002), mented DNA patterns.
Genetics in Television and Films 377
Cloning Characters ety over normal characters who have not bene-
Clones are often depicted as evil creatures fited from biotechnology and are relegated to
that prey on humans. The feature film The Boys an underclass because of their imperfections.
from Brazil (1978) reveals the potential horrific Vincent, a frustrated janitor who aspires to be-
results if Nazi sympathizers successfully cloned come an astronaut, uses DNA to adopt the ap-
Adolf Hitler. Clones are sometimes shown to be pearance of the elite. His genetic transforma-
dutiful, almost robotic, helpers. In Star Wars Ep- tion enables him to achieve his professional
isode II: Attack of the Clones (2002), thousands of ambition. Vincents emotional traits are shown
clonetroopers are created as soldiers during to be superior to the physical beauty of the ge-
the clone wars. In these movies, cloning con- netically engineered people.
cepts are more futuristic than realistic. Beginning in 2002, MTV aired Clone High, a
Jurassic Park and its two sequels captured controversial cartoon featuring clones of sig-
worldwide attention for cloning. Those movies nificant historical leaders. These characters are
are based on the concept that scientists cloned presented as angst-ridden teenagers whom the
dinosaurs from DNA preserved in amber. Sci- scripts hint represent genetic determinism. For
entists criticize this movies premise of cloning example, Joan of Arc is an atheist, suggesting
a dinosaur from fragments of ancient genetic that she might have been genetically prone to
material as improbable, stating that locating an that behavior if she had not been influenced by
egg and host animal capable of transforming cultural factors.
the DNA into a dinosaur would be difficult if
not impossible. More important, DNA of the Reactions
age required for dinosaurs (more than 65 mil- Genetic-based movie and television pro-
lion years old), even if recovered, would almost gramming impacts audiences by influencing
certainly be far too degraded to make
cloning possible.
The Brazilian soap opera O clone (2001-
2002; the clone) chronicles Dr. Albieri se-
cretly creating the clone Leo. Albieri is
concerned for Leos health, referring to
cloned sheep Dollys premature aging,
and addresses ethical issues related to
cloning. Leo suffers identity problems,
questions his potential life span, and re-
sents unwanted public attention.
how people perceive and accept or reject bio- principles and whether the results could be
technology. Although these media expand duplicated off film.
awareness of genetics, they usually are not re- Simon, Anne. The Real Science Behind the X-Files:
liable educational resources and perpetuate Microbes, Meteorites, and Mutants. New York:
misunderstandings. Advertisements for the fic- Simon & Schuster, 1999. The official science
tional O clone, designed as news broadcasts, adviser to the television series discusses the
were so realistic that many viewers thought an authenticity of many of the genetic plots.
actual person had been cloned. Turney, Jon. Frankensteins Footsteps: Science, Ge-
Errors detract from programs being credi- netics, and Popular Culture. New Haven,
ble cinema. Movies and series offer simplified Conn.: Yale University Press, 1998. Science
depictions of complex scientific processes, sug- communication expert analyses how people
gesting they require minimal time and effort perceive genetics as presented in films.
and consistently produce positive results. View-
ers develop unrealistic expectations that genet- Web Site of Interest
ics can quickly solve mysteries because of the The Science Behind the X-Files. http://huah
immediacy of DNA testing in brief episodes. .net/scixf/xeve.html. Describes the genetics-
Dr. J. Craig Venter criticizes popular cul- related science presented in each episode of
tures concentration on genetic determinism this television series, and provides relevant
because such emphasis and negative cinematic links to scientific experts and research insti-
portrayals might cause people to reject bio- tutes.
technology instead of recognizing its merits.
Experts worry about cinema geneticists acting
irresponsibly and unprofessionally. In an effort
to improve depictions, some scientists have Genome Size
served as genetics advisers for film and televi-
sion productions. Field of study: Molecular genetics
Elizabeth D. Schafer Significance: Genome size, the total amount of ge-
See also: Ancient DNA; Biological Deter- netic material within a cell of an organism, varies
minism; Chromosome Theory of Heredity; 200,000-fold among species. Since the 1950s it
Classical Transmission Genetics; Cloning; Clon- has been clear that there is no obvious link between
ing: Ethical Issues; Criminality; DNA Finger- an organisms complexity and the size of its ge-
printing; Eugenics; Eugenics: Nazi Germany; nome, although numerous hypotheses to explain
Evolutionary Biology; Forensic Genetics; Ge- this paradox exist.
netic Code, Cracking of; Genetic Engineering:
Historical Development; Genetic Engineering: Key terms
Social and Ethical Issues; Human Genetics; Hu- C-value: the characteristic genome size for a
man Genome Project; Lamarckianism; Men- species
delian Genetics; Patents on Life-Forms; Pater- chromosome: a self-replicating structure, con-
nity Tests; Race; Sociobiology. sisting of DNA and protein, that contains
part of the nuclear genome of a eukaryote;
Further Reading also used to describe the DNA molecules
DeSalle, Robert, and David Lindley. The Science comprising the prokaryotic genome
of Jurassic Park and The Lost World. New genome: the entire genetic complement of an
York: BasicBooks, 1997. Authors reveal how organism
the cloning of dinosaurs would be impossi- junk DNA: a disparaging (and now known to
ble to achieve. be inaccurate) characterization of the non-
Glassy, Mark C. The Biology of Science Fiction Cin- coding DNA content of a genome
ema. Jefferson, N.C.: McFarland, 2001. Can- reassociation kinetics: a technique that uses
cer researcher critiques films for plausibility hybridization of denatured DNA to reveal
of biotechnology and explains scientific DNA classes differing in repetition frequency
Genome Size 379
repetitive DNA: a DNA sequence that is re- will renature more rapidly than unique DNA
peated two or more times in a DNA mole- sequences. Unique DNA sequences usually rep-
cule or genome resent protein-coding regions, whereas repeti-
tive DNA generally does not encode traits. In
Genome Sizes in Prokaryotes vs. many genomes, three types of DNA can be
Eukaryotes identified by reassociation kinetics: highly re-
Wide variation in genome size exists among petitive DNA, middle repetitive DNA, and
species, from 580,000 bases in the bacterium unique DNA. Prokaryotes have little or no re-
Mycoplasma genitalium to 670 billion bases in petitive DNA. Among eukaryotes, the amounts
the protist Amoeba dubia. In general, prokary- of the three types of DNA varies. The share of
otic genomes are smaller than the genomes of the genome dedicated to genes is relatively
eukaryotes, although a few prokaryotes have constant, whereas the amount of repetitive
genomes that are larger than those of some DNA, 10-70 percent of the total, varies widely
eukaryotes. The largest known prokaryotic ge- even within families of organisms. The exis-
nome (10 million bases in the cyanobacte- tence of noncoding DNA appears to account
rium Nostoc punctiforme) is several times larger for the lack of correlation between genome size
than the genomes of parasitic eukaryotic micro- and complexity because complexity may be
sporidia, with genome sizes of approximately more directly related to number of genes, a
3 million bases. Within the prokaryotes, the number which does appear to have more corre-
archaea have a relatively small range of ge- lation to organismal complexity.
nome sizes, with the majority of species in the The variation in the amount of repetitive
1- to 3-million-base range, while bacterial spe- DNA, even within families, may be related to
cies have been found with genomes differing the spontaneous rate of DNA loss. Small ge-
by twentyfold. nomes may be small because they throw away
Contrary to expectations, there is no obvi- junk DNA very efficiently, whereas large ge-
ous correlation between genome size and nomes may be less able to weed out unneces-
organismal complexity in eukaryotes. For ex- sary DNA. Studies on several invertebrates sup-
ample, the genome of a human is tenfold port this hypothesis: Species within a family
smaller than the genome of a lily, twenty-five- with large genomes have substantially lower
fold smaller than the genome of a newt, and spontaneous DNA losses.
two-hundred-fold smaller than the genome of Genome size does have a positive correla-
an amoeba. The characteristic genome size of tion with cell size and a negative correlation
a species is called the C-value; the lack of rela- with cell division rate in a number of taxa. Be-
tionship between genome size, number of cause of these correlations, genome size is asso-
genes, and organismal complexity has been ciated with developmental rate in numerous
termed the C-value paradox. species. This correlation is not exact, however.
For some organisms (particularly plants) with
Reasons for Size Differences relatively simple developmental complexity,
The majority of DNA in most eukaryotes is developmental rate is constrained by external
noncoding. Previously known as junk DNA, factors such as seasonal changes, while for oth-
this DNA (comprising up to 98.5 percent of ers (amphibians with time-limited morphogen-
some genomes) does not contain the coding esis) developmental complexity overwhelms
sequences for proteins. The complexity of the effects of developmental rate.
DNA can be characterized using a technique
called reassociation kinetics. DNA is sheared Differences in Chromosome Number
into pieces of a few hundred bases, heated to The genomes of eukaryotes are organized
denature into single strands, then allowed to into sets of two or more linear DNA molecules,
renature during cooling. The rate of renatur- each contained in a chromosome. The number
ation is related to the sequence complexity: of chromosomes varies from 2 in females of the
DNA sequences present in numerous copies ant species Myrmecia pilosula to 46 in humans to
380 Genomic Libraries
94 in goldfish. These numbers represent the of the clones together contain most or all of the ge-
diploid number of chromosomes. A genome nome. To find a specific gene, scientists can screen
that contains three or more full copies of the the library using labeled probes of various kinds.
haploid chromosome number is polyploid. As
a general rule polyploids can be tolerated in Key terms
plants but are rarely found in animals. One rea- genome: all the genetic material carried by a
son is that the sex balance is important in ani- cell
mals and variation from the diploid number re- lambda () phage: a virus that infects bacteria
sults in sterility. Chromosome number appears and then makes multiple copies of itself by
to be unrelated to genome size or to most other taking over the infected bacteriums cellular
biological features of the organism. machinery
For most of the prokaryotes studied, the pro- ligation: the joining together of two pieces of
karyotic genome is contained in a single, circu- DNA using the enzyme ligase
lar DNA molecular, with the possible addition
of small, circular, extrachromosomal DNA mol- What Is a Genomic Library?
ecules called plasmids. However, some prokar- Scientists often need to search through all
yotes have multiple chromosomes, some of the genetic information present in an organ-
which are linear; and some prokaryotes have ism to find a specific gene. It is thus convenient
several very large plasmids, nearly the size of to have collections of genetic sequences stored
the bacterial chromosome. so that such information is readily available.
Lisa M. Sardinia These collections are known as genomic li-
See also: Ancient DNA; Evolutionary Biol- braries.
ogy; Gene Families; Genomics; Human Genet- The library metaphor is useful in explain-
ics; Molecular Clock Hypothesis; Noncoding ing both the structure and function of these
RNA Molecules; Plasmids; Pseudogenes; Re- information-storage centers. If one were inter-
petitive DNA; Transposable Elements. ested in finding a specific literary phrase, one
could go to a conventional library and search
Further Reading through the collected works. In such a library,
Petrov, Dmitri A. Evolution of Genome Size: the information is made up of letters organized
New Approaches to an Old Problem. Trends in a linear fashion to form words, sentences,
in Genetics 17, no. 1 (2001): 23-28. Petrov, a and chapters. It would not be useful to store
longtime researcher on genome complexity, this information as individual words or letters
reviews current theories of genome com- or as words collected in a random, jumbled
plexity and offers new explanations for the fashion, as the informations meaning could
lack of relationship between genome size not then be determined. The more books a li-
and organismal complexity. brary has, the closer it can come to having the
Petsko, Gregory A. Size Doesnt Matter. Ge- complete literary collection, although no col-
nome Biology 2, no. 3 (2001): comment 1003.1- lection can guarantee that it has every piece of
1003.2. Expands the discussion of genome written word. The same is true of a genomic li-
size to proteome, or functional, size. brary. The stored pieces of genetic information
cannot be individual bits but must be ordered
sequences that are long enough to define a
gene. The longer the string of information, the
Genomic Libraries easier it is to make sense of the gene they make
up, or encode. The more pieces of genetic in-
Fields of Study: Bioinformatics; Techniques formation a library has, the more likely it is to
and methodologies contain all the information present in a cell.
Significance: A genomic library is a collection of Even a large collection of sequences, however,
clones of DNA sequences, each containing a rela- cannot guarantee that it contains every piece of
tively short piece of the genome of an organism. All genetic information.
Genomic Libraries 381
Chromosomal DNA
Overlapping
Fragments
Vector DNA
Chromosomal DNA
Library of
Overlapping
Genomic Clones
Vector DNA
Genomic libraries are collections of clones of chromosomal DNA segments. These must be constructed in such a way that the order of
the segments can be determined. To accomplish this, regions of each cloned segment overlap with other segments. (U.S. Department
of Energy Human Genome Program, http://www.ornl.gov/hgmis)
382 Genomic Libraries
DNA samples are stored in the Big Bertha freezer at the Armed Forces Institute of Pathology in Gaithersburg, Maryland. (AP/
Wide World Photos)
start and which to proceed to next. Similarly, cleases, enzymes that recognize specific short
without some way of tracking the order of the stretches of DNA and cleave the DNA at spe-
genetic information, it would be impossible to cific positions. To create a library, scientists em-
assemble the sequence of each subfragment ploy restriction enzymes that recognize four-
into the big continuum of the entire chromo- base-pair sequences for cutting. Normally, the
some. The fragments are thus cut so that their result of cleavage with such an enzyme would
ends overlap. With even a few hundred base be fragments with an average size of 256 base
pairs of overlap, the shared sequences at the pairs. If the amount of enzyme in the reaction is
end of the fragments can be used to determine limited, however, only a limited number of sites
the relative position of the different fragments. will be cut, and much longer fragments can be
The different pieces can then be connected generated. The ends created by this cleavage
into one long unit, or sequence. are usable for direct ligation into vectors, but
There are two common ways to fragment the distribution of cleavage sites is not as ran-
DNA, the basic unit of genetic information, to dom as that produced by shearing.
generate a library. The first is to disrupt the In a conventional library, information is im-
long strands of DNA by forcing them rapidly printed on paper pages that can be easily repli-
through a narrow hypodermic needle, creating cated by a printing press and easily bound into
forces that tear, or shear, the strands into short a complete unit such as a book. Genetic infor-
fragments. The advantage of this method is mation is stored in the form of DNA. How can
that the fragment ends are completely random. the pieces of a genome be stored in such a way
The disadvantage is that the sheared ends must that they can be easily replicated and main-
be modified for easy joining, or ligation. The tained in identical units? The answer is to take
other method is to use restriction endonu- the DNA fragments and attach, or ligate, them
Genomic Libraries 383
into lambda phage DNA. When the phage in- incubated in a salt buffer containing radio-
fects bacteria, it makes copies of itself. If the active single-stranded DNA. The radioactive
genomic fragment is inserted into the phage DNA, or probe, is a short stretch of sequence
DNA, then it will be replicated also, making from the gene to be isolated. If the full gene is
multiple exact copies (or clones) of itself. present on the filter, the probe will hybridize
To make an actual library, DNA is isolated with it and become attached to the filter. The
from an organism and fragmented as described. filter is washed, removing all the radioactivity
Each fragment is then randomly ligated into a except where the probe has hybridized. The fil-
lambda phage. The pool of lambda phage con- ters are exposed to film, and a dark spot devel-
taining the inserts is then spread onto an agar ops over the location of the positive plaque.
plate coated with a lawn or confluent layer of The ink spots on the filter can then be used to
bacteria. Wherever a phage lands, it begins to align the spot on the filter with the positive
infect and kill bacteria, leaving a clear spot, or plaque on the plate. The plaque can be puri-
plaque, in the lawn. Each plaque contains fied, and the genomic DNA can then be iso-
millions of phages with millions of identical lated for further study.
copies of one fragment from the original ge- It may turn out that the entire gene is not
nome. If enough plaques are generated on the contained in the fragment isolated from one
plate, each one containing some random piece phage. Since the library was designed so that
of the genome, then the entire genome may be the ends of one fragment overlap with the adja-
represented in the summation of the DNA cent fragment, the ends can be used as a probe
present in all the plaques. Since the fragment to isolate neighboring fragments that contain
generation is random, however, the complete- the rest of the gene. This process of increasing
ness of the genomic library can only be esti- the amount of the genome isolated is called ge-
mated. It takes 800,000 plaques containing an nomic walking.
average genomic fragment of 17,000 base pairs J. Aaron Cassill
to give a 99 percent probability that the total See also: Bioinformatics; cDNA Libraries;
will contain a specific human gene. While this DNA Fingerprinting; DNA Sequencing Tech-
may sound like a large number, it takes only fif- nology; Forensic Genetics; Genetic Testing:
teen teacup-sized agar plates to produce this Ethical and Economic Issues; Genetics, Histori-
many plaques. A genetic library pool of phage cal Development of; Genomics; Human Ge-
can be stored in a refrigerator and plated out nome Project; Icelandic Genetic Database;
onto agar petri dishes whenever needed. Linkage Maps; Proteomics; Restriction En-
zymes; Reverse Transcriptase.
How Can a Specific Gene Be Pulled out of
a Library? Further Reading
Once the entire genome is spread out as a Bird, R. Curtis, and Bruce F. Smith, eds. Genetic
collection of plaques, it is necessary to isolate Library Construction and Screening: Advanced
the one plaque containing the specific se- Techniques and Applications. New York:
quences desired from the large collection. To Springer, 2002. A laboratory manual.
accomplish this, a dry filter paper is laid onto Bishop, Martin J., ed. Guide to Human Genome
the agar dish covered with plaques. As the mois- Computing. 2d ed. San Diego: Academic Press,
ture from the plate wicks into the paper, it car- 1998. Guides researchers with organizing, an-
ries with it some of the phage. An ink-dipped alyzing, storing, and retrieving information
needle is pushed through the filter at several about genome organization, DNA sequence
spots on the edge, marking the same spot on information, and macromolecular function.
the filter and the agar. These will serve as com- Cooper, Necia Grant, ed. The Human Genome
mon reference points. The filter is treated with Project: Deciphering the Blueprint of Heredity.
a strong base that releases the DNA from the Foreword by Paul Berg. Mill Valley, Calif.:
phage and denatures it into single-stranded University Science Books, 1994. Chapters in-
form. The base is neutralized, and the filter is clude Understanding Inheritance: An In-
384 Genomics
troduction to Classical and Molecular Ge- categories: regions, maps, and variations of
netics, Mapping the Genome: The Vision, the human genome.
the Science, the Implementation, DNA Li- National Center for Biotechnology Informa-
braries: Recombinant Clones for Mapping tion. http://www.ncbi.nlm.nih.gov. A cen-
and Sequencing, and Computation and tral repository for biological information,
the Genome Project: A Shotgun Wedding. including links to genome projects and ge-
Hoogenboom, H. R. Designing and Opti- nomic science. Maintains GenBank, a com-
mizing Library Selection Strategies for Gen- prehensive, annotated collection of publicly
erating High-Affinity Antibodies. Trends in available DNA sequences.
Biotechnology 15 (1997). Contains detailed in-
formation about laboratory techniques used
to engineer monoclonal antibodies.
Sambrook, Joseph, et al. Molecular Cloning: A
Laboratory Manual. 3d ed. Cold Spring Har- Genomics
bor, N.Y.: Cold Spring Harbor Laboratory
Press, 1989. A standard manual for more Field of study: Molecular genetics
than twenty years, provides complete descrip- Significance: Genomics involves studying the en-
tions of 250 laboratory protocols in DNA sci- tire complement of genes that an organism pos-
ence, including techniques for isolating, an- sesses. A genomic approach to biology uses modern
alyzing and cloning both large and small molecular and computational techniques in con-
DNA molecules; cDNA cloning and exon junction with large-scale experimental approaches
trapping, amplification of DNA, mutagene- to sequence, identify, map, and determine the
sis, and DNA sequencing; and methods to function of genes. It is also concerned with the
screen expression libraries, analyze tran- structure and evolution of the genome as a whole.
scripts and proteins, and detect protein-
protein interactions. Key terms
Sandor, Suhai, ed. Theoretical and Computational bacterial artificial chromosomes (BACs):
Methods in Genome Research. New York: Ple- cloning vectors that hold inserts of 100-200
num Press, 1997. Covers topics such as math- kilobase pairs of foreign DNA
ematical modeling, three-dimensional mod- expressed sequence tags (EST) library: a
eling of proteins, and applications, such as survey of expressed sequence tags, which
drug design, construction and use of data- are partial sequences from messenger RNA
bases, techniques of sequence analysis and (mRNA)
functional domains, and approaches to link-
age analysis. Definition
Watson, James, et al. Recombinant DNA. New A genome comprises all of the DNA that oc-
York: W. H. Freeman, 1992. Uses accessible curs in each cell of an organism. For prokary-
language and exceptional diagrams to give a otes, which are always single-celled, it com-
concise background on the methods, under- prises all of the DNA within the bacterial cell
lying concepts, and far-reaching applica- that is specific to that species. Other DNA mole-
tions of recombinant DNA technology. cules may also reside in a bacterial cell, such as
plasmids (small extra pieces of circular DNA)
Web Sites of Interest and bacteriophage DNA (bacterial virus DNA).
Johns Hopkins University. The Genome Data- These extra pieces are not considered a part
base. http://gdbwww.gdb.org. The official of the genome. In eukaryotes, the genome
central storage center for gene mapping typically includes just the DNA in the nucleus,
data compiled in the Human Genome Initia- which is composed of linear chromosomes.
tive, an international effort to decode and All eukaryotic cells also have DNA in their mi-
analyze human DNA. Intended for scien- tochondria, the organelle that carries out a
tists, the site presents information in three portion of cellular respiration. It is a circular
Genomics 385
molecule and is sometimes referred to as the chondria, another type of organelle called a
mitochondrial genome or simply mitochon- chloroplast, which also has a circular DNA mol-
drial DNA (mtDNA). Plants and some single- ecule. This DNA is called the chloroplast ge-
celled organisms have, in addition to mito- nome, or simply chloroplast DNA (cpDNA).
Sequenced Organisms
Many genomesfrom vertebrate mitochondria at portant. For example, the small size of the Fugu
about 16,000 base pairs (bp) to mammals at more genome or the intermediate size of the marsupial ge-
than 3 billion bphave been completed, and al- nome makes these valuable because of their unique-
though there still is no one repository for all these ness, while at the same time they possess copies of
data, the National Center for Biotechnology Infor- different variants of many of the same genes. Such
mation maintains GenBank, which keeps track of comparisons may provide insights into gene function
many. Prokaryotic genomes (both Euacteria, or sim- and interactions among genes and their products.
ply Bacteria, and Archaea) are now relatively minor Nonvertebrate animal genomes have been se-
projects on the order of 0.6-8 megabase pairs (Mbp), quenced for Ciona intestinalis (the sea-squirt), Anoph-
and the number completed is now in the hundreds, eles gambiae (the malaria mosquito), Drosophila melan-
because large sequencing centers are capable of ogaster (the fruit or vinegar fly), and Caenorhabditis
completing thirty or more per month. briggsae and C. elegans (nematode worms). Projects
Compared to the prokaryotes, eukaryotic ge- soon to be completed include Apis mellifera ligustica
nomes generally involve much more work. Verte- (the honeybee), Culex and Aedes (mosquitoes),
brate genomes that have either been completed or Glossina morsitans (the tsetese fly), and Brugia malayi
mostly sequenced and are awaiting assembly include (the nematode that causes elephantiasis). For com-
Homo sapiens (humans) at about 3.3 billion bp, Mus parative reasons a cnidarian and a mollusk would be
musculus (the mouse) at about 3 billion bp, Rattus valuable.
norvegicus (the rat) at about 2.8 billion bp, Danio rerio Fungi projects include Aspergillus species, Candida
(the zebra fish) at about 1.7 bp, Fugu rubripes (the albicans (which causes thrush infections), Cryptococcus
pufferfish) at about 3.6 million bp, and Tetraodon neoformans, Neurospora crassa (orange bread mold),
nigroviridis (another form of pufferfish) at 3.8 mil- Phanerochaete chrysosporium (white wood rot), Saccha-
lion bp. Projects for which more than 90 percent of romyces cerevisiae (bakers and brewers yeast), Schizo-
sequencing may be complete by 2010 (if not sooner) saccharomyces pombe (fission yeast), and Pneumocystis
include Pan paniscus (the chimpanzee) at about 3.3 carinii (which causes pneumonia). Many more are
billion bp, Macaca mulatta (the rhesus monkey), soon to start.
Papio cynocephalus (the yellow baboon), Bos taurus Plants often have very large genomes because of
(the cow), Sus scrofa (the pig), Canis familiaris (the duplication events (tetraploidy). Arabidopsis thaliana
dog), Felis catus (the cat), Equus caballus (the horse), (thale cress) at about 115 Mbp and Oryza sativa
Oryctolagus cuniculus (the rabbit), Gallus gallus (the (rice) at about 430 Mbp have been completed, and
chicken), Xenopus tropicalis (a frog), and Xenopus large-scale EST sequencing projects are under way
laevis (another species of frog). These include most for wheat, potato, cotton, tomato, barley and corn,
of the well-known experimental vertebrates as well which all have much larger genomes.
as others of commercial importance. As in the Hu- A wide variety of parasites are also being se-
man Genome Project, annotation, closing gaps, and quenced: Cryptosporidium parvum, which causes diar-
checking assemblies may require additional years. rhea; Plasmodium falciparum, which causes malaria;
Beyond the next few years, there is strong advocacy Toxoplasma gondii, a microsporidian; Encephalitozoon
for genomic sequences of less well-known experimen- cuniculi, kinetoplastids; Leishmania major, which
tal animals, including Peromyscus (the deer mouse) causes leishmaniasis; Trypanosoma brucei, which causes
and Tupaia (the tree shrew), as well as representatives sleeping sickness; Trypanosoma cruzi, which causes
of distinct evolutionary lineages such as elephants. Se- Chagas disease; Thalassiosira pseudonana, a diatom;
quencing the genomes of such animals is important, Dictyostelium discoideum, a slime mold; and Entamoeba
since the best animals for comparative genomics are histolytica, which causes amebic dysentery.
not necessarily experimentally or commercially im- Peter J. Waddell and Michael J. Mclachlan
386 Genomics
Because the genome includes all of the on bacterial genomes because of their small
genes that are expressed in an organism, know- size and lack of repetitive DNA. However, the
ing its nucleotide sequence is considered the amount of repetitive sequence in eukaryotes
first step in a complete understanding of the can lead to difficulties for sequence assembly
genetics of an organism. It must be emphasized and gap filling. Therefore, a mapped, clone-
that much more work follows this first step, be- based approach may be needed to finish such
cause just knowing the nucleotide sequence of sequences. A genomic sequencing project may
all the genes does not necessarily identify their use a combination of the mapped clone method
function or how they interact with other genes. and whole genome shotgun sequencing to pro-
One important side benefit of having the com- duce a completed genomic sequence.
plete genome sequence is that it can greatly An important adjunct to the genomic se-
speed the discovery of mutant genes. The hu- quence is an extensive catalog of expressed se-
man genome sequence, completed by the Hu- quence tags (ESTs), or full-length mRNAs from
man Genome Project in 2003, has already en- many different tissue types. This is achieved by
abled medical geneticists to find a number of reverse transcribing mRNA to complementary
genes for genetic defects. DNA (cDNA) and then sequencing. If a ge-
nome is impractically large to sequence at pres-
Sequencing Whole Genomes ent (due to large amounts of noncoding DNA),
A number of complementary strategies are this stage alone can yield much useful informa-
involved in sequencing a genome. One ap- tion.
proach is the shotgun sequencing of mapped
clones. Large sections of DNA are cloned into Annotation
vectors such as bacterial artificial chromo- The annotation process involves gathering
somes (BACs). A physical map of each BAC is and presenting information about the location
made using techniques such as restriction map- of genes, regulatory elements, structural ele-
ping or the assignment of previously known se- ments, repetitive DNA, and other factors. It is
quence elements. The BAC maps are com- important to integrate any previously known
pared to identify overlapping clones, forming a information regarding the genome, such as lo-
map of long contiguous regions of the genome. cation of ESTs, at this stage. A powerful ap-
BACs are selected from this map and the inserts proach to identifying genes is to map ESTs
are randomly fragmented into short pieces, 1-2 and mRNAs to the genome. This will identify
kilobase pairs (kb), and subcloned into vec- many of the protein-coding genes and can re-
tors. Subclones are selected at random and se- veal the intron-exon structure plus possible al-
quenced. Many subclones are sequenced (of- ternative splicing of the gene. It will not iden-
ten enough to provide sevenfold coverage of tify most functional RNA genes, and how to
the clone) and then assembled to yield the con- do so effectively is an open question. Indeed,
tiguous sequence of the original BAC insert. how many functional RNA genes there may be
The sequences from overlapping BACs are in eukaryotic genomes is unclear. For example,
then assembled. In the finishing stage, addi- in humans approximately thirty-five thousand
tional bridging sequences are obtained to close protein-coding genes have been identified, but
gaps where there were no overlapping clones. there is evidence of many more transcribed
Whole genome shotgun sequencing involves sequences, and exactly what these are is un-
randomly fragmenting the whole genome and known.
sequencing clones without an initial map. Small Some genes can be identified in the genomic
clones (up to around 2 kb) are sequenced and sequence by the comparative approachthat
assembled into contiguous regions with the is, by showing significant sequence similarity
help of sequences from larger (10-50 kb) clones (for example, via BLAST algorithm) with anno-
that form a scaffold. The sequence is then tated genes from other organisms. Such an ap-
linked to a physical map of the organisms proach becomes more powerful as the genomes
chromosomes. This method works effectively of more organisms are published.
Genomics 387
Functional Genomics
The availability of information identifying
the majority of genes in an organism allows new
kinds of experiments to be devised, and on a Image not available
larger scale than ever before. Functional ge-
nomics, for example, aims to assign a func-
tional role to each gene and identify the tissue
type and developmental stage at which it is
expressed. Identifying all genes in a genome
makes it possible to determine the effect of al-
tering the expression of each gene, through
the use of knockouts, gene silencing, or trans-
genic experiments. Technologies such as mi-
croarray analysis allow mRNA expression levels
to be measured for tens of thousands of genes
simultaneously, while proteomic methods such
as mass spectroscopy are beginning to allow
high-throughput measurements of proteins. In
these areas genomics overlaps with transcrip- A researcher examines DNA samples at the W. M. Keck Center
tomics, proteomics, and specialties such as gly- for Comparative and Functional Genomics at the University of
comics. Illinois, Urbana. (AP/Wide World Photos)
Structural Genomics
Structural genomics touches upon pro- structures are experimentally determined us-
teomics in the need to consider structural ing methods such as X-ray crystallography and
changes when there are post-translational nuclear magnetic resonance (NMR) spectros-
changes or binding with other molecules. copy. Computational methods of structural
Structural genomics aims to define the three- prediction, either ab initio (from the begin-
dimensional folding of all protein products ning) or alternatively by computational predic-
that an organism produces. The structure of a tion, aided by the known structure of a related
protein can provide insights into its function protein, are generally inferior to direct experi-
and mode of action. Identifying all the genes in mental approaches, but these fields are rapidly
a genome allows the amino acid sequence of advancing and are the key to the future.
each protein to be inferred from the DNA, and
comparisons between them allow proteins (or Comparative Genomics
characteristic sections of a protein, called folds Comparative genomics expands knowledge
or domains) to be identified and classified into through the comparison of different organ-
families. isms genomes. This is essential to the annota-
Structural prediction typically proceeds via tion of genomic sequences. For example, both
each gene being cloned and then expressed. otherwise unknown genes and particularly reg-
The protein product is then purified, and its ulatory elements in humans and mice were first
388 Genomics
revealed by identifying conserved regions of ect. The whole journal issue contains many
their genomic sequences. This can identify other papers considering the structure,
genes homologous to those in other species or function, and evolution of the human ge-
identify a new member of a gene family. Com- nome.
paring genomes can give insights into evolu- Venter, J. C., et al. The Sequence of the Hu-
tionary questions about a particular gene or man Genome. Science 291, no. 5507 (2001):
the organisms themselves. Important informa- 1304-1351. Report on the Celera Genomics
tion can also be discovered about the regula- human genome project.
tion of different genes, the effects of different
gene expression patterns between different Web Sites of Interest
species, and how the genome of each species Department of Energy. Joint Genome Institute.
came to be the way it is. Comparative genomics http://www.jgi.doe.gov. A collaboration be-
essentially rests upon phylogenetic methodol- tween the Department of Energys Lawrence
ogy to describe the pattern and process of mo- Berkeley, Lawrence Livermore, and Los
lecular evolution (phylogenomics). Alamos National Laboratories. Includes an
Peter J. Waddell and Michael J. Mclachlan introduction to genomics, a research time
See also: Bioinformatics; cDNA Libraries; line that starts with Darwins work in 1859,
Chromosome Walking and Jumping; DNA Se- and links.
quencing Technology; Gene Families; Genetic Human Genome Sequencing Center. http://
Engineering; Genome Size; Genomic Libraries; www.hgsc.bcm.tmc.edu. Baylor College of
Human Genome Project; Molecular Clock Hy- Medicine. Posts an ongoing counter of hu-
pothesis; Protein Structure; Protein Synthesis; man genome sequencing completed world-
Proteomics; Reverse Transcription; RNA World. wide.
National Center for Biotechnology Informa-
Further Reading tion. http://www.ncbi.nlm.nih.gov. A cen-
International Human Genome Sequencing tral repository for biological information,
Consortium. Initial Sequencing and Analy- including links to genome projects and ge-
sis of the Human Genome. Nature 409, no. nomic science. Maintains GenBank, a com-
6822 (2001): 860-921. The publication of prehensive, annotated collection of publicly
the first draft of the Human Genome Proj- available DNA sequences.
Hardy-Weinberg Law counteract that belief, pointing out that by
Field of study: Population genetics themselves, sexual reproduction and Mendel-
Significance: The Hardy-Weinberg law is the foun- ian inheritance have no effect on an alleles
dation for theories about evolution in local popu- commonness. Implicit in Hardys paper was the
lations, often called microevolution. First formu- idea that populations could be viewed as con-
lated in 1908, it continues to be the basis of glomerations of independent alleles, what has
practical methods for investigations in fields from come to be called a gene pool. Alleles ran-
plant breeding and anthropology to law and pub- domly combine in pairs to make up the next
lic health. generation. This simplification is similar to New-
tons view of objects as simple points with mass.
Key terms Hardy, an English mathematician, wrote only
allele frequency: the proportion of all the one paper in biology. Several months earlier,
genes at one chromosome location (locus) Wilhelm Weinberg, a German physician, inde-
within a breeding population pendently and in more detail had proposed the
gene flow: movement of alleles from one pop- law that now bears both their names. In a series
ulation to another by the movement of indi- of papers, he made other contributions, in-
viduals or gametes cluding demonstrating Mendelian heredity in
gene pool: the total set of all the genes in all in- human families and developing methods for
dividuals in an interbreeding population distinguishing environmental from genetic vari-
genetic drift: random changes in allele fre- ation. Weinberg can justifiably be regarded as
quencies caused by chance events the father of human genetics, but his work, like
Mendels, was neglected for many years. The
Introduction fact that his law was known as Hardys law until
The Hardy-Weinberg law can be phrased in the 1940s is an indictment of scientific paro-
many ways, but its essence is that the genetic chialism.
makeup of a population, which meets certain
assumptions, will not change over time. More The Hardy-Weinberg Paradigm
important, it allows quantitative predictions The Hardy-Weinberg law is actually a para-
about the distribution of genes and genotypes digm, a theoretical framework for studying na-
within and among generations. It may seem ture. Hardy and Weinberg envisioned popula-
strange that theories about fundamental mech- tions as collections of gametes (eggs and sperm)
anisms of evolution are based on a definition of that each contain one copy of each gene. Most
conditions under which evolution will not oc- populations consist of diploid organisms that
cur. It is the nature of science that scientists have two copies of each gene. Each generation
must make predictions about the phenomena of individuals can be regarded as a random
being studied. Without something with which sample of pairs of gametes from the previous
to compare the results of experiments or obser- generations gamete pool. The proportion of
vations, science is impossible. Sir Isaac New- gametes that contain a particular allele is the
tons law of inertia plays a similar role in phys- frequency of that allele.
ics, stating that an objects motion will not Imagine a population of one hundred indi-
change unless it is affected by an outside force. viduals having a gene with two alleles, A and a.
After the rediscovery of Mendelian genetics There are three genotypes (combinations of
in 1900, some scientists initially thought domi- alleles) in the population: AA and aa (homo-
nant alleles would become more common than zygotes), and Aa (heterozygotes). If the popu-
recessive alleles, an error repeated in each gen- lation has the numbers of each genotype listed
eration of students. In 1908, Godfrey Hardy in the table Genome Frequencies, then the ge-
published his paper Mendelian Proportions notype frequencies can be computed as shown.
in a Mixed Population in the journal Science to The individuals of each genotype can be
390 Hardy-Weinberg Law
gene flow, nonrandom mating, genetic drift, 2pq is the frequency of heterozygotes (8 per-
and natural selection, respectively. cent of adult African Americans). Since p + q =
Despite its seeming limitations, the Hardy- 1, q = 1 - 0p and 2p(1 - p) = 0.08. From this he
Weinberg law has been crucially useful in three computed p = 0.042 (about 4 percent). From
major ways. First, its predictions of allele and the medical literature, Neel knew the frequency
genotype frequencies in the absence of evolu- of the sickle trait in several African populations
tion provide what statisticians call the null hy- and computed the sickle allele frequency to be
pothesis, which is essential for statistically rig- as high as 0.10 (since then the frequency has
orous hypothesis tests. If measured frequencies been found to be as high as 0.20). These are ex-
do not match predictions, then evolution is oc- traordinarily high frequencies for a lethal re-
curring. This redefines evolution from a vague cessive allele and begged the question: Why was
change in species over time to a more useful, it so common?
quantitative change in allele or genotype fre- The Hardy-Weinberg assumptions provided
quencies. However, it is a definition that can- a list of possibilities, including nonrandom
not be used in the domain of macroevolution mating (mathematical models based on Hardy-
and paleontology above the level of biological Weinberg showed nonrandom mating distorts
species. Similarly, Newtons definition of a mov- genotype frequencies but cannot change allele
ing object does not apply in quantum physics. frequencies), mutation (for the loss of sickle al-
Second, Hardy-Weinberg provides a concep- leles via death of homozygotes to be balanced
tual framework for investigation. If evolution is by new mutations, scientists estimated the mu-
happening, a checklist of potential causes of tation rate from normal to sickle allele would
evolution can be examined in turn. Finally, the have to be about three thousand times higher
Hardy-Weinberg paradigm provides the foun- than any known human mutation rate, which
dation for mathematical models of each evolu- seemed unlikely), and gene flow (models
tionary force. These models help biologists de- showed gene flow reduces differences between
termine whether a specific evolutionary force local populations caused by other evolution-
could produce observed changes. ary forces; gene flow from African populations
caused by slavery explained the appearance of
Using the Hardy-Weinberg Law the sickle allele in North America but not high
Sickle-cell disease is a severe disease of chil- frequencies in Africa).
dren characterized by reduced red blood cell Another possibility was genetic drift. Models
number, bouts of pain, fever, gradual failure of had shown deleterious alleles could rise to high
major organs, and early death. In 1910, physi- frequencies in very small populations (smaller
cians noticed the disease and associated it with than one thousand). It was possible the sickle
distortion (sickling) of red blood cells. They allele drifted to a high frequency in a hu-
realized that victims of the disease were almost man population reduced to small numbers by
entirely of African descent. Studies showed that some catastrophe (population bottleneck)
the blood of about 8 percent of adult American or started by a small number of founders (the
blacks exhibited sickling, although few actually founder effect). If so, the population had
had the disease. By the 1940s, they knew sick- since grown far above the size at which drift
ling was even more common in some popula- is significant. Moreover, drift was random; if
tions in Africa, India, Greece, and Italy. there had been several small populations, some
In 1949, James Neel proved the disease was would have drifted high and some low. It was
caused by a recessive gene: Children homozy- unlikely that drift would maintain high fre-
gous for the sickle allele developed the disease quencies of a deleterious allele in so many large
and died. Heterozygotes showed the sickle trait populations in different locations. Therefore,
but did not develop the disease. Using the the remaining possibility, natural selection, was
Hardy-Weinberg law, Neel computed the allele the most reasonable possibility: The heterozy-
frequency among American blacks as follows: gotes must have some selective advantage over
Letting p = the frequency of the sickle allele, the normal homozygotes.
392 Heart Disease
A few years later, A. C. Allison was doing field over, it is premature to celebrate the end of
work in Africa and noted that the incidence of the disturbing questions raised by eugenics.
the sickle-cell trait was high in areas where ma- Progress in molecular biology makes it possible
laria was prevalent. A search of the literature to detect deleterious alleles in heterozygotes,
showed this was also true in Italy and Greece. making eugenics more practical. Questions of
In 1954, Allison published his hypothesis: In whether genes play a major role in criminality
heterozygotes, sickle-cell alleles significantly im- and mental illness are still undecided. Debate
proved resistance to malaria. It has been re- about such medical and social issues may be in-
peatedly confirmed. Scientists have found al- formed by knowledge of the Hardy-Weinberg
leles for several other blood disorders that also law, but decisions about what to do lie outside
provide resistance to malaria in heterozygotes. the domain of science.
Frank E. Price
Impact and Applications See also: Consanguinity and Genetic Dis-
The Hardy-Weinberg law has provided sci- ease; Eugenics; Eugenics: Nazi Germany; Evo-
entists with a more precise definition of evolu- lutionary Biology; Genetic Load; Genome Size;
tion: change in allele or genotype frequencies. Heredity and Environment; Inbreeding and
It allows them to measure evolution, provides a Assortative Mating; Natural Selection; Poly-
conceptual framework for investigation, and ploidy; Population Genetics; Punctuated Equi-
continues to serve as the foundation for the librium; Quantitative Inheritance; Sickle-Cell
theory of microevolution. Beyond population Disease; Sociobiology; Speciation.
genetics and evolution, the Hardy-Weinberg
paradigm is used in such fields as law (analysis Further Reading
of DNA fingerprints), anthropology (human Provine, William. The Origins of Theoretical Pop-
migration), plant and animal breeding (main- ulation Genetics. 1971. 2d ed. Chicago: Uni-
taining endangered species), medicine (genetic versity of Chicago Press, 2001. Provides a
counseling), and public health (implementing comprehensive overview of the history of
screening programs). In these and other disci- population genetics, including the Hardy-
plines, the Hardy-Weinberg law and its deriva- Weinberg law.
tives continue to be useful.
The Hardy-Weinberg law also has implica-
tions for social issues. In the early twentieth
century, growing knowledge of genetics fueled
a eugenics movement that sought to improve Heart Disease
society genetically. Eugenicists in the 1910s
and 1920s promoted laws to restrict immigra- Field of study: Diseases and syndromes
tion and promote sterilization of mental de- Significance: Individual susceptibility to cardio-
fectives, criminals, and other bad stock. The vascular (heart) disease involves the interaction of
Hardy-Weinberg law is often credited with the complex genetic traits, as well as factors loosely de-
decline of eugenics. The ratio 2pq/q 2 = 1 makes fined as environmental. Only in rare circum-
it clear that if a recessive trait is rare (as most stances do specific mutations result in disease;
deleterious alleles are), most copies of a reces- more often, quantitative differences in gene prod-
sive allele are hidden in apparently normal het- ucts reflect a minimum threshold necessary for
erozygotes. Selecting against affected individu- overt disease.
als will be inefficient at best. However, a host of
respected scientists championed eugenics into Key terms
the 1920s and 1930s, long after the implica- angina pectoris: chest pain that can be indic-
tions of Hardy-Weinberg were understood. It ative of heart disease
was really the reaction to the horrors of Nazi angiotensin-cleaving enzyme (ACE): a pro-
leader Adolf Hitlers eugenics program that tein indirectly involved in regulation of blood
made eugenics socially unacceptable. More- pressure
Heart Disease 393
apolipoprotein A1 (APO A1): a molecule only a limited role. The form or quantity of the
that binds cholesterol in the bloodstream, gene product may define susceptibility to dis-
facilitating its removal by the liver ease; often, however, the environment may play
atherosclerosis: narrowing of coronary ar- a major role in determining the significance
teries that results from plaque formation in played by that product.
the vessel
cholesterol: a steroid derivative that is a nor-
mal constituent of cell membranes, but Cholesterol
which plays a role in plaque formation in ar- Cholesterol was the first component in blood
teries in which the concentration could be correlated
integrin B3 (ITGB3): a glycoprotein found in with risk for heart disease. While other mole-
platelet membranes that plays a role in ad- cules found in the bloodstream are now known
herence to capillary surfaces to also play undefined roles in CHD, elevated
low-density lipoprotein receptor (LDLR): cholesterol concentration remains one of the
a protein on surface of liver cells that re- more important risk factors.
moves cholesterol and other lipids from the The concentration of cholesterol is respon-
bloodstream sive to a variety of processes under genetic con-
quantitative trait locus (QTL) (pl. quan- trol. These take the form of either cholesterol
titative trait loci): a group of genes that packaging or removal. Once in the blood-
interact in defining physical or biochemical stream, cholesterol becomes linked with any of
characteristics such as development of dis- a variety of proteins or other molecules. Low-
ease density lipoprotein (LDL) is often referred to
as bad cholesterol, while high-density lipo-
Forms and Genetic Basis protein (HDL) is called the good cholesterol.
Coronary heart disease (CHD) is arguably The apo A1 protein, product of the APOA1
the leading cause of death among older adults. gene, binds with cholesterol in forming HDLs.
While CHD may take a variety of forms, most At least certain forms of CHD are associated
commonly it is associated with a narrowing of with variants of the gene product apo A1, which
the coronary arteries that supply oxygen and form lower concentrations of HDL. Likewise,
other nutrients to heart tissue. Eventually, the the APOA1 gene can express variants that in-
artery may be completely blocked. While cho- crease the concentration of LDLs, with a con-
lesterol or other lipids certainly play a role in cordant increase in risk of CHD.
the process, other factors or systems are also in- The concentration of packaged cholesterol
volved. Most of these involve genetically en- is also reflected by its rate of removal from the
coded proteins or protein-utilizing systems. bloodstream. In part, this is a function played
Since heart disease often runs in families, by the liver. Liver cells have LDL receptors, the
there is clearly a genetic element in its develop- function of which is to bind and remove LDLs.
ment. Generally, development of disease in At least 350 genetic variants have been de-
populations can be described as a continuum, scribed for the LDLR gene, resulting in sig-
with the quantitative level and rate of CHD de- nificant quantitative differences among per-
velopment varying among individuals; even ac- sons in their efficiency of LDL removal. Persons
counting for the role of the environment, some with those receptor variants that function in-
individuals are more susceptible than others. efficiently often are at increased risk of heart
The genes that are involved can be mapped, in disease. For example, hypercholesterolemia, a
some cases to specific sites on chromosomes, condition in which cholesterol may be three to
and until the genes are actually identified they four times the normal level, is often the result
are referred to as quantitative trait loci (QTLs). of reduced numbers of LDL receptors. Persons
At least 250 genes or QTLs have now been with this condition are at extremely high risk
linked in some manner with CHD develop- for development of atherosclerosis and may
ment. This is not to say that environment plays suffer heart attacks even as young adults.
394 Heart Disease
Defects in the Blood-Clotting System ing from CHD have been shown to express an
While the buildup of plaque in coronary ar- unusual variant of this gene, resulting in an in-
teries is a major factor in heart disease, a heart creased capacity of platelets to initiate clot for-
attack is often triggered by clot formation at the mation.
site of narrowing. The uneven nature or struc- A second gene in the blood-clotting category
ture of the plaque may itself be sufficient for encodes the protein thrombospondin (TSP),
clot formation. Nevertheless, the discovery that one of a family of proteins that regulate adhe-
persons with variants of certain clot-associated sion of cells to capillary surfaces. Epidemiolog-
or inflammatory factors may show increased ical studies of persons with coronary artery dis-
risk of clot formation suggests genetic factors ease have shown that certain variations of this
may also play a role. gene are found in a large proportion of patients,
Clot formation begins when blood platelets while other variants seem associated with a de-
attach to the surface at the site of an injury. creased risk of disease.
Among the molecules found in the cell mem-
brane of platelets is a glycoprotein encoded by Quantitative Trait Loci
the ITGB3 gene. The normal function of this Quantitative traits are those expressed at
molecule is to enable the platelet to attach to varying levels in the population. To date, most
the surface of the blood capillary. However, a QTL studies have involved genetic crosses of
large proportion of middle-aged adults suffer- rats or mice; mice in particular are simple to in-
breed and share some genetic
similarities with humans. Other
genes have been found as a
result of the Human Genome
Project.
Approximately thirty QTLs
have been defined in humans.
Individual genes that make up
QTLs are themselves heteroge-
neous, existing as multiple vari-
ants or alleles. Clearly, CHD is
a complex disorder involving
the interaction of many gene
products of numerous alleles,
Image not available and the specific role played by
such loci in most forms of CHD
remains to be explained. The
association of one type of QTL
linked to a risk factor for CHD,
that of left ventricular hyper-
trophy (LVH), provides a pro-
totype for understanding the
interaction of gene products in
development of disease.
LVH represents a condition
in which the mass of the lower
portion of the heart increases,
raising the level of blood pres-
At the Nebraska Heart Institute in August, 2002, Dr. Vish Bhoopalam discusses sure and increasing the strain
gene therapy used to stimulate growth of new capillaries near the heart. (AP/Wide on the heart. Since LVH is a
World Photos) significant risk factor in devel-
Heart Disease 395
opment of coronary disease, an understand- cleaving enzyme, converts the inactive precur-
ing of the process is important in its preven- sor to the active form. Inactivation of angioten-
tion. sin II is carried out by the product of the ACE2
Using crosses among inbred strains of rats, gene, angiotensin-converting enzyme 2.
researchers have found that genetic markers It is known that high blood pressure in some
for LVH can be mapped to certain QTLs. The individuals may be aggravated by diets high in
quantitative expression of a protein, atrial natri- salt. Animals that exhibit similar characteris-
uretic factor (ANF), appeared to correlate with tics are often found to express decreased con-
the extent of LVH in rats: The higher the con- centrations of the ACE2 enzyme, resulting in
centration of ANF, the lower was the ventricu- greater salt retention as well as higher blood
lar mass. A specific gene, natriuretic peptide pressure. Whether a similar situation exists in
precursor A (Nppa), was found in the region, humans is unclear, though there is evidence
and it encoded the ANF precursor protein. that reduced levels of ACE2 production may
The relationship between QTLs and CHD play an analogous role in humans.
remains more elusive. Human populations ob-
viously do not lend themselves to similar forms Nature vs. Nurture
of crosses, so identification of candidate QTLs For most populations, the risk of CHD repre-
has generally been limited to studies between sents a continuum, with some individuals at low
twins, or at least siblings. These studies have risk and others at increasingly elevated risk. Ex-
demonstrated that both genetics and the envi- cluding those situations in which specific ge-
ronment play roles of indeterminate impor- netic variation is directly the cause of CHD, as
tance in CHD. If one sibling develops disease, in the situation of hypercholesterolemia, in
the other is at significantly higher risk for the most persons the genetic pattern merely re-
same. At the same time, certain behavioral risk lates to the ability of environmental factors to
factors such as smoking or obesity also increase trigger disease. For example, while elevated
the incidence of cardiovascular disease. blood pressure is a significant factor in long-
Most candidate QTLs have been limited to term cardiovascular injury, environmental fac-
an association with hypertension; mutations in tors such as obesity, diet, level of stress, and
certain such genes have been observed in hy- level of exercise may themselves determine the
pertensive cases responsive to reduced levels of extent of hypertension.
salt intake. The actual function of the gene The single most important environmental
products has not been determined. Since there factor associated with CHD that can be con-
exists a clear relationship between elevated trolled is that of tobacco use. While genetic
blood pressure and development of heart dis- variation may play a role in susceptibility to the
ease, these would qualify as candidate loci. effects of tobacco smoke, there is no question
that a cause-and-effect relationship between
Blood Pressure the extent of smoking and increased risk for
The regulation of blood pressure by the disease exists.
body involves a number of complementary sys- As the role played by specific genes in devel-
tems. One of these mechanisms involves the opment of CHD becomes more apparent, not
molecule angiotensin II. Produced within the only is there the potential for improved treat-
liver, angiotensin II constricts small arteries, in- ments, but methods both for screening and
creasing blood pressure, and regulates salt up- prevention become possible. Persons at greater
take by the kidney. risk may be identified on the basis of possessing
Angiotensin II is first synthesized as an in- certain genetic variants, and methods of treat-
active precursor molecule, angiotensinogen; ment may be determined as a result of knowing
subsequent cleavage is required for activation. a specific cause.
Regulation of angiotensin concentration is in Richard Adler
part a function of two different gene products. See also: Congenital Defects; Diabetes; Ge-
The product of the ACE gene, an angiotensin- netic Testing; Hereditary Diseases; Heredity
396 Hemophilia
philiacs. Patients with mild hemophilia may be the use of elastic bandages and ice. Exercise is
treated with a synthetic hormone known as recommended to help strengthen and protect
desmopressin acetate (DDAVP). the joint. Painkillers are used to reduce the
Treatment with the plasma clotting factors chronic pain associated with joint swelling and
has increased longevity and quality of life. In inflammation, although hemophiliacs cannot
addition, many patients are able to treat bleed- use products containing aspirin or antihista-
ing episodes as outpatients with home infu- mines because they prolong bleeding. Patients
sions or self-infusions of the clotting factors. and their families have also benefited from ge-
However, problems do exist with the treatment netic education, counseling, and testing. He-
of hemophilia. Various illnesses, such as HIV, mophilia centers can provide information on
liver disease, or cardiovascular disease, have how the disease is transmitted, potential ge-
resulted from contamination of the clotting netic risks, and whether a person is a carrier.
factors. Several techniques are used to reduce This knowledge provides options for family
the risk of contamination, and most difficul- planning as well as support in coping with the
ties were largely eliminated by the mid-1990s. disease.
Bleeding into the joints is often controlled by Virginia L. Salmon, updated by Bryan Ness
Prior to the development of recombinant factor VIII, The results are encouraging. Previously untreated
patients with hemophilia were treated with coagula- patients with hemophilia who have had severe bleed-
tion factors prepared from the blood of thousands ing episodes have responded well to recombinant
of different donors. While these coagulation factor products. The majority of the bleeds (71-91 percent)
concentrates were highly effective in treating acute in most studies resolved with a single dose. Patients
bleeding episodes, they also proved to be the source rarely have side effects, and those they experience
of infection with hepatitis and human immunodefi- are mild. About one-third of patients developed in-
ciency (HIV) viruses. Many patients with hemophilia hibitors to recombinant factor VIII, but several of
became seriously ill and died from a treatment that these inhibitors disappeared over time. No one has
was designed to save their lives. found evidence of the transmission of infectious
Once the risk of viral infection from these pooled agents in the recombinant factor concentrates.
donations was recognized in the early 1980s, bio- Newer studies show that treatment at home by the
medical manufacturers introduced measures to in- patients themselves, preventive treatment prior to
activate the viruses during the process of preparing necessary surgery, and treatment in previously
the concentrates. The next, even more important, treated patients are effective and safe, with minimal
step in improving hemophilia treatment was the de- adverse effects.
velopment of recombinant factors VIII and IX using In the United States, recombinant factor VIII was
DNA technology. Early studies demonstrated that licensed for use in 1992. These products are now
the recombinant factors were as effective as the used in United States, Canada, Europe, Japan, and
pooled blood concentrates and had few adverse ef- elsewhere. Recombinant factors are considered in
fects. most areas the treatment of choice for the treatment
The first recombinant factor VIII concentrate was of patients with severe hemophilia. Unfortunately,
introduced in 1987. Large-scale multinational stud- these products are not readily available and are ex-
ies of the safety and effectiveness of recombinant fac- tremely costly, meaning that physicians must select
tor VIII began in human subjects in 1989. All of these which patients are most appropriate for using re-
studies are classified as prospective or cohort combinant factor VIII. In general, patients who have
studies where patients are enrolled, treated, and fol- not been treated before and who are not infected
lowed through many years. Since prospective studies with hepatitis or HIV viruses are the candidates most
are considered the most methodologically sound, likely to receive these products until the supplies are
they yield scientific information that is highly re- greater and the costs lower.
spected. Rebecca Lovell Scott
Hereditary Diseases 399
Causes and Impact of Hereditary Congenital defects are birth defects and may
Diseases be caused by genetic factors, environmental
Twentieth century medicine was hugely suc- factors (such as trauma, radiation, alcohol, in-
cessful in conquering infectious diseases. Elim- fection, and drugs), or the interaction of genes
ination, control, and treatment of diseases such and environmental agents. Alan Emery and
as smallpox, measles, diphtheria, and plague David Rimoin noted that the proportion of
have greatly decreased infant and adult mortal- childhood deaths attributed to nongenetic
ity. Improved prenatal and postnatal care have causes was estimated to be 83.5 percent in Lon-
also decreased childhood mortality. Shortly af- don in 1914 but had declined to 50 percent in
ter the rediscovery of Mendelism in the early Edinburgh by 1976, whereas childhood deaths
1900s, reports of genetic determination of attributed to genetic causes went from 16.5 per-
human traits began to appear in medical and cent in 1914 to 50 percent in 1976. These
biological literature. For the first half of the changes reflect societys increased ability to
twentieth century, most of these reports were treat environmental causes of disease, resulting
regarded as interesting scientific reports of iso- in a larger proportion of the remaining dis-
lated clinical diseases that were incidental to eases being caused by genetic defects. Rimoin,
the practice of medicine. The field of medical J. Michael Connor, and Reed Pyeritz estimate
genetics is considered to have begun in 1956 that single-gene disorders have a lifetime fre-
with the first description of the correct number quency of 20 in 1000, chromosomal disorders
of chromosomes in humans (forty-six). Between have a frequency of 3.8 in 1000, and multifac-
1900 and 1956, findings were accumulating in torial disorders have a frequency of 646 in
cytogenetics, Mendelian genetics, biochemical 1000. It is evident that hereditary diseases are
genetics, and other fields that began to draw and will be of major concern for some time.
medicine and genetics together.
The causes of hereditary diseases fall into Single-Gene Defects
four major categories: Single-gene defects result from a change or
mutation in a single gene and are referred to as
(1) single-gene defects or Mendelian disorders
Mendelian disorders or inborn errors of me-
(such as cystic fibrosis, Huntingtons dis-
tabolism. In 1865, Gregor Mendel described
ease [Huntingtons chorea], color blind-
the first examples of monohybrid inheritance.
ness, and phenylketonuria)
In a trait governed by a single locus with two al-
(2) chromosomal defects involving changes in
leles, individuals inherit one allele from each
the number or alterations in the structure
parent. If the alleles are identical, the individ-
of chromosomes (such as Down syndrome,
ual is said to be homozygous. If the alleles are
Klinefelter syndrome, and Turner syn-
different, the individual is said to be heterozy-
drome)
gous. Single-gene defects are typically reces-
(3) multifactorial disorders, caused by a com-
sive. A single copy of a dominant allele will be
bination of genetic and environmental fac-
expressed the same in homozygous and hetero-
tors (such as congenital hip dislocation,
zygous individuals. A recessive allele, on the
cleft palate, and cardiovascular disease)
other hand, is expressed in homozygous indi-
(4) mitochondrial disorders caused by muta-
viduals (often called homozygotes). In hetero-
tions in mitochondrial genes (such as
zygotes, the dominant allele hides or masks
Leber hereditary optic neuropathy)
the expression of the recessive allele. This helps
These four categories are relatively clear-cut. explain why recessive single-gene defects pre-
It is likely that genetic factors also play a less dominate. Dominant single-gene defects are al-
well-defined role in all human diseases, includ- ways expressed when present and never remain
ing susceptibility to many common diseases hidden. As a result, natural selection quickly
and degenerative disorders. Genetic factors may removes these defects from the population.
affect a persons health from the time before Genes can be found either on sex chromo-
birth to the time of death. somes or non-sex chromosomes (called auto-
Hereditary Diseases 401
Angelman Deletion in chromosome 15 Klinefelter syn- Males that are XXY autosomal
syndrome drome dominant disorder
Burkitts Reciprocal translocation involv- Metafemale Females with more than two
lymphoma ing chromosomes 8 and 14 (or (multiple X X chromosomes
occasionally 22 or 2) syndrome)
somes). One pair of chromosomes (two chro- leles to express a recessive trait. Additionally, a
mosomes of the 46 in humans) have been male inherits X-linked alleles from his mother,
designated sex chromosomes because the com- because he only gets a Y chromosome from his
bination of these two chromosomes determines father.
the sex of the individual. Human males have
an unlike pair of sex chromosomes, one called Chromosomal Disorders
the X chromosome and a smaller one called Chromosomal disorders are a major cause of
the Y chromosome. Females have two X chro- birth defects, some types of cancer, infertility,
mosomes. Genes on the X or Y chromosomes mental retardation, and other abnormalities.
are considered sex-linked. However, since Y They are also the leading cause of spontane-
chromosomes contain few genes, sex-linked ous abortions. Deviations from the normal
usually refers to genes on the X chromosome; number of forty-six chromosomes, or struc-
when greater precision is required, genes on the tural changes, usually result in abnormalities.
X chromosome are referred to as X-linked. Variations in the number of chromosomes may
Inheritance patterns for X-linked traits are involve just one or a few chromosomes, a condi-
different than for autosomal traits. Because tion called aneuploidy, or complete sets of chro-
males only have one X chromosome, any al- mosomes, called polyploidy. Polyploidy among
lele, whether normally recessive or dominant, live newborns is very rare, and the few poly-
will be expressed. Therefore, recessive X-linked ploid babies who are born usually die within a
traits are typically much more common in men few days of birth as a result of severe malforma-
than in women, who must have two recessive al- tions. The vast majority of embryos and fetuses
Whereas some variations in an individuals genetic code will not affect the protein produced, others will, possibly resulting in disease
or sensitivity to environmental triggers for the disease. (U.S. Department of Energy Human Genome Program, http://
www.ornl.gov/hgmis)
Hereditary Diseases 403
cardiovascular diseases, rheumatoid arthritis, ile X Syndrome; Gender Identity; Heart Disease;
psychosis, dyslexia, epilepsy, and mental retar- Hemophilia; Hermaphrodites; Homosexuality;
dation. In total, multifactorial disorders account Human Genetics; Human Genome Project;
for more genetic diseases than do single-gene Huntingtons Disease; Hypercholesterolemia;
and chromosome disorders combined. Inborn Errors of Metabolism; Infertility; Kline-
felter Syndrome; Lactose Intolerance; Meta-
Impact and Applications females; Mitochondrial Diseases; Monohybrid
In 2003, the Human Genome Project Inheritance; Neural Tube Defects; Phenylke-
achieved its goal of mapping the entire human tonuria (PKU); Prader-Willi and Angelman Syn-
genome. The complete specifications of the ge- dromes; Prion Diseases: Kuru and Creutzfeldt-
netic material on each of the twenty-two auto- Jakob Syndrome; Pseudohermaphrodites;
somes and the X and Y chromosomes will im- Sickle-Cell Disease; Smallpox; Swine Flu; Tay-
prove the understanding of the biological and Sachs Disease; Testicular Feminization Syn-
molecular bases of hereditary diseases. Once drome; Thalidomide and Other Teratogens;
the location of a gene is known, it is possible to Turner Syndrome; XYY Syndrome.
make a better prediction of how that gene is
transmitted within a family and of the probabil- Further Reading
ity that an individual will inherit a specific ge- Dykens, Elisabeth M., Robert M. Hodapp, and
netic disease. Brenda M. Finucane. Genetics and Mental Re-
For many hereditary diseases, the protein tardation Syndromes: A New Look at Behavior
produced by the gene and its relation to the and Interventions. Baltimore: Paul H. Brookes,
symptoms of the disease are not known. Lo- 2000. Reviews the genetic and behavioral
cating a gene facilitates this knowledge. It be- characteristics of nine mental retardation
comes possible to develop new diagnostic tests syndromes, giving in-depth information on
and therapies. The number of hereditary disor- genetic causes, prevalence, and physical and
ders that can be tested prenatally and in new- medical features of Down, Williams, fragile
borns will increase dramatically. In the case of X, and Prader-Willi syndromes, as well as five
those single genes that do not produce clinical other less frequently diagnosed syndromes.
symptoms until later in life, many more of these Faraone, Stephen V., Ming T. Tsuang, and
disorders will be diagnosed before symptoms Debby W. Tsuang. Genetics of Mental Disorders:
appear, opening the way for better treatments A Guide for Students, Clinicians, and Researchers.
and even prevention. Possibilities will exist to New York: Guilford Press, 1999. Reviews the
develop the means of using gene therapy to re- complex interplay of genes and environmen-
pair or replace the disease-causing gene. The tal factors involved in the causation and ex-
identification and mapping of single genes and pression of frequently encountered disorders
those identified as having major effects on mul- including schizophrenia, bipolar disorder,
tifactorial disorders will greatly affect hereditary depression, and Alzheimers disease.
disease treatment and genetic counseling tech- Gilbert, Patricia. Dictionary of Syndromes and In-
niques. It is evident that knowledge of genes, herited Disorders. 3d ed. Chicago: Fitzroy Dear-
both those that cause disease and those that born, 2000. Lists syndromes and inherited
govern normal functions, will begin to raise disorders with notes on alternative names, in-
many questions about legal, ethical, and moral cidence, causes, characteristics, management
issues. implications, and future prospects for indi-
Donald J. Nash, updated by Bryan Ness viduals with these conditions; contact infor-
See also: Albinism; Alcoholism; Alzheimers mation for self-help groups; and a glossary.
Disease; Autoimmune Disorders; Breast Can- Goldstein, Sam, and Cecil R. Reynolds, eds.
cer; Burkitts Lymphoma; Cancer; Color Blind- Handbook of Neurodevelopmental and Genetic
ness; Congenital Defects; Consanguinity and Disorders in Children. New York: Guilford
Genetic Disease; Cystic Fibrosis; Diabetes; Down Press, 1999. Highlights the role of genetics
Syndrome; Dwarfism; Emerging Diseases; Frag- in shaping the development and lives of
406 Heredity and Environment
many children and surveys disorders pri- ed. New York: McGraw-Hill, 2001. An au-
marily affecting learning and behavior and thority on heredity of disease and genetic in-
those with broader-spectrum effects, includ- heritance, covering genetic perspectives, ba-
ing attention-deficit hyperactivity disorder, sic concepts, how inherited diseases occur,
Tourettes syndrome, and autism. diagnostic approaches, and the effects of
Jorde, Lynn B., et al. Medical Genetics. 2d ed. St. hormones.
Louis, Mo.: Mosby, 1999. Explains basic mo- Wynbrandt, James, and Mark D. Ludman. The
lecular genetics, chromosomal and single- Encyclopedia of Genetic Disorders and Birth De-
gene disorders, immunogenetics, cancer ge- fects. 2d ed. New York: Facts On File, 2000.
netics, multifactorial disorders, and fetal Six hundred entries cover the spectrum of
therapy. clinical and research information on heredi-
Lewis, Ricki. Case Workbook in Human Genetics. tary conditions and birth defects in a non-
2d ed. New York: McGraw-Hill, 2000. Pre- technical manner. Illustrated.
sents problems based on specific diseases, in-
cluding acute leukemia, alcoholism, fragile Web Sites of Interest
X syndrome, gonadal dysgenesis, muscular Centers for Disease Control, Office of Ge-
dystrophy, nephrolithiasis, Tangier disease, nomics and Disease Prevention. http://www
Tay-Sachs disease, and thyroid cancer. .cdc.gov/genomics/default.htm. Offers in-
McKusick, Victor A., comp. Mendelian Inheri- formation on the genetic discoveries and
tance in Man. Baltimore: Johns Hopkins Uni- prevention of diseases in humans. Includes
versity Press, 1994. Comprehensive catalog links to related resources.
of Mendelian traits in humans. Filled with Dolan DNA Learning Center, Your Genes Your
medical terminology, clinical descriptions, Health. http://www.ygyh.org. Sponsored by
and fascinating accounts of many traits. the Cold Spring Harbor Laboratory, this site,
Pasternak, Jack J. An Introduction to Human Mo- a component of the DNA Interactive Web
lecular Genetics: Mechanisms of Inherited Dis- site, offers information on more than a dozen
eases. Bethesda, Md.: Fitzgerald Science Press, inherited diseases and syndromes.
1999. Discusses treatment advances, funda- Genetic Alliance. http://www.geneticalliance
mental molecular mechanisms that govern .org. An international advocacy group of
human inherited diseases, the interactions those with genetic conditions. This site pro-
of genes and their products, and the conse- vides links to information on the diseases,
quences of these mechanisms on disease public policy, and support organizations for
states in major organ systems such as mus- a broad array of hereditary diseases.
cles, the nervous system, and the eyes. Also Medline Plus. http://www.nlm.nih.gov/medline
addresses cancer and mitochondrial disor- plus. Medline, sponsored by the National In-
ders. Illustrations (some color), chapter sum- stitutes of Health, is one of the first stops for
maries, review questions, glossary. any medical question, and it offers informa-
Pierce, Benjamin A. The Family Genetic Source- tion and references on most genetic dis-
book. New York: John Wiley & Sons, 1990. An eases, birth defects, and disorders.
introduction to the principles of heredity
and a catalog of more than one hundred hu-
man traits. Topics include heredity, inheri-
tance patterns, chromosomes and chromo-
somal abnormalities, genetic risks, genetic
counseling, and family history. Written for
Heredity and Environment
the general reader, with short descriptions, Field of study: Human genetics
and includes suggested readings, appendi- Significance: Heredity and environment is the
ces, glossary, and index. modern incarnation of the age-old debate on the ef-
Scriver, Charles, et al., eds. The Metabolic and fects of nature versus nurture. Research in the field
Molecular Bases of Inherited Disease. 4 vols. 8th has implications ranging from the improvement of
Heredity and Environment 407
crop plants to the understanding of the heritability that behave according to simple and predict-
of behavioral traits in humans. able patterns. Mendel did not use the term
gene to refer to these particles (he called
Key terms them factors), and his pioneering work re-
genotype: the genes that are responsible for mained largely unknown to the scientific com-
physical or biochemical traits in organisms munity for the remainder of the nineteenth
heritability: a measure of the genetic varia- century. Immediately following the rediscov-
tion for a quantitative trait in a population ery of Mendels laws in 1900, the Danish biolo-
phenotype: the physical and biochemical traits gist Wilhelm Johannsen proposed the funda-
of a plant or animal mental distinction between phenotype and
phenotypic plasticity: the ability of a geno- genotype. The phenotype is the ensemble of
type to produce different phenotypes when all physical and biochemical traits of a plant or
exposed to different environments animal. The composite of all the genes of an in-
quantitative trait locus (QTL) mapping: a dividual is its genotype. To some extent, the ge-
molecular biology technique used to iden- notype determines the phenotype.
tify genes controlling quantitative traits in
natural populations Reaction Norm: Environments and Genes
reaction norm: the graphic illustration of the Come Together
relationship between environment and phe- It was immediately clear to Johannsen that
notype for a given genotype the appearance of a trait is the combined result
of both the genotype and the environment, but
Nature vs. Nurture and the Origin of to understand how these two factors interact
Genetics took the better part of the twentieth century
Is human behavior controlled by genes or by and is still a preeminent field of research in
environmental influences? The nature vs. nur- ecological genetics. One of the first important
ture controversy has raged throughout hu- discoveries was that genotypes do not always
man history, eventually leading to the modern produce the same phenotype but that this var-
antithesis between hereditarianism and envi- ies with the particular environment to which a
ronmentalism in biological research. These two genotype is exposed. For instance, if geneti-
schools of thought have shaped a dispute that cally identical fruit flies are raised at two tem-
is at once a difficult scientific problem and peratures, there will be clear distinctions in sev-
a thorny ethical dilemma. Many disciplines, eral aspects of their appearance, such as the
chiefly genetics but also the cognitive sciences, size and shape of their wings, even though the
have contributed to the scientific aspect of the genes present in these animals are indistin-
discussion. At the same time, racist and sexist guishable.
overtones have muddled the inquiry and inex- This phenomenon can be visualized in a
tricably linked it to the implementation of so- graph by plotting the observed phenotype on
cial policies. Nevertheless, the relative degree the y-axis versus the environment in which that
of influence of genes and environments in de- phenotype is produced on the x-axis. A curve
termining the characteristics of living organ- describing the relationship between environ-
isms is a legitimate and important scientific ment and phenotype for each genotype is called
question, apart from any social or ethical con- a reaction norm. If the genotype is insensitive
sideration. to environmental conditions, its reaction norm
At the beginning of the twentieth century, will be flat (parallel to the environmental axis);
scientists rediscovered the laws of heredity first most genotypes, however, respond to alterations
formulated by Gregor Mendel in 1865. Mendel in the environment by producing distinct phe-
understood a fundamental concept that under- notypes. When the latter case occurs, that ge-
lies all genetic analyses: Each discrete trait in a notype is said to exhibit phenotypic plasticity.
living organism, such as the color of peas, is in- One can think of plasticity as the degree of re-
fluenced by minute particles inside the body sponsiveness of a given genotype to changes in
408 Heredity and Environment
Molecular Genetics out if and to what extent these genes are vari-
The modern era of the study of nature-nur- able in natural populations. According to neo-
ture interactions relies on the developments Darwinian evolutionary theory, natural selec-
in molecular genetics that characterized the tion is effective only if populations harbor
whole of biology throughout the second half different versions of the same genes, thereby
of the twentieth century. In 1993, Carl Schlich- providing an ample set of possibilities from
ting and Massimo Pigliucci proposed that spe- which the most fit combinations are passed to
cific genetic elements known as plasticity genes the next generation. Thomas Mitchell-Olds pi-
supervise the reaction of organisms to their oneered a combination of statistical and molec-
surroundings. A plasticity gene normally en- ular techniques known as quantitative trait loci
codes a protein that functions as a receptor of (QTL) mapping, which allows researchers to
environmental signals; the receptor gauges the pinpoint the location in the genome of those
state of a relevant environmental variable such genes that are both responsible for phenotypic
as temperature and sends a signal that initiates plasticity and variable in natural populations.
a cascade of effects eventually leading to the These genes are the most likely targets of nat-
production of the appropriate phenotype. For ural selection for the future evolution of the
example, many trees shed their leaves at the on- species.
set of winter in order to save energy and water
that would be wasted by maintaining structures Complex Traits: Behavior and Intelligence
that are not used during the winter months. The most important consequence of nature-
The plants need a reliable cue that winter is in- nurture interactions is their application to the
deed coming to best time the shedding pro- human condition. Humans are compelled to
cess. Deciduous trees use photoperiod as an in- investigate questions related to the degree of
dicator of seasonality. A special set of receptors genetic or environmental determination of
known as phytochromes sense day length, and complex traits such as behavior and intelli-
they initiate the shedding whenever day length gence. Unfortunately, such a quest is a poten-
becomes short enough to signal the onset of tially explosive mixture of science, philosophy,
winter. Phytochromes are, by definition, plas- and politics, with the latter often perverting
ticity genes. the practice of the first. For example, the origi-
Research on plasticity genes is a very active nal intention of intelligence quotient (IQ) test-
field in both evolutionary and molecular ge- ing in schools, introduced by Alfred Binet at
netics. Johanna Schmitts group has demon- the end of the nineteenth century, was simply
strated that the functionality of photoreceptors to identify pupils in need of special attention
in plants has a direct effect on the fitness of the in time for remedial curricula to help them.
organism, thereby implying that natural selec- Soon, however, IQ tests became a widespread
tion can alter the characteristics of plasticity tool to support the supposed scientific dem-
genes. Harry Smith and collaborators have con- onstration of the innate inferiority of some
tributed to the elucidation of the action of races, social classes, or a particular gender
photoreceptors, uncovering an array of other (with the authors of such studies usually fall-
genes that relate the receptors signals to differ- ing into the superior race, social class, or gen-
ent tissues and cells so that the whole organism der). During the 1970s, ethologist Edward Wil-
can appropriately respond to the change in en- son freely extrapolated from behavioral studies
vironmental conditions. Similar research is on- on ant colonies to reach conclusions about hu-
going on an array of other types of receptors man nature; he proposed that genes directly
that respond to nutrient availability, water sup- control many aspects of animal and human be-
ply, temperature, and a host of other environ- havior, thereby establishing the new and con-
mental conditions. troversial discipline of sociobiology.
From an evolutionary point of view, it is The reaction against this trend of manipu-
important not only to uncover which genes lating science to advance a political agenda has,
control a given type of plasticity but also to find in some cases, overshot the mark. Some well-
410 Heredity and Environment
intentioned biologists have gone so far as to im- questions fully, the more compelling argument
ply either that there are no genetic differences that has been made so far is that the actual
among human beings or that they are at least ir- answer should not matter to society, in that
relevant. This goes against everything that is every human being is entitled to the same
known about variation in natural populations rights and privileges of any other one, regard-
of any organism. There is no reason to think less of real and sometimes profound differ-
that humans are exceptions: Since humans can ences in genetic makeup. Even the best science
measure genetically based differences in be- is simply the wrong tool to answer ethical ques-
havior and problem-solving ability in other spe- tions.
cies and relate these differences to fitness, the Massimo Pigliucci
argument that such differences are somehow See also: Aggression; Alcoholism; Altruism;
unimportant in humans is based on social good- Artificial Selection; Behavior; Biological Clocks;
will rather than scientific evidence. Biological Determinism; Criminality; Develop-
The problem with both positions is that they mental Genetics; Eugenics; Gender Identity;
do not fully account for the fact that nature- Genetic Engineering: Medical Applications; Ge-
nurture is not a dichotomy but a complex inter- netic Engineering: Social and Ethical Issues;
action. In reality, genes do not control behav- Genetic Screening; Genetic Testing; Genetic
ior; their only function is to produce a protein, Testing: Ethical and Economic Issues; Heredity
whose only function is to interact with other and Environment; Homosexuality; Human Ge-
proteins at the cellular level. Such interactions netics; Inbreeding and Assortative Mating; In-
do eventually result in what is observed as a telligence; Miscegenation and Antimiscegena-
phenotypeperhaps a phenotype that has a tion Laws; Natural Selection; Sociobiology;
significant impact on a particular behavior Twin Studies; XYY Syndrome.
but this occurs only in a most indirect fashion
and through plenty of environmental influ- Further Reading
ences. On the other hand, plants, animals, and Carson, Ronald A., and Mark A. Rothstein. Be-
even humans are not infinitely pliable by envi- havioral Genetics: The Clash of Culture and Bi-
ronmental occurrences. Some behaviors are ology. Baltimore: Johns Hopkins University
indeed innate, and others are the complex out- Press, 1999. Experts from a range of disci-
come of a genotype-environment feedback that plinesgenetics, ethics, neurosciences, psy-
occurs throughout the life span of an organ- chiatry, sociology, and lawaddress the cul-
ism. In short, nature-nurture is not a matter of tural, legal, and biological underpinnings of
either/or but a question of how the two relate behavioral genetics.
and influence each other. Cartwright, John. Evolution and Human Behav-
As for humans, it is very likely that the pre- ior: Darwinian Perspectives on Human Nature.
cise extent of the biological basis of behavior Cambridge, Mass.: MIT Press, 2000. Offers
and intelligence will never be determined be- an overview of the key theoretical principles
cause of insurmountable experimental diffi- of human sociobiology and evolutionary psy-
culties. While it is technically feasible, it cer- chology and shows how they illuminate the
tainly is morally unacceptable to clone humans ways humans think and behave. Argues that
and study their characteristics under controlled humans think, feel, and act in ways that once
conditions, the only route successfully pursued enhanced the reproductive success of our
to experimentally disentangle nature and nur- ancestors.
ture in plants and animals. Studies of human Clark, William R., and Michael Grunstein. Are
twins help little, since even those separated We Hardwired? The Role of Genes in Human Be-
at birth are usually raised in similar societal havior. New York: Oxford University Press,
conditions, with the result that the effects of 2000. Explores the nexus of modern genet-
heredity and environment are hopelessly con- ics and behavioral science, revealing that few
founded from a statistical standpoint. Regard- elements of behavior depend upon a single
less of the failure of science to answer these gene; instead, complexes of genes, often
Hermaphrodites 411
Hermaphrodites
Hermaphrodites Hermaphrodites are individuals who have
both male and female gonads. At birth, her-
Field of study: Diseases and syndromes maphrodites can have various combinations of
Significance: Hermaphrodites are people born with external genitalia, ranging from completely fe-
both male and female sexual parts. Early identifi- male to completely male genitalia. Most her-
cation and thorough medical evaluation of these maphrodites have external genitalia that are
individuals can help them lead relatively normal ambiguous (genitalia somewhere between nor-
lives. mal male and normal female) and often consist
412 Hermaphrodites
not specific for the desired sex of the individ- works to create a world free of shame, se-
ual. An additional reason to remove the abnor- crecy, and unwanted surgery for intersex
mal gonad is that the cells of the gonad(s) that people (individuals born with anatomy or
have a 46,XY karyotype are at an increased risk physiology which differs from cultural ideals
of becoming cancerous. of male and female). Includes links to infor-
Patricia G. Wheeler mation on such conditions as clitoromegaly,
See also: Gender Identity; Homosexuality; micropenis, hypospadias, ambiguous geni-
Metafemales; Pseudohermaphrodites; Steroid tals, early genital surgery, adrenal hyperpla-
Hormones; Testicular Feminization Syndrome; sia, Klinefelter syndrome, androgen insensi-
X Chromosome Inactivation; XYY Syndrome. tivity, and testicular feminization.
Johns Hopkins University, Division of Pediat-
Further Reading ric Endocrinology, Syndromes of Abnormal
Dreger, Alice Domurat. Hermaphrodites and the Sex Differentiation. http://www.hopkins
Medical Invention of Sex. Cambridge, Mass.: medicine.org/pediatricendocrinology. Site
Harvard University Press, 1998. Traces the provides a guide to the science and genetics
evolution of what makes a person male or fe- of sex differentiation, including a glossary.
male and shows how the answer has changed Click on patient resources.
historically depending on when and where National Organization for Rare Disorders
the question was asked. (NORD). http://www.rarediseases.org. Of-
Gilbert, Ruth. Early Modern Hermaphrodites: Sex fers information and articles about rare ge-
and Other Stories. New York: Palgrave, 2002. netic conditions and diseases, including true
Examines the conceptions and depictions of hermaphrodism, in several searchable data-
hermaphrodites between the sixteenth and bases.
eighteenth centuries in a range of artistic,
mythological, scientific, and erotic contexts.
Moore, Keith. The Developing Human: Clinically
Oriented Embryology. 7th ed. Amsterdam: High-Yield Crops
Elsevier Science, 2003. Details embryology
from a clinical perspective, providing discus- Field of study: Genetic engineering and
sions of the stages of organs and systems de- biotechnology
velopment, including the genital system. Significance: The health and well-being of the
Zucker, Kenneth J. Intersexuality and Gender worlds large population is primarily dependent
Identity Differentiation. Annual Review of on the ability of the agricultural industry to pro-
Sex Research 10 (1999). An extensive over- duce high-yield food and fiber crops. Advances in
view of intersexuality, gender identity forma- the production of high-yield crops will have to con-
tion, psychosexual differentiation, concerns tinue at a rapid rate to keep pace with the needs of
about pediatric gender reassignment, her- an ever-increasing population.
maphroditism and pseudohermaphrodit-
ism, gender socialization, childrearing, and Key terms
more. Includes a discussion of terminology, cultivar: a subspecies or variety of plant de-
a summary, tables, and a bibliography. veloped through controlled breeding tech-
niques
Web Sites of Interest Green Revolution: the introduction of scien-
Androgen Insensitivity Syndrome Support tifically bred or selected varieties of grain
Group. http://www.medhelp.org/www/ais. (such as rice, wheat, and maize), which, with
A comprehensive educational and informa- high enough inputs of fertilizer and water,
tional site with links to related resources. greatly increased crop yields
Intersex Society of North America. http://www monoculture: the agricultural practice of con-
.isna.org. The society is a public awareness, tinually growing the same cultivar on large
education, and advocacy organization which tracts of land
414 High-Yield Crops
5 5.3
5.0
4.5
4 4.1
3.7
3 3.3
3.0
2.6 2.6
2
1.8
1.4
1 1.1
0.8
0
1950 1960 1970 1980 1990 2000 2010 2020
The exponential and ongoing rise in the globes human population makes the need for high-yield, dependable food crops ever more
compelling.
Source: Data are from U.S. Bureau of the Census International Data Base and John Clarke, Population and the Environment: Com-
plex Interrelationships, in Population and the Environment (Oxford, England: Oxford University Press, 1995), edited by Bryan
Cartledge.
High-Yield Crops 415
Genetic Modification
The advent of recombinant DNA technol-
ogy has brought greater precision into the pro-
cess of producing high-yield cultivars and has
made it possible to transfer genetic characteris- Grain crops such as rice, wheat, and (above) corn, grown here
tics between any two plants, regardless of how for research by DeKalb Genetics Corporation, are among those
closely related. The first step generally involves that have been genetically modified to increase yield and nutri-
the insertion of a gene or genes that might in- tional value. (AP/Wide World Photos)
crease yield into a piece of circular DNA called
a plasmid. The plasmid is then inserted into a
bacteria, and the bacteria is then used as a vec- production of high-yield crops will have to con-
tor to transfer the gene into the DNA of an- tinue at a rapid rate to keep pace. New technol-
other plant. This technology has resulted in ge- ogies will have to be developed, and many of
netically modified crops such as golden rice these new technologies will center on advances
(fortified with vitamin A), herbicide-resistant in genetic engineering. It is hoped that such
soybeans, and new strains such as triticale, which advances will lead to the development of new
promise to ameliorate world hunger at the high-yield crop varieties that require less water,
same time that they threaten to reduce biodi- fertilizer, and chemical pesticides.
versity and alter other plants through genetic D. R. Gossett, updated by Bryan Ness
drift. See also: Biofertilizers; Biopesticides; Cell
Culture: Plant Cells; Cloning; Cloning: Ethical
Impact and Applications Issues; Cloning Vectors; Genetic Engineering;
As the human population grows, pressure Genetic Engineering: Agricultural Applica-
on the worlds food supply will increase. Con- tions; Genetic Engineering: Historical Devel-
sequently, researchers are continually seeking opment; Genetic Engineering: Industrial Ap-
better ways to increase food production. In or- plications; Genetic Engineering: Risks; Genetic
der to accomplish this goal, advances in the Engineering: Social and Ethical Issues; Geneti-
416 Homeotic Genes
cally Modified (GM) Foods; Hybridization and agriculture student, which serves as one of
Introgression; Lateral Gene Transfer; Trans- the most valuable sources available on the
genic Organisms. practical aspects of the production of high-
yield crops.
Further Reading
Avery, Dennis T. Saving the Planet with Pesticides Web Site of Interest
and Plastic: The Environmental Triumph of High- Food and Agriculture Organization of the
Yield Farming. 2d ed. Indianapolis, Ind.: Hud- United Nations. Biotechnology in Food and
son Institute, 2000. Argues that high-yield Agriculture. http://www.fao.org. Addresses
agriculture using chemical pesticides, fertil- the role of biotechnology in worldwide food
izers, and biotechnology is the solution to en- production.
vironmental problems, not a cause of them,
as environmental activists have averred.
Bailey, L. H., ed. The Standard Cyclopedia of Horti-
culture. 2d ed. 3 vols. New York: Macmillan, Homeotic Genes
1963. Since the 1920s, a standard reference
that still offers basic information; its original Field of study: Developmental genetics
subtitle reads: a discussion, for the amateur, Significance: Embryonic development and organo-
and the professional and commercial grower, genesis proceed by way of a complex series of cas-
of the kinds, characteristics and methods of caded gene activities, which culminate in the acti-
cultivation of the species of plants grown in vation of the homeotic genes to specify the final
the regions of the United States and Canada identities of body parts and shapes. The discovery
for ornament, for fancy, for fruit and for veg- of homeotic genes has provided the key to under-
etables; with keys to the natural families and standing these patterns of development in multi-
genera, descriptions of the horticultural ca- cellular organisms. Knowledge of homeotic genes
pabilities of the states and provinces and de- not only is helping scientists understand the vari-
pendent islands, and sketches of eminent ety and evolution of body shapes (morphology) but
horticulturists. also is providing new insights into genetic diseases
Chrispeels, Maarten J., and David E. Sadava. and cancer.
Plants, Genes, and Agriculture. Boston: Jones
and Bartlett, 1994. A textbook on the use of Key terms
biotechnology in crop production. Contains promoter: the control switch in genes where
sections related to the use of biotechnology transcription factors bind to activate or re-
to transfer desirable traits from one plant to press the conversion of DNA information
another. into proteins
Janick, Jules. Horticultural Science. 4th ed. New transcription factor: a protein with special-
York: W. H. Freeman, 1986. Contains sec- ized structures that binds specifically to the
tions on horticultural biology, environment, promoters in genes and controls the genes
technology, and industry and covers the fun- activity
damentals associated with the production of
high-yield crops. The Discovery of Homeotic Genes
Lynch, J. M. Soil Biotechnology: Microbiological One of the most powerful tools in genetic re-
Factors in Crop Productivity. Malden, Mass.: search is the application of mutagenic agents
Blackwell, 1983. Contains some excellent in- (such as X rays) that cause base changes in the
formation on the potential for genetically DNA of genes to create mutant organisms.
engineering microorganisms to improve These mutants display altered appearances, or
crop production. phenotypes, giving the geneticist clues about
Metcalfe, D. S., and D. M. Elkins. Crop Produc- how the normal genes function. Few geneti-
tion: Principles and Practices. 4th ed. New York: cists have used this powerful research tool as
Macmillan, 1980. A text for the introductory well as the recipient of the 1995 Nobel Prize in
Homeotic Genes 417
the more anatomically complex the animal, fectly formed, bilateral limbs. Sometimes mu-
the more homeotic genes it will have in its tations in homeobox genes cause malformed
chromosomes. Experimental evidence from limbs, extra digits on the hands or feet, or fin-
several laboratories has supported Ruddles hy- gers fused together, conditions known as syn-
pothesis. polydactyly; often limb and hand deformities
The questions posed earlier about the func- are accompanied by genital abnormalities. Sev-
tions of extra DNA in the homeotic clusters and eral reports in 1997 provided experimental evi-
the role of the homeobox in gene function dence for mutated homeobox genes in certain
were finally answered. It seems that all homeo- leukemias and cancerous tumors. Beginning in
tic genes code for transcription factors, or pro- 1996, the number of reports describing corre-
teins that control the activity or expression of lations between mutated homeobox genes and
other genes. The homeobox portion codes for specific cancers and other developmental ab-
a section of protein that binds to base sequences normalities increased dramatically. Although
in the promoters of other genes, thus stimulat- no specific gene-based therapies have been
ing those genes to express their proteins. The proposed for treating such diseases, the merger
earlier idea of homeotic genes as selector genes between the accumulated molecular knowledge
makes sense; the protein products of homeotic of homeotic genes and the practical gene ma-
genes bind to the promoter control regions of nipulation technologies spawned by animal
many other genes and activate them to make cloning will likely lead to new treatments for
complex structures such as legs and wings. The limb deformities and certain cancers.
homeotic genes themselves are under the con- Chet S. Fornari
trol of other genes making transcription fac- See also: Developmental Genetics; Evolu-
tors that bind to the extra DNA in the homeotic tionary Biology; Model Organism: Drosophila
clusters. The bound transcription factors con- melanogaster.
trol the differential expression of homeotic
genes in many different cellular environments
throughout the developing embryo, all along Further Reading
its anterior to posterior axis. Embryonic devel- DeRobertis, Eddy. Homeobox Genes and the
opment and organogenesis proceed by way of Vertebrate Body Plan. Scientific American 269
a complex series of cascaded gene activities, (July, 1990). A classic article on homeobox
which culminate in the activation of the home- gene studies.
otic genes to specify the final identities of body Lewin, B. Genes VII. New York: Oxford Univer-
parts and shapes. sity Press, 2001. Provides an integrated ac-
count of the structure and function of genes
Impact and Applications and incorporates all the latest research in
In a 1997 episode of the television series The the field, including topics such as accessory
X-Files, a mad scientist transforms his brother proteins (chaperones), the role of the pro-
into a monster with two heads. Federal Bureau teasome, reverse translocation, and the pro-
of Investigation (FBI) agent Dana Scully pa- cess of X chromosome inactivation. More
tiently explains to her partner Fox Mulder that than eight hundred full-color illustrations.
the scientist altered his brothers homeobox Lodish, Harvey, et al. Molecular Cell Biology. 4th
genes, causing the mutant phenotype. Science ed. New York: W. H. Freeman, 2000. Con-
fiction indeedbut with the successful cloning tains a clear, detailed discussion of homeotic
of Dolly the sheep in 1997, the prospect of ma- genes.
nipulating homeobox genes in embryos is no Raff, Rudolf. The Shape of Life: Genes, Develop-
longer far-fetched. ment, and the Evolution of Animal Form. Chi-
The first concern of scientists is to elucidate cago: University of Chicago Press, 1996. A
more molecular details about the actual pro- detailed but readable account of how genes
cesses by which discrete genes transform an and evolution influence the shape of animal
undifferentiated egg cell into a body with per- bodies.
Homosexuality 419
estly and to induce higher levels of homosexu- dividuals are exclusively homosexual and expe-
ality. rience no direct individual fitness (that is, no
Stress hormones generally reduce the pro- offspring are produced), homosexuals can re-
duction of sex hormones. The level and timing duce the reproductive cost by increasing their
of stress experienced by women during preg- inclusive fitness via contributions to relatives
nancy may therefore also affect the amount offspring. Consistent with the latter hypothesis,
of sex hormones experienced prenatally and there is some evidence that gay men exhibit in-
hence the sexual differentiation and organi- creased levels of empathy, an accepted indica-
zational phase of early brain development. tor of altruism.
Studies suggest that some women who experi- Homosexuality is one of the three most com-
ence stress during pregnancy may be more mon expressions of human sexual orientation
likely to have homosexual children, but the and has been observed throughout human his-
data are still preliminary. tory and across religions and cultures. Like
Given that most homosexuals do not have other complex behavioral traits, sexual orien-
one of the aforementioned hormonal condi- tation appears to be influenced by both biologi-
tions and most individuals who do have them cal and environmental factors. There is some
are heterosexual, the neuroendocrine theory evidence that situational or opportunistic ho-
alone does not appear to account for the origin mosexuality may differ from obligatory homo-
of homosexuality. sexuality and that the mechanisms influencing
sexual orientation may be different in gay men
Neuroanatomical Influences and lesbians.
Although stereotypes exist, there is no over- Cathy Schaeff
all lesbian or gay physique. There is some evi- See also: Behavior; Biological Clocks; Gen-
dence that gay mens brains may differ from der Identity; Heredity and Environment; Her-
heterosexual mens in some structures where maphrodites; Human Genetics; Metafemales;
sexual dimorphism also occurs (for example, in- Pseudohermaphrodites; Steroid Hormones;
terstitial nuclei of the anterior hypothalmus 3, Testicular Feminization Syndrome; X Chromo-
suprachiasmatic nucleus in the anterior hypo- some Inactivation; XYY Syndrome.
thalamus and the anterior commissure), pre-
sumably due to the organizational effects of sex Further Reading
hormones. Structure size varies considerably Diamant, L., and R. McAnuity, eds. The Psychol-
both within and between sexes; however, all ogy of Sexual Orientation, Behavior, and Identity:
three structures appear to differ significantly in A Handbook. Westport, Conn.: Greenwood
size for gay versus heterosexual men. It is not Press, 1995. Draws from biological and psy-
yet clear whether these differences cause ho- chological research to provide a compre-
mosexual activity or are caused by it. hensive overview of the major theories about
sexual orientation; to summarize recent de-
Evolutionary Perspective velopments in genetic and neuroanatomic
Evolutionary biologists have suggested that research; to consider the role of social insti-
homosexuality may persist because there is lit- tutions in shaping current beliefs; and to dis-
tle cost associated with the behavior. In situa- cuss the social construction of gender, sexu-
tions in which homosexuality is not exclusive ality, and sexual identity.
(that is, most individuals engage in hetero- Hamer, D. H., S. Hu, et al. A Linkage Between
sexual as well as homosexual liaisons) homo- DNA Markers on the X Chromosome and
sexuals would experience little or no decline in Male Sexual Orientation. Science 261 (1993):
reproductive success. This could occur when 321-327. The first study to identify genetic
marriage is compulsory, where there are strict markers for male sexual orientation.
gender roles and religious requirements, or Haynes, Felicity, and Tarquam McKenna. Un-
when homosexual behavior is situational or op- seen Genders: Beyond the Binaries. New York:
portunistic. Similarly, in situations in which in- Peter Lang, 2001. Explores the effects of bi-
Human Genetics 421
nary stereotypes of sex and gender on trans- dysmorphology: Abnormal physical develop-
sexuals, homosexuals, cross-dressers, and ment resulting from genetic disorder
transgender and intersex people. forensic genetics: the application of genet-
Hu, S., et al. Linkage Between Sexual Orienta- ics, particularly DNA technology, to the anal-
tion and Chromosome Xq28 in Males but ysis of evidence used in civil cases, criminal
Not in Females. Nature Genetics 11 (1995): cases, and paternity testing
248-256. Determined that the DNA marker gene therapy: the use of a viral or other vector
on the X chromosome does not correspond to incorporate new DNA into a persons cells
to lesbianism. with the objective of alleviating or treating
McWhirter, David P., et al. Homosexuality/Hetero- the symptoms of a disease or condition
sexuality: Concepts of Sexual Orientation. New gene transfer: Using a viral or other vector to
York: Oxford University Press, 1990. Dis- incorporate new DNA into a persons cells.
cusses sexual orientation and the current Gene transfer is used in gene therapy
usefulness of the Kinsey Scale. Includes other genetic screening: the use of the techniques
scales proposed by contributors to this work. of genetics research to determine a persons
risk of developing, or his or her status as a
Web Sites of Interest carrier of, a disease or other disorder
Parents, Families, and Friends of Lesbians and genetic testing: the process of investigating a
Gays. http://www.pflag.org. Site includes a specific individual or population of people
section on frequently asked questions and to detect the presence of genetic defects
information about local chapters, news, and genomics: the branch of genetics dealing with
public advocacy. the study of the genetic sequences of organ-
Sexuality Information and Education Council isms, including the human being
of the United States. http://www.siecus.org. pharmacogenomics: The branch of human
A vast resource on all aspects of sex and sexu- medical genetics that evaluates how an indi-
ality. Includes links for teenagers, public pol- viduals genetic makeup influences his or
icy issues, school health, a searchable bibli- her response to drugs
ography database, and more. proteomics: the study of how proteins are ex-
pressed in different types of cells, tissues,
and organs
toxicogenomics: evaluating ways in which ge-
Human Genetics nomes respond to chemical and other pol-
lutants in the environment
Fields of study: Human genetics and social
issues Human Genome Project
Significance: Human genetics is concerned with Human genetics is the discipline concerned
the study of the human genome. The study of hu- with identifying and studying the genes carried
man genetics includes identifying and mapping by humans, the control and expression of traits
genes; determining their function, mode of trans- caused by these genes, their transmission from
mission, and inheritance; and detecting mutated generation to generation, and their expression
or nonfunctioning genes. Important aspects of in offspring. Modern human genetics properly
modern human genetics include gene testing or begins with the elucidation of the structure of
genetic screening, gene therapy, and genetic coun- DNA in 1953 by James D. Watson and Francis
seling. H. Crick. This discovery led to very rapid ad-
vances in acquisition of genetic information
Key terms and ultimately spawned the Human Genome
bioinformatics: The science of compiling and Project (HGP), which was initiated in 1986 by
managing genetic and other biology data us- the DOE (Department of Energy). In 1990 the
ing computers, requisite in human genome DOE combined efforts with the National Insti-
research tutes of Health (NIH) and private collaborators,
422 Human Genetics
including the Wellcome Trust of the United Almost all modern human genetics is di-
Kingdom, along with private companies based rectly related to the enormous mass of genetic
in Japan, France, Germany, and China. The ul- data obtained and made available by the HGP.
timate goal of HGP was to determine the pre- Some of the many themes now being explored
cise genetic makeup of humans as well as ex- include medical genetics, genetic bioinfor-
plore human genetic variation and human gene matics, proteomics, toxicogenomics, the inher-
function. The first high-quality draft of the hu- itance and prevention of gene-related cancers
man genetic sequence was completed in April and other diseases, and policy and ethical is-
of 2003, thereby providing a suitable salute to sues related to genetic concerns of humans.
the fiftieth anniversary of the discovery of DNA, The human genome consists of genes lo-
which opened the modern era of human ge- cated in chromosomes, along with a much
netics. smaller gene content, found in mitochondria,
that is called mitochondrial DNA or mtDNA.
About 99.7 percent of the human genome is lo-
cated in the chromosomes, and another 0.3
Human Chromosomes percent consists of the mtDNA genome, which
encodes for a number of enzymes involved in
Normal (pair) cellular respiration. The mtDNA is inherited
almost entirely through the female line, so its
genetic transmission and expression differ from
that of classical Mendelian genetics. Studies of
human mtDNA have revealed a number of
1 2 3 4 5 medical pathologies associated with this unique
mode of inheritance transmission. Studies have
also proven useful in determining significant
trends in the evolutionary development of Homo
sapiens and elucidating relationships with the
6 7 8 9 10 11 12 near-species Homo neanderthalensis (the now ex-
tinct Neanderthals).
The HGP effort decoded the genetic ar-
rangementthe gene sequence of roughly 3
13 14 15 16 17 18 billion nucleotide base pairs of between 25,000
and 45,000 genes that collectively form the hu-
man genome. Many, but not all, of these have
been sequenced and their locations on chromo-
19 20 21 22 X Y somes mapped. Structurally, base-sequencing
studies reveal that human genes showed great
Trisomy (three) variations in size, ranging from several thousand
base pairs to some genes comprising nearly half
a million base pairs. The genetic functions have
13 21 18 been determined for about half of the human
genes that have been identified and sequenced.
HGP provided so much information that a new
Genetic diseases are caused by defects in the number of chromo-
field called bioinformatics was developed to
somes, in their structure, or in the genes on the chromosome
(mutation). Shown here is the human complement of chromo-
handle the enormous amounts of genetic se-
somes (23 pairs) and three errors of chromosome number quencing data for the human genome.
(trisomies) that lead to the genetic disorders Pataus syndrome
(trisomy 13), Edwards syndrome (trisomy 18), and the more Bioinformatics
common Down syndrome (trisomy 21). (Hans & Cassidy, The purpose of bioinformatics is to help or-
Inc.) ganize, store, and analyze genetic biological in-
Human Genetics 423
Proteomics
Bioinformatics provides the basis for all A heterozygous AO mother and a heterozygous BO father can
modern studies of human genetics, including produce children with any of the four blood types.
analysis of genes and gene sequences, deter-
mining gene functions, and detecting faulty
genes. The study of genes and their functions is can be screened with gene testing procedures
called proteomics, which involves the compara- to determine if they carry such genes. Follow-
tive study of protein expression. That is, exactly ing detection of a defective gene, several op-
what is the metabolic and morphological rela- tions may be explored and implemented, in-
tionship between the protein encoded within cluding genetic counseling, gene therapy, and
the genome and how that protein works. Ge- pharmacogenetics.
neticists are now classifying proteins into fami- At least four thousand diseases of humans
lies, superfamilies, and folds according to their are known to have a genetic basis and can be
configuration, enzymatic activity, and sequence. passed from generation to generation. In addi-
Ultimately proteomics will complete the pic- tion to many kinds of human cancers, all of
ture of the genetic structure and functioning of which have a genetic basis, human genetic dis-
all human genes. orders include diabetes, heart disease, and cys-
tic fibrosis. Other diseases and disorders that
Toxicogenomics have been directly linked to human genetic
Another newly developing field that relies anomalies include predispositions for colon
on bioinformatics is the study of toxicogenom- cancer, Alzheimers disease, and breast cancer.
ics, which is concerned with how human genes
respond to toxins. Currently, this field is spe- Gene Testing
cifically concerned with evaluating how envi- In a gene-testing protocol, a sample of blood
ronmental factors negatively interact with mes- or body fluids is examined to detect a genetic
senger RNA (mRNA) translation, resulting in anomaly such as the transposition of part of a
disease or dysfunction. chromosome or an altered sequence of the
bases that comprise a specific gene, either of
Medical Genetics which can lead to a genetically based disorder
Almost all of modern human medical genet- or disease. Currently more than six hundred
ics rests on the identification of human gene se- tests are available to detect malfunctioning or
quences that were provided by the HGP and nonfunctioning genes. Most gene tests have fo-
made accessible through bioinformatics. Hu- cused on various types of human cancers, but
man medical genetics begins with recognition other tests are being developed to detect ge-
of defective genes that are either nonfunction- netic deficiencies that cause or exacerbate in-
ing or malfunctioning and that cause diseases fectious and vascular diseases.
or tissue malformation. Once defective genes The emphasis on the relationship between
have been identified and cataloged, patients genetics and cancer lies in the fact that all hu-
424 Human Genetics
man cancers are genetically triggered by genes impact of a disease or other genetic disorder.
or have a genetic basis. Some cancers are inher- Some examples of somatic cell gene therapy
ited as mutations, but most result from ran- protocols now being tested include ones for ad-
dom genetic mutations that occur in specific enosine deaminase (ADA) deficiency, cystic fi-
cells, often precipitated by viral infections brosis, lung cancer, brain tumors, ovarian can-
or environmental factors not yet well under- cer, and AIDS.
stood. In somatic gene therapy a sample of the pa-
At least four types of genetic problems have tients cells may be removed and treated, and
been identified in human cancers. The nor- then reintegrated into body tissue carrying the
mal function of oncogenes, for example, is to corrected gene. An alternative somatic cell ther-
signal the start of cell division. However, when apy is called gene replacement, which typically
mutations occur or oncogenes are overex- involves insertion of a normally functioning
pressed, the cells keep on dividing, leading to gene. Some experimental delivery methods for
rapid growth of cell masses. The genetic inheri- gene insertion include use of retroviral vectors
tance of certain kinds of breast cancers and and adenovirus vectors. These viral vectors are
ovarian cancers results from the nonfunction- used because they are readily able to insert
ing tumor-suppressor genes that normally stop their genomes into host cells. Hence, adding
cell division. When genetically altered tumor- the needed (or corrective) gene segment to
suppressor genes are unable to stop cell divi- the viral genome guarantees delivery into the
sion, cancer results. Conversely, the genes that cells nuclear interior. Nonviral delivery vec-
cause inheritance of colon cancer result from tors that are being investigated for gene re-
the failure of DNA repair genes to correct mu- placement include liposome fat bodies, human
tations properly. The accumulation of muta- artificial chromosomes, and naked DNA (free
tions in these proofreading genes makes them DNA, or DNA that is not enclosed in a viral par-
inefficient or less efficient, and cells continue ticle or any other package).
to replicate, producing a tumor mass. Another type of somatic gene therapy in-
If a gene screening reveals a genetic prob- volves blocking gene activity, whereby poten-
lem several options may be available, including tially harmful genes such as those that cause
gene therapy and genetic counseling. If the de- Marfan syndrome and Huntingtons disease
tected genetic anomaly results in disease, then are disabled or destroyed. Two types of gene-
pharmacogenomics holds promise of patient- blocking therapies now being investigated in-
specific drug treatment. clude the use of antisense molecules that target
and bind to the messenger RNA (mRNA) pro-
Gene Therapy duced by the gene, thereby preventing its trans-
The science of gene therapy uses recombi- lation, and the use of specially developed ribo-
nant DNA technology to cure diseases or dis- zymes that can target and cleave gene sequences
orders that have a genetic basis. Still in its ex- that contain the unwanted mutation.
perimental stages, gene therapy may include Germ-line therapy is concerned with alter-
procedures to replace a defective gene, repair ing the genetics of male and female reproduc-
a defective gene, or introduce healthy genes tive cells, the gametes, as well as other body
to supplement, complement, or augment the cells. Because germ-line therapy will alter the
function of nonfunctional or malfunctioning individuals genes as well as those of his or her
genes. Several hundred protocols are being offspring, both concepts and protocols are still
used in gene therapy trials, and many more are very controversial. Some aspects of germ-line
under development. Current trials focus on therapy now being explored include human
two major types of gene therapy, somatic gene cloning and genetic enhancement.
therapy and germ-line gene therapy. The next steps in human genetic therapy in-
Somatic gene therapy focuses on altering a volve determining the underlying mechanisms
defective gene or genes in human body cells in by which genes are transcribed, translated, and
an attempt to prevent or lessen the debilitating expressed, which is called proteomics.
Human Genetics 425
seemingly useless repetitive DNA may actually has revealed differences in DNA sequences o
play a number of important genetic roles, from about 0.33 percent, which is considerably less
providing a substrate on which new genes can than seen in other primate species. These mi-
evolve to maintaining chromosome structure nor differences strongly suggest that all mem-
and participating in some sort of genetic con- bers of the human species, Homo sapiens, are far
trol. Consequently, it is now out of fashion more closely related to one another than are
among geneticists to refer to these parts of the members of many other vertebrate species.
genome as junk DNA, but rather as DNA of un- A separate study compared human gene se-
known function. quences among different human populations
across the globe. This study revealed that the
Forensic Genetics highest variations in DNA sequences are found
Law enforcement agencies are increasingly among the modern human populations of Af-
relying on a branch of human genetics called rica. Since populations that exhibit the highest
forensic genetics. The aims of forensic genetics genome variations are thought to be the oldest
typically are to determine the identity or non- populations (because chance mutations have a
identity of suspects in crimes, based on an anal- longer time to accumulate in older populations
ysis of DNA found in hair, blood, and other as opposed to younger populations), these re-
body substances retrieved from the scene of the sults strongly suggest that modern humans orig-
crime in comparison with that of suspects. Pop- inated in Africa and subsequently dispersed
ularly called DNA fingerprinting, forensic ge- into other regions of the world. This out of Af-
netics relies on the fact that the DNA of every rica theory has received compelling support
human carries unique tandem repeats of 20 or from the DNA evidence, and the theory also ex-
more kilobase pairs that can be compared and plains why all other human populations are so
identified using radioactive probes. Thus, com- remarkably similar. Since all other global hu-
parisons can establish identity or nonidentity man populations show minimal DNA sequence
to a very high level of probability. DNA finger- differences, it is hypothesized that a small group
printing is also used in recognizing genetic of humans emigrated from Africa to spread
parentage of children, identifying victims across and eventually colonize the other conti-
sometimes from fragments of bodiesand nents. Tests of gene sequences along Y chro-
identifying relationships of missing children. mosomes show similar patterns, leading to the
proposal that all humans today came from a mi-
Phylogeny and Evolution tochondrial Eve and a Y chromosome Adam
Another rapidly developing field in human who lived between 160,000 and 200,000 years
genetics is the use of human gene sequences ago.
in both nuclear and mitochondrial DNA DNA-based phylogeny studies are also shed-
(mtDNA) to explore questions of human ori- ding light on the relationship between the Ne-
gins, evolution, phylogeny, bioarchaeology, and anderthals (Homo neanderthalensis), a species
past human migration patterns. that disappeared between 30,000 and 60,000
Much of the analytical work has involved years ago, and the modern Cro-Magnon hu-
mtDNA to study relationships. Because it is in- mans (Homo sapiens) that replaced them. Com-
herited strictly through the egg line or female parisons of mtDNA between the two Homo
component, mtDNA is somewhat more useful, species indicate that Neanderthals began di-
but comparisons of DNA sequences along the Y verging from modern humans half a million
chromosome of human populations have also years ago and were significantly different in ge-
yielded valuable information regarding human nomic content to be placed in a separate spe-
origins and evolution. cies. These findings also support the suggestion
One of the more interesting of these studies that Neanderthals were ecologically replaced by
involves comparing mtDNA over a broad spec- modern humans rather than genetically amal-
trum of global human populations. Compari- gamated into present human populations, as
sons of DNA sequencing of these populations was once proposed. Although such arguments
Human Genetics 427
are not universally accepted, many more genet- L. White. Medical Genetics. 2d ed. St. Louis,
icists, paleoanthropologists, and forensic scien- Mo.: Mosby, 2000. Provides both an intro-
tists are now using comparative analysis of DNA duction to the field of human genetics and
sequences among and between human popula- chapters on clinical aspects of human genet-
tions to study questons of human evolutionary ics such as gene therapy, genetic screening,
history. and genetic counseling.
Dwight G. Smith Pasternak, Jack J. An Introduction to Human Mo-
See also: Aggression; Aging; Bioethics; Bio- lecular Genetics: Mechanisms of Inherited Dis-
informatics; Biological Determinism; Criminal- eases. Bethesda, Md.: Fitzgerald Science Press,
ity; DNA Fingerprinting; Eugenics; Eugenics: 1999. Discusses treatment advances, funda-
Nazi Germany; Evolutionary Biology; Forensic mental molecular mechanisms that govern
Genetics; Gender Identity; Gene Therapy; Gene human inherited diseases, the interactions
Therapy: Ethical and Economic Issues; Genetic of genes and their products, and the conse-
Counseling; Genetic Screening; Genetic Test- quences of these mechanisms on disease
ing; Genetic Testing: Ethical and Economic Is- states in major organ systems such as muscles,
sues; Human Genome Project; Human Growth the nervous system, and the eyes. Also ad-
Hormone; In Vitro Fertilization and Embryo dresses cancer and mitochondrial disorders.
Transfer; Insurance; Intelligence; Miscegena- Rudin, Norah, and Keith Inman. An Introduc-
tion and Antimiscegenation Laws; Patents on tion to Forensic DNA Analysis. Boca Raton,
Life-Forms; Paternity Tests; Prenatal Diagnosis; Fla.: CRC Press, 2002. An overview of many
Race; Sterilization Laws. DNA typing techniques, along with numer-
ous examples and a discussion of legal impli-
Further Reading cations.
Andrews, Lori B. The Clone Age: Adventures in Shostak, Stanley. Becoming Immortal: Combining
the New World of Reproductive Technology. New Cloning and Stem-Cell Therapy. Albany: State
York: Henry Holt, 1999. A lawyer specializ- University of New York Press, 2002. Exam-
ing in reproductive technology, Andrews ex- ines the question of whether human beings
amines the legal ramifications of human are equipped for potential immortality.
cloning, from privacy to property rights. Wilson, Edward O. On Human Nature. Cam-
Baudrillard, Jean. The Vital Illusion. Edited by bridge, Mass.: Harvard University Press,
Julia Witwer. New York: Columbia University 1978. A look at the significance of biology
Press, 2000. A sociological perspective on and genetics on how we understand human
what human cloning means to the idea of behaviors, including aggression, sex, and al-
what it means to be human. truism and the institution of religion.
Fridell, Ron. DNA Fingerprinting: The Ultimate
Identity. New York: Scholastic, 2001. The his- Web Sites of Interest
tory of the technique, from its discovery to American Society of Human Genetics (ASHG).
early uses. Aimed at younger readers and http://www.faseb.org/genetics/ashg/ashg
nonspecialists. menu.htm. Founded in 1948, a group of
Hartwell, L. H., L. Hood, M. L. Goldberg, A. E. several thousand physicians, genetic coun-
Reynolds, L. M. Silber, and R. C. Veres. Genet- selors, researchers, publishing the American
ics: From Genes to Genomes. 2d ed. New York: Journal of Human Genetics.
McGraw-Hill, 2004. A comprehensive text- Association of Professors of Human or Medical
book on genetics, including human genetics Genetics (APHMG). http://www.faseb.org/
discussed in a comparative context. genetics/aphmg/aphmg1.htm. This site of
Hekimi, Siegfried, ed. The Molecular Genetics of the North American group of academicians
Aging. New York: Springer, 2000. Part of the in medical and graduate schools features in-
Results and Problems in Cell Differentiation formation on core curricula and workshops.
series. Illustrated. Johns Hopkins University. The Genome Data-
Jorde, L. B., J. C. Carey, M. J. Bamshad, and R. base. http://gdbwww.gdb.org. The official
428 Human Genome Project
central storage center for gene mapping on the experimental data of Rosalind Franklin
data compiled in the Human Genome Initia- and others. It was fitting then, that fifty years
tive, an international effort to decode and later, in April of 2003, the complete sequence
analyze human DNA. Intended for scien- of the human genome was published, marking
tists, the site presents information in three probably one of the greatest achievements not
categories: regions, maps, and variations of only in genetics but in all of science. During the
the human genome. years ahead, thousands of scientists will mine
National Center for Biotechnology Informa- these data for information about the human
tion. http://www.ncbi.nlm.nih.gov. Main- body, how its genes shape development and be-
tains GenBank, a comprehensive, annotated havior, and the role mutations play in diseases.
collection of publicly available DNA se-
quences. Origins of the Human Genome Project
Sanger Centre, Wellcome Trust. http://www The Human Genome Project (HGP) began
.sanger.ac.uk. One of the premier genome as a result of the catastrophic events of World
research centers, focusing on large-scale se- War II: the dropping of atomic bombs on the
quencing projects and analysis. Offers many Japanese cities of Nagasaki and Hiroshima.
data resources, software, databases, and in- There were many survivors who had been ex-
formation on career opportunities. posed to high levels of radiation, known to
cause mutations. Such survivors were stigma-
tized by society and were considered poor mar-
riage prospects, because of potential genetic
Human Genome Project damage. The U.S. Atomic Energy Commission
of the U.S. Department of Energy (DOE) estab-
Fields of study: History of genetics; Human lished the Atomic Bomb Casualty Commission
genetics; Techniques and methodologies in 1947 to assess mutations in such survivors.
Significance: The Human Genome Project will However, there were no suitable methods to
have a profound effect in the twenty-first century, measure these mutations, and it would be many
providing the means to identify disease-causing years before suitable techniques would be de-
mutations (including those involved in cancer), to veloped. Knowing the sequence of the human
design new drugs, to provide human gene therapy, genome would be the greatest tool for identify-
to learn how genes control development, and to un- ing human mutations.
derstand the origins and evolution of the human
race. Advances in Molecular Biology
As in all areas of science, progress in molecu-
Key terms lar biology was limited by available technology.
genome: the entire complement of genetic ma- Many advances in molecular biology made fea-
terial (DNA) in a cell sible the undertaking of the HGP. Starting in
genomics: that branch of genetics dealing with the 1970s, techniques were developed to iso-
the study of genetic sequences late and clone individual genes. By 1977, Wal-
proteomics: that branch of genetics dealing ter Gilbert and Frederick Sanger had inde-
with the expression, function, and structure pendently developed methods for sequencing
of proteins DNA, and in 1977 Sangers group published
single nucleotide polymorphism (SNP): the sequence of the first genome, the small bac-
differences at the individual nucleotide level terial virus Phi X174. In 1985, Kary Mullis and
among individuals colleagues developed the method of polymer-
ase chain reaction (PCR), in which extremely
Perspective small amounts of DNA could be amplified bil-
April 25, 2003, was the fiftieth anniversary of lions of times, providing significant amounts
the publication of the double helix model of of specific DNA for analysis. Finally, in 1986,
DNA by James Watson and Francis Crick, based Leroy Hood and Applied Biosystems developed
Human Genome Project 429
Craig Venter of Celera Genomics (at the microphone) and Francis Collins, Director of the National Institutes of Health (right), an-
nounce the initial sequencing of the human genome on June 26, 2000, with President Bill Clinton in attendance. (AP/Wide
World Photos)
an automated DNA sequencer that could se- from the DOE and the National Research Coun-
quence DNA hundreds of times faster than was cil, the Human Genome Project was launched
previously possible. Additional advances in com- in 1990 with James Watson as head. The goal
puter technology now made it possible to se- was completion in 2005 at a cost of $1.00 per
quence the human genome. base pair. In 1992, Watson resigned over a con-
troversy surrounding the patenting of human
The Holy Grail of Molecular Biology sequences. Francis Collins took over as head of
In 1985 a conference of leading scientists the HGP at the National Institutes of Health
was held at the University of California, Santa (NIH). The sequencing of genetic model or-
Cruz, to discuss the feasibility of sequencing ganisms, in addition to the human genome,
the entire human genome. Biologists were look- was one of the goals of the HGP. This included
ing for the equivalent of a Manhattan Project genomes of the bacterium Escherichia coli, yeast,
for biology. The Manhattan Project was the the fruit fly Drosophila melanogaster, the round
concerted effort of physicists to develop atomic worm Caenorhabditis elegans, and other organ-
weapons during World War II and resulted in isms. Moreover, 10 percent of the funding was
huge increases of government funding for phys- to be directed toward studies of the social, ethi-
ics research. Walter Gilbert called the HGP the cal, and legal implications of learning the hu-
Holy Grail of molecular biology. With impetus man genome.
430 Human Genome Project
Competition Between the Public and Corporation formed the biotech company
Private Sectors Celera Genomics to sequence the human ge-
Craig Venter, a former National Institutes of nome privately. Celera had more than three
Health researcher, left the NIH and formed a hundred of the worlds fastest automated se-
private company, The Institute for Genome Re- quencers and a supercomputer to analyze data.
search (TIGR). TIGR, using a different ap- Meanwhile, public funds supported scientists
proach (known as the shotgun method) was in the United States, the United Kingdom, Ja-
able to sequence the 1.8 million-base-pair ge- pan, Canada, Sweden, and fourteen other coun-
nome of the first free-living organism, the bac- tries working on HGP sequencing. The public
terium Haemophilus influenzae, in less than a sector was now in competition with Celera. To
year. In 1998 Venter along with Perkin-Elmer assure free access, each day new sequence data
from the public projects were
made available on the Internet.
about 18,000. It was surprising that a complex teins derived from their DNA sequence. If a
human had less than twice the number of particular protein is involved in a disease pro-
genes as the lowly roundworm. The human ge- cess, specific drugs to interfere with it may
nome also contains 740 genes that encode sta- be designed. Humanity is just beginning to
ble RNAs. The genome of the mouse, another reap the benefits from the Human Genome
model genetic organism, will provide interest- Project.
ing comparisons to the human genome. Ralph R. Meyer
See also: Behavior; Bioinformatics; Chro-
Whose Genome Is It? mosome Theory of Heredity; Genetic Code,
Although more than 99.99 percent of the Cracking of; Genetic Engineering; Genomic
DNA sequences of all humans are identical, Libraries; Genomics; Hereditary Diseases; Hu-
there are many differences. An important ques- man Genetics; Icelandic Genetic Database; Poly-
tion is, Whose genome is it? Craig Venter has merase Chain Reaction; Proteomics; Race.
acknowledged that Celera has been sequencing
mostly his DNA. However, the final sequence Further Reading
database is an average or consensus ge- Collins, Francis, and Karin G. Jegalian. Deci-
nome. Every human carries many and perhaps phering the Code of Life. Scientific American
even hundreds of mutations. Even before the 281, no. 6 (1999): 86-91. A description in lay
HGP was completed, databases listing single terms of the progress and goals of the HGP.
nucleotide polymorphisms were being estab- Dennis, Carina, and Richard Gallagher. The Hu-
lished. These databases list the types of genetic man Genome. London: Palgrave Macmillan,
variations that occur at individual nucleotides 2002. Written by two editors of the British
in the genome. For example, a cancer gene da- journal Nature, the book gives a description
tabase lists the types of mutations that have of the HGP in lay terms and provides some
been identified in specific cancer-causing genes of the information from the first draft of the
and the frequency of such mutations. Muta- human genome.
tions in genes such as BRCA1 and BRCA2 are re- International Human Genome Sequencing
sponsible for breast and ovarian cancers, while Consortium. Initial Sequencing and Analy-
mutations in the tumor-suppressor gene p53 sis of the Human Genome. Nature 409, no.
have been found in the majority of human tu- 6822 (2001): 860-921. The publication of
mors. the first draft of the Human Genome Project.
The whole journal issue contains many other
The Future: Genomics and Proteomics papers considering the structure, function,
The Human Genome Project has given rise and evolution of the human genome.
to two new fields of study. Genomics is the study _______. The Human Genome. Science 291
of genomes. To do so requires databases and (2001): 1145-1434. This special issue pro-
search engines to seek out information from vides data from the first draft of the human
these sequences. Today there are hundreds of genome sequence.
such databases already established. Scientists Sulston, John, and Georgina Ferry. The Com-
can search for complete gene sequences if they mon Thread: A Story of Science, Politics, Ethics,
know only a short segment of a gene. They can and the Human Genome. Washington, D.C.:
look for related sequences within the same ge- Joseph Henry Press, 2002. A chronicle of
nome or among different species. From such the race for the HGP from the perspective of
information one can study the evolution of par- a British Nobel Laureate Sir John Sulston,
ticular genes. head of Sanger Centre, the British research
The next step is to define the human pro- unit involved in the HGP. Describes the ef-
teome, giving rise to the field of proteomics. fort to ensure public access to the genome
Proteomics seeks to determine the expression data.
patterns of genes, the functions of the proteins Wolfsberg, Tyra G., Kris A. Wetterstrand, Mark
produced, and the structure of specific pro- S. Guyer, Francis S. Collins, and Andreas D.
432 Human Growth Hormone
of dwarfism are inability to grow at a normal has been concluded that growth hormone
rate or attain adult size. Many dwarfs are two to acts to cause all body bones to grow until adult
three feet tall. In contrast, some giants have size is reached. It is unclear why animals and
reached heights of more than eight feet. The humans from one family exhibit adult size vari-
advent of gigantism often begins with babies ation. The differences are thought to be ge-
born with pituitary tumors that cause the pro- netic and related to production and coopera-
duction of too much HGH, resulting in contin- tion of HGH, other hormones, and growth
ued excess growth. People who begin overse- factors.
creting HGH as adults (also caused by tumors) Genetic research has produced transgenic
do not grow taller. However, the bones in their HGH in bacteria through the use of genetic en-
feet, hands, skull, and brow ridges overgrow, gineering technology. The gene that codes for
causing disfigurement and pain, a condition HGH is spliced into a special circular piece of
known as acromegaly. DNA called a plasmid expression vector, thus
Dwarfism that is uncomplicated by the ab- producing a recombinant expression vector.
sence of other pituitary hormones is treated This recombinant vector is then put into bacte-
with growth hormone injections. Humans un- rial cells, where the bacteria express the HGH
dergoing such therapy can be treated with gene. These transgenic bacteria can then be
growth hormones from humans or primates. grown on an industrial scale. After bacterial
Growth hormone from all species is a protein growth ends, a huge number of cells are har-
made of approximately two hundred amino ac- vested and HGH is isolated. This method en-
ids strung into a chain of complex shape. How- ables isolation of enough HGH to treat anyone
ever, differences in amino acids and chain ar- who needs it.
rangement in different species cause shape
differences; therefore, growth hormone used Impact and Applications
for treatment must be extracted from a related One use of transgenic HGH is the treatment
species. Treatment for acromegaly and gigan- of acromegaly, dwarfism, and gigantism. The
tism involves the removal of the tumor. In cases availability of large quantities of HGH has also
where it is necessary to remove the entire pitu- led to other biomedical advances in growth
itary gland, other hormones must be given in and endocrinology. For example, growth hor-
addition to HGH. Their replacement is rela- mone does not affect EPCs in tissue culture.
tively simple. Such hormones usually come Ensuing research, first with animal growth hor-
from animals. Until recently, the sole source of mone and later with HGH, uncovered the EPC
HGH was pituitaries donated to science. This stimulant somatomedin. Somatomedin stimu-
provided the ability to treat fewer than one lates growth in other tissues as well and belongs
thousand individuals per year. Molecular ge- to a protein group called insulin-like growth
netics has solved that problem by devising the factors. Many researchers have concluded that
means to manufacture large amounts of trans- the small size of women compared to men is
genic HGH. caused by estrogen-diminished somatomedin
action on EPCs. Estrogen, however, stimulates
Growth Hormone Operation and female reproductive system growth by interact-
Genetics ing with other insulin-like growth factors.
In the mid-1940s, growth hormone was iso- Another interesting experiment involving
lated and used to explain why pituitary extracts HGH and genetic engineering is the produc-
increase growth. One process associated with tion of rat-sized mice. This venture, accom-
HGH action involves cartilage cells at the ends plished by putting the HGH gene into a mouse
of long bones (such as those in arms and chromosome, has important implications for
legs). HGH injection causes these epiphysial understanding such mysteries as the basis for
plate cells (EPCs) to rapidly reproduce and species specificity of growth hormones and max-
stack up. The EPCs then die and leave a layer imum size control for all organisms. Hence, ex-
of protein, which becomes bone. From this it periments with HGH and advancements in ge-
434 Huntingtons Disease
netic engineering technology have led to, and Web Sites of Interest
should continue to lead to, valuable insights ABC News Online, Standing Tall. http://abc
into the study of growth and other aspects of news.go.com/sections/living/goodmorning
life science. america/growthhormone_030619.html. A
Sanford S. Singer June, 2003, news report on children using
See also: Cloning; Dwarfism; Genetic Engi- human growth hormone to increase their
neering: Historical Development; Genetics, stature.
Historical Development of; Prader-Willi and National Institutes of Health, National Library
Angelman Syndromes; Turner Syndrome. of Medicine, Growth Disorders. http://www
.nlm.nih.gov/medlineplus/growthdisorders
.html. Information on all aspects of growth
Further Reading disorders and HGH treatment.
Eiholzer, Urs. Prader-Willi Syndrome: Effects of
Human Growth Hormone Treatment. New York:
Karger, 2001. Discusses the therapeutic use
of somatotropin, among other topics. Huntingtons Disease
Flyvbjerg, Allan, Hans Orskov, and George Al-
berti, eds. Growth Hormone and Insulin-like Field of study: Diseases and syndromes
Growth Factor I in Human and Experimental Significance: Huntingtons disease is an auto-
Diabetes. New York: John Wiley & Sons, 1993. somal dominant neurodegenerative disorder. The
Discusses advances regarding the effects of symptoms of this incurable, fatal condition in-
growth hormone and insulin-like growth fac- clude uncontrollable body movements and pro-
tors in relation to metabolism in diabetes gressive dementia. The relevant gene contains a
and the development of complications. domain of repeating triplets composed of the nucle-
Shiverick, Kathleen T., and Arlan L. Rosen- otides cytosine (C), adenine (A), and guanine
bloom, eds. Human Growth Hormone Pharma- (G). Mutation of this gene causes an increase in
cology: Basic and Clinical Aspects. Boca Raton, triplet number, triggering the dysfunction and
Fla.: CRC Press, 1995. Describes the research death of certain neurons in the brain.
on and clinical applicability of the human
growth hormone. Illustrated. Key terms
Smith, Roy G., and Michael O. Thorner, eds. CAG expansion: a mutation-induced increase
Human Growth Hormone: Research and Clinical in the number of consecutive CAG nucleo-
Practice. Totowa, N.J.: Humana Press, 2000. tide triplets in the coding region of a gene
Provides recent findings about regulation of genetic anticipation: progressively earlier
the hormone and its action at the molecular onset of a hereditary disease in successive
level. generations
Thorner, M., and R. Smith. Human Growth Hor- polyglutamine tract: in a protein, an amino
mone: Research and Clinical Practice. Vol. 19. acid sequence consisting exclusively of glu-
Totowa, N.J.: Humana Press, 1999. Exam- tamine, encoded by repeating CAG triplets
ines the use of human growth hormone
therapies in the treatment of short stature Characteristics
and various diseases. Studying an extended New York family in
Ulijaszek, J. S., M. Preece, and S. J. Ulijaszek. 1872, Dr. George Huntington first documented
Cambridge Encyclopedia of Human Growth and the heritable malady that bears his name. Hun-
Development Growth Standards. New York: Cam- tingtons disease (HD) was originally known as
bridge University Press, 1998. Broadly dis- Huntingtons chorea because of its hallmark
cusses genetic growth anomalies in relation jerky involuntary movements (the term cho-
to environmental, physiological, social, eco- rea comes from the Greek choros, meaning
nomic, and nutritional influences on hu- dance). Patients also experience marked cog-
man growth. nitive and psychiatric decline. HDs gradual
Huntingtons Disease 435
onset usually begins between ages thirty and The HD Gene and Its Product
forty, although its symptoms can first appear HD is inherited as a dominant mutation of a
within an age range of two to eighty years. The gene located on the short arm of chromosome
disease typically progresses to death within fif- 4. The cloning of the HD gene in 1993 provided
teen or twenty years of diagnosis. HD affects major impetus to understanding its function.
about one in ten thousand people of European The HD gene encodes a 348 kDa cytoplasmic
descent, and fewer than one in one million protein called huntingtin. Normally, the HD
people in African and Japanese populations. gene contains a stretch of repeating nucleo-
In HD, degeneration of neurons in specific tide triplets consisting of C (cytosine), A (ade-
brain regions occurs over time. Hardest hit is a nine), and G (guanine). Healthy HD alleles
particular subset of neurons in the striatum, a contain anywhere from 9 to 35 CAG repeats.
brain structure critical for movement control. The CAG triplet encodes the amino acid gluta-
Also affected is the frontal cortex, which is in- mine; therefore, normal huntingtin contains a
volved in cognitive processes. As the communi- polyglutamine tract. Huntingtin is expressed
cation link between the striatum and cortex is throughout the brain (and indeed, the body);
broken through ongoing neuronal death, un- however, its regular function remains unclear.
controllable chorea as well as intellectual and In neurons, huntingtin is thought to be im-
psychiatric symptoms develop and worsen. portant in counterbalancing programmed cell
The gene for Huntingtons disease is located on chromosome 4. Huntingtons is one of the rare single-gene disorders, clearly detected
genetically. Other genetic disease conditions have been located to chromosome 4, also shown here. (U.S. Department of Energy
Human Genome Program, http://www.ornl.gov/hgmis.)
436 Huntingtons Disease
death by promoting the expression of growth may affect the expression of a host of addi-
factors. Huntingtin may therefore help protect tional proteins. In fact, the expression of
striatal neurons throughout life. huntingtin itself (from the remaining normal
HD allele) is significantly reduced. This dimi-
The HD Mutation nution of the availability of normal huntingtin
Mutant HD alleles contain an expansion of may also contribute to neuronal demise. How-
the CAG repeat. The magnitude of this expan- ever, it is still unknown why only certain neu-
sion can range from 36 to more than 60 CAG rons die despite huntingtins ubiquitous ex-
repeats (rarely, as many as 250 repeats have pression.
been observed). There is an inverse relation-
ship between repeat number and age of disease
onset: Higher repeat numbers are usually linked Living with HD
to younger onset. People with 36-39 CAG re- The cloning of the HD gene has enabled di-
peats may never show disease symptoms, rect genetic testing for the HD mutation. With a
whereas people with 40-60 repeats usually de- blood test, at-risk individuals can learn not only
velop HD in mid-adulthood, and those with whether they carry the CAG expansion but also
more than 60 repeats often experience onset at its length. Knowing ones carrier status and
less than twenty years of age. predicted age of onset can eliminate doubt and
Although original HD mutations clearly must assist in making life plans, but the prospect of
occur, they are rare and of unknown cause. developing a fatal disease can be far more stress-
However, HDs inheritance patterns shed light ful than the uncertainty. This may explain why
on the mechanisms of CAG expansion. HD ex- a relatively low percentage of those with a fam-
hibits genetic anticipation: Affected members ily history of HD have opted to be tested. When-
of successive generations may show earlier on- ever testing is performed, it is accompanied by
set, particularly when the pathogenic allele is extensive counseling both before and after the
inherited paternally. It is thought that CAG ex- results are known.
pansion occurs during the repair of DNA strand Current treatments for HD are palliative and
breaks, when CAG loops are retained in the include antidepressants and sedatives. Strat-
nucleotide sequence during gap repair. If this egies now under study are aimed at preventing
happens in reproductive cells (particularly CAG expansion, counteracting the toxic effects
sperm), a larger CAG expansion will be present of mutant huntingtin, and delivering neuro-
in the offspring. protective agents to the brain. Another tactic is
to replace the dying striatal neurons with trans-
Consequences of CAG Expansion planted fetal neurons or stem cells. This ap-
The direct result of CAG expansion within proach has shown some promise: Following
the HD gene is that mutant huntingtin has a striatal grafts, a small number of HD patients
polyglutamine tract of variable but abnormally have experienced improvement in motor and
long length. Misfolding and aggregation of cognitive function.
mutant huntingtin ensues. Cleavage of the mu- Mary A. Nastuk
tant protein occurs, generating a fragment that See also: Behavior; Biological Clocks; Blot-
can enter the nucleus. Visible cytoplasmic and ting: Southern, Northern, and Western; Chro-
nuclear huntingtin aggregates are a key patho- matin Packaging; Chromosome Walking and
logical feature of the striatal neurons destined Jumping; DNA Replication; Gene Therapy: Eth-
to die. This aggregation represents a different ical and Economic Issues; Genetic Counseling;
(albeit toxic) function for huntingtin. The ag- Genetic Testing; Genetic Testing: Ethical and
gregates contain not only mutant huntingtin Economic Issues; Hereditary Diseases; In Vitro
but also several other critical proteins whose Fertilization and Embryo Transfer; Inborn Er-
functions are effectively withheld. Because rors of Metabolism; Insurance; Pedigree Analy-
some of these sequestered proteins are tran- sis; Prader-Willi and Angelman Syndromes; Re-
scription factors, transcriptional dysregulation petitive DNA; Stem Cells.
Hybridization and Introgression 437
One of the rarest of hybrids is the zebrass, a cross between a zebra and a donkey. (AP/Wide World Photos)
through pollen exchange with the wild-type Hybridization and introgression may intro-
(original) plants. Backcrossing, which is also duce novel adaptive traits. The subjects have
called introgression, increases hybrids biologi- raised controversy, because transgenes intro-
cal fitness. duced into crops have the potential for spread-
The term transgenic or genetically modi- ing into related weeds or wild plants. Scientists
fied organism (GMO) has been applied to have hypothesized that transgenes might move
plants and animals in which techniques of re- from the genetically modified crop plants to
combinant DNA have been used to modify spe- weeds. The possibility of spreading transgenes
cific parts of the genome of an organism. When via introgression and bridging, from geneti-
the procedure is successful, the resulting or- cally modified crops to related weed species, is
ganism may stably express a novel protein, ex- a concern; introduction of herbicide-resistant
press a protein with novel properties, or carry a cultivars into commercial agriculture could lead
change in the regulation of some of its genes. to the creation of superweeds.
Usually, such a change is designed to improve Some researchers believe that if herbicide-
the ability of the organism to grow (for in- resistant genes were to become more common in
stance, by resisting pests or using nutrients weeds as a result of widespread use of herbicide-
more efficiently) or to improve the usefulness resistant crops, farmers who rely on herbicides
of the organism (by improving its nutritive to manage weeds would be forced to use greater
value, using it to manufacture pharmaceuti- amounts and a larger number of herbicides.
cally important molecules, or employing it to To solve problem of horizontal gene trans-
carry out environmentally important processes fer, the producers of transgenic crops naturally
such as digesting environmental toxins). turn to gene technology. They propose to re-
440 Hybridization and Introgression
against SRBC after mice have been immunized included in a complex mixture of other biolog-
with them, the investigators expected that one ical molecules such as a cell extract.
well in about 100,000 or more might have a Following the first report of monoclonal anti-
clone of hybrid cells making antibody that re- bodies, biologists began to realize the implica-
acted against this antigen. The supernatants tions of being able to produce a continuous
(liquid overlying settled material) from hun- supply of antibodies with selected and well-
dreds of wells were tested, and the large major- defined reactivity patterns. There was discus-
ity were found to react with the immunizing sion of magic bullets that would react specifi-
antigen. Further work with other antigens con- cally with and carry specific cytotoxic agents to
firmed that a significant fraction of hybrid cells tumor cells without adverse effects on normal
formed with spleen cells of immunized mice cells. Biologists working in various experimen-
produce antibodies reacting with the antigen tal systems realized how specific and reliable
recently injected into the mouse. The produc- sources of antibody reagent might contribute
tion of homogeneous antibodies from clones to their investigations, and entrepreneurs
of hybrid cells thus became a practical way to started several biotechnology companies to de-
obtain reliable supplies of well-defined immu- velop and apply monoclonal antibody methods.
nological reagents. This initial enthusiasm was quickly moderated
The antibodies can be collected from the as some of the technical difficulties involved in
media in which the cells are grown, or the hy- production and use of these antibodies became
bridomas can be injected into mice so that apparent; with time, however, many of the pro-
larger concentrations of monoclonal antibod- jected advantages of these reagents have be-
ies can be collected from fluid that collects in come a reality.
the abdominal cavity of the animals.
Monoclonal Reagents
Specific Antibodies Against Antigen A survey of catalogs of companies selling
Mixtures products used in biological research confirms
One advantage of separating an animals an- that many of the conventional antisera com-
tibody response into individual antibody com- monly used as research reagents have been
ponents by hybridization and separation of cells replaced with monoclonal antibodies. These
derived from each fusion event is that antibod- products are advantageous to the suppliers, be-
ies that react with individual antigenic compo- ing produced in constant supply with standard-
nents can be isolated even when the mouse is ized protocols from hybrid cells, and the users,
immunized with a complex mixture of anti- who receive well-characterized reagents with
gens. For example, human tumor cells injected known specificities free of other antibodies that
into a mouse stimulate the production of many could produce extraneous and unexpected re-
different types of antibodies. A few of these actions when used in some assay conditions.
antibodies may react specifically with tumor Antibodies are available against a wide range of
cells or specific types of human cells, but, in a biomolecules reflecting current trends in re-
conventional antisera, these antibodies would search; examples include antibodies against cy-
be mixed with other antibodies that react with toskeletal proteins, protein kinases, and onco-
any human cell and would not be easily sepa- gene proteins, gene products involved in the
rated from them. If the tumor cells are injected transition of normal cells to cancer cells.
and hybridomas are made and screened to de- Immunologists were among the first to take
tect antibodies that react with tumor cells and advantage of monoclonal antibody technol-
not with most normal cells, it is possible to iso- ogy. They were able to use them to trap the
late antibodies that are useful for detection and spleen cells making antibodies against small,
characterization of specific types of tumor cells. well-defined molecules called haptens and to
Similar procedures can also be used to make then characterize the antibodies produced by
antibodies against a single protein after the the hybridomas. This enabled them to define
mouse has been immunized with this protein classes of antibodies made against specific anti-
Hybridomas and Monoclonal Antibodies 443
genic determinants and to derive information found, there are several antibodies in use for
about the structure of the antibody-binding tumor detection and for experimental forms of
sites and how they are related to the determi- cancer therapy. Monoclonal antibodies that re-
nants they bind. Other investigators produced act selectively with cancer cells but not normal
antibodies that reacted specifically against sub- cells can be used to deliver cytotoxic molecules
sets of lymphocytes playing specific roles in the to the cancer cells. Monoclonal reagents are
immune responses of animals and humans. also used to deliver isotopes that can be used to
These reagents were then used to study the detect the presence of small concentrations of
roles that these subsets of immune cells play in cancer cells that would not normally be found
responses to various types of antigens. until the tumors grew to a larger size.
Antibodies that react with specific types of
immune cells have also been used to modulate Human Monoclonal Antibodies
the immune response. For example, antibodies The majority of monoclonal antibodies made
that react with lymphocytes that would nor- against human antigens were mouse antibod-
mally react with a transplanted tissue or organ ies derived from the spleens of immunized
can be used to deplete these cells from the cir- mice. When administered to humans in clinical
culation and thus reduce their response against settings, the disadvantage of the animal origin
the transplanted tissue. of the antibodies soon became apparent. The
human immune system recognized the mouse
Monoclonal Antibodies as Diagnostic antibodies as foreign proteins and produced
Reagents an immune response against them, limiting
Monoclonal antibodies have been used as their usefulness. Even when the initial response
both in vitro and in vivo diagnostic reagents. By to an antibodys administration was positive,
the 1980s, many clinical diagnostic tests such the immune reaction against the foreign pro-
as assays for hormone or drug levels relied tein quickly limited its effectiveness. In an at-
upon antisera as detecting reagents. Antibod- tempt to avoid this problem, human mono-
ies reacting with specific types of bacteria and clonal antibodies have been developed using
viruses have also been used to classify infec- several methods. The first is the hybridization
tions so that the most effective treatment can of human lymphocytes stimulated to produce
be determined. In the case of production of antibodies against the antigen of interest with
antibodies for typing microorganisms, it has mouse plasmacytomas or later with human
frequently been easier to make type-specific plasmacytoma cell lines. This method has been
monoclonal antibodies than it had been to pro- used successfully, although it is limited by the
duce antisera that could be used to identify the ability to obtain human B cells or plasma cells
same microorganisms. stimulated against specific antigens because it
Companies supplying these diagnostic re- is not possible to give an individual a series of
agents have gradually switched over to the use immunizations and then remove stimulated
of monoclonal antibody products, thus facili- cells from the spleen. Limited success has re-
tating the standardization of the reactions and sulted from the fusion of circulating lympho-
the protocols used for the clinical tests. The cytes from immunized individuals or fusion of
reproducibility of the assays and the reagents lymphocytes that have been stimulated by the
has made it possible to introduce some of these antigen in cell cultures. Investigators have re-
tests that depend upon measurement of con- ported some success in making antitumor mon-
centrations of substances in urine as kits that oclonal antibodies by fusing lymph node cells
can be used by consumers in their own homes. from cancer patients with plasmacytoma cell
Kits have been made available for testing glu- lines and screening for antibodies that react
cose levels of diabetics, for pregnancy, and for with the tumor cells.
the presence of certain drugs. There has also been some success at hu-
Although the much-hoped-for magic bul- manizing mouse antibodies using molecular
let that would eradicate cancer has not been genetic techniques. In this process, the portion
444 Hybridomas and Monoclonal Antibodies
of the genes that make the variable regions of to the antigen can be multiplied and then used
the mouse antibody protein that reacts with a to generate recombinant antibody molecules
particular antigen is spliced in to replace the in culture.
variable region of a human antibody molecule Researchers have also experimented with in-
being produced by a cultured human cell or troducing antibody genes into plants, resulting
human hybridoma. What is produced is a hu- in plants that produce quantities of the specific
man antibody protein that has the binding antibodies. Hybridomas or bacteriophages ex-
specificity of the original mouse monoclonal pressing specific antibodies of interest may be a
antibody. When such antibodies are used for potential source of the antibody gene sequences
human therapy, the reaction against the in- introduced into these plant antibody factories.
jected protein is reduced compared to the ad- Roger H. Kennett
ministration of the whole mouse antibody mol- See also: Allergies; Antibodies; Autoim-
ecules. mune Disorders; Burkitts Lymphoma; Cancer;
Another application of antibody engineer- Genetic Engineering; Genetic Engineering:
ing is the production of bispecific antibodies. Medical Applications; Immunogenetics; Model
This has been accomplished by fusing two hy- Organism: Mus musculus; Oncogenes; Organ
bridomas making antibodies against two differ- Transplants and HLA Genes; Synthetic Anti-
ent antigens. The result is an antibody that con- bodies.
tains two types of binding sites and thus binds
and cross-links two antigens, bringing them Further Reading
into close proximity to each other. Gibbs, W. W. Plantibodies: Human Antibodies
Produced by Field Crops Enter Clinical
Recombinant Antibodies Trials. Scientific American 277 (November,
Advances in molecular genetic techniques 1997). Details experiments in introducing
and in the characterization of the genes for the antibody genes into plants.
variable and constant regions of antibody mol- Hoogenboom, H. R. Designing and Opti-
ecules have made it possible to produce new mizing Library Selection Strategies for Gen-
forms of monoclonal antibodies. The genera- erating High-Affinity Antibodies. Trends in
tion of these recombinant antibodies is not de- Biotechnology 15 (1997). Contains detailed in-
pendent upon the immunizing of animals but formation about laboratory techniques used
on the utilization of combinations of antibody to engineer monoclonal antibodies.
genes generated using the in vitro techniques Kontermann, Roland, and Stefan Dbel, eds.
of genetic engineering. Geneticists discovered Antibody Engineering. New York: Springer,
that genes inserted into the genes for fibers ex- 2001. A detailed look at basic methods, pro-
pressed on the surface of bacterial viruses called tocols for analysis, and recent and develop-
bacteriophages are expressed and detectable ing technologies. Illustrations, bibliography,
as new protein sequences on the surface of the index.
bacteriophage. Investigators working with anti- Mayforth, Ruth D. Designing Antibodies. San
body genes found that they could produce pop- Diego: Academic Press, 1993. Serves as a
ulations of bacteriophage expressing combi- practical introduction to designing antibod-
nations of antibody-variable genes. Molecular ies for use in medicine or science: making
genetic methods have made it possible to gen- monoclonal antibodies, designing them for
erate populations of bacteriophage expressing human therapy, targeting, idiotypes, and
different combinations of antibody-variable catalytic antibodies.
genes with frequencies approaching the num- Stigbrand, T., et al. Twenty Years with Mono-
ber present in an individual mouse or human clonal Antibodies: State of the Art. Acta
immune system. The population of bacterio- Oncologica 35 (1996). Provides an overview of
phage can be screened for binding to an anti- the development of monoclonal antibodies.
gen of interest, and the bacteriophage express- Van de Winkel, J. G., et al. Immunotherapeutic
ing combinations of variable regions binding Potential of Bispecific Antibodies. Immunol-
Hypercholesterolemia 445
ogy Today 18 (December, 1997). Looks at the lates in the bloodstream, which is enough to
potential uses of bispecific antibodies. meet the bodys needs. Cholesterol is present
Wang, Henry Y., and Tadayuki Imanaka, eds. in animal-derived foods, but is also produced
Antibody Expression and Engineering. Washing- by the liver. The liver manufactures and regu-
ton, D.C.: American Chemical Society, 1995. lates the amount of lipoproteins in the body.
Explores monoclonal antibody synthesis and The normal range of total cholesterol is less
reviews research on the expression of anti- than 200 milligrams per deciliter (mg/dl) of
body fragments. Illustrated. blood. A total cholesterol level between 200-
240 mg/dl is borderline high, and a total cho-
lesterol level above 240 mg/dl is considered
high. The normal range of LDL cholesterol is
less than 130 mg/dl, and the normal range of
Hypercholesterolemia HDL cholesterol is greater than 35 mg/dl. Hy-
percholesterolemia is diagnosed when the to-
Field of study: Diseases and syndromes tal cholesterol level is higher than the normal
Significance: Hypercholesterolemia represents a range, and the term hypercholesterolemia is
significant risk factor for coronary artery disease often used to refer to familial cholesterolemia
and stroke. Diet as well as genetics influence the de- as well.
velopment of hypercholesterolemia.
Causes of Hypercholesterolemia
Key terms Hypercholesterolemia itself may be asymp-
apolipoprotein B (Apo-B): a protein essential tomatic but can still be damaging to the vascu-
for cholesterol transport lar system. Excess amounts of cholesterol in the
high-density lipoprotein (HDL): a small, blood can build up along the walls of the arter-
denser form of cholesterol, popularly known ies, which results in hardening and narrowing
as the good cholesterol because it can trans- of the arteries, called atherosclerosis. Severe
port cholesterol from tissues to the liver atherosclerosis can lead to a blockage of blood
low-density lipoprotein (LDL): the bad flow. Atherosclerosis in the heart causes cardio-
cholesterol that tends to deposit into the tis- vascular disease (such as heart attacks). The re-
sues, especially in the vessel walls sult of atherosclerosis in the brain can be a
stroke. Atherosclerosis can also occur in the ex-
Cholesterols Role in the Body tremities of the body, such as the legs, causing
Cholesterol is a steroid lipid, a type of fat pain and blood clots.
molecule that is essential for life. It is an impor- Hypercholesterolemia occurs when the body
tant component of cell membranes and is used is unable to use or eliminate excessive amounts
by the body to synthesize various steroid hor- of cholesterol. Several diseases can contribute
mones. When cooled, cholesterol is a waxy sub- to hypercholesterolemia, such as diabetes, thy-
stance, which cannot dissolve in the blood- roid disorders, and liver diseases. However, the
stream. It is transported in the bloodstream in most important cause of hypercholesterolemia
complexes of cholesterol and protein called is a combination of diet and genetic factors.
lipoproteins. Cholesterol naturally exists in animal prod-
There are two different classes of lipopro- ucts, such as meats (particularly fatty meats),
teins in the bloodstream. Low-density lipopro- eggs, milk, cheese, liver, and egg yolks. Large
tein (LDL) cholesterol is the bad cholesterol intakes of these products can certainly increase
that tends to deposit into the tissues, especially ones cholesterol level, not only because they
in the vessel walls. High-density lipoprotein have high concentrations of cholesterol itself
(HDL), a smaller, denser molecule, is the but, more important, because they contain fats
good cholesterol, because it can transport that prompt the body to make cholesterol. The
cholesterol from tissues to the liver. genetic influence on hypercholesterolemia is
About one tablespoon of cholesterol circu- also significant.
446 Hypercholesterolemia
Kri Steffnsson, founder of deCODE Genetics, speaking before the forty-first annual meeting of the American Society of Hematology
in December, 1999. (AP/Wide World Photos)
interrelated objectives for the database were dividuals predisposition to a particular disease
defined: (1) discovering the genes involved in but also to predict diseases within the entire
complex diseases and (2) finding new drugs population of Iceland before they actually oc-
through pharmacogenomics to combat those cur. This new form of medical intervention
same diseases once their genes were identified. could be used to plan public health policies for
Working with volunteers, deCODE launched groups of people. Predicting diseases is a signif-
an initiative to discover genes involved in more icant departure from current public health
than fifty common diseases, such as diabetes practice, which develops treatment regimens
and asthma. Genes involved in all fifty diseases only after a disease appears, not before. What
have been mapped at least to a chromosome. began as a single countrys genetic database
Three genes have been isolated, including one has now grown into the recognition of the po-
for schizophrenia. Based upon this early and tential role of genetics in worldwide public
rapid success, the company has entered into health policy and planning.
new pharmacogenomic partnerships with ad-
ditional companies with the aim to discover Ethical Concerns
drugs that can effectively counter the diseases The Act on a Health Sector Database is silent
that have been genetically mapped. on what data were to be used, how they would
be used, informed consent issues, and the right
Potential Uses to privacy. Heavily encrypting all the informa-
Because the database will contain the infor- tion in the database, removing all personal in-
mation of the entire Icelandic people, it is also formation that could identify patients individu-
considered a population genetic database. Its ally, and security testing the database were a
data could be used not only to determine an in- result of these privacy concerns.
Immunogenetics 449
Informed consent issues have created the Kaiser, Jocelyn. Population Databases Boom:
most serious problems. The act presumes in- From Iceland to the U.S. Science 298 (1995):
formed consent unless an individual opts 1158-1161. Discusses the development of
out, which many feel violates the intent of con- health and genetic information databases in
sent. Icelandic physicians have filed a lawsuit to several countries, including how they are do-
clarify this issue, since Icelandic law requires ing it and what new controversies are arising.
that physicians guarantee full informed con- Palsson, Bernhard, and Snorri Thorgeirsson.
sent. Decoding Developments in Iceland. Na-
A second major concern is the licensing of ture Biotechnology (1999) 17, no. 5: 406. A
Icelands complete genetic profile to a com- short article that covers the early history of
pany. Because Iceland has a nationalized the Icelandic Genetic Database. Lists stable
health plan, medical records have always been URLs for the Icelandic governments Web
considered a national resource. Many feel that site on the Health Sector Database Act, as
Icelandic genetic records are also a national re- well as a site that contains the full text of
source and should remain with the people. Re- most of the articles published about the da-
lated to this issue is concern that granting the tabase.
rights to only a single company will prevent sci- Wilie, Jean E., and Geraldine P. Mineau. Bio-
entific research both in Iceland and elsewhere medical Databases: Protecting Privacy and
on any genes deCODE may identify. Promoting Research. Trends in Biotechnology
Although controversial, the database con- 21, no. 3 (2003): 113-116. Addresses the ten-
tinues to provide guidance and lessons for sion that develops between biomedical re-
other nations in developing new genetic data- search with population databases and the
bases. Ethical, medical, and social issues first need to protect the people whose data re-
raised in Iceland have quickly become issues sides in the databases.
worldwide as population genetic databases pro-
liferate. This, in turn, has resulted in an active Web Sites of Interest
debate on the role of genetic information in Association of Icelanders for Ethics in Science
worldwide public health and whether it should and Medicine. http://www.mannvernd.is.
be permitted to operate in all countries, if at all. Site of an organization opposed to the Ice-
Diane C. Rein landic Genetic Database.
See also: Bioinformatics; Genetic Screen- deCode Genetics. http://www.decode.com.
ing; Genetic Testing: Ethical and Economic Is- Site of the company compiling the Icelandic
sues; Genomic Libraries; Genomics; Human Genetic Database.
Genome Project; Linkage Maps; Pedigree Anal- Mapping the Icelandic Genome. http://sunsite
ysis; Population Genetics. .berkeley.edu/biotech/iceland. Site devoted
to the scientific, political, economic, reli-
Further Reading gious, and ethical issues surrounding the de-
Anna, George J. Rules for Research on Hu- Code Project and its global implications.
man Genetic Variation: Lessons from Ice-
land. The New England Journal of Medicine
342, no. 24 (2000): 1830-1833. Deals with
the major ethical problems that arose from
the creation of the Icelandic Genetic Data-
Immunogenetics
base and how they could be avoided in the Field of study: Immunogenetics
future. Significance: Immunogenetics is primarily con-
Greely, Henry T. Icelands Plan for Genomics cerned with the major histocompatibility genes that
Research: Facts and Implications. Jurimet- identify self tissues, the genes in B lymphocytes that
rics Journal 40 (2000): 153-191. Covers the direct antibody synthesis, and the genes that direct
history of the database and the ethical and the synthesis of T lymphocyte receptors. This same
medical issues, presented in a legal context. genetic control that directs immune cell embryonic
450 Immunogenetics
development and activation from an antigenic nized that a number of antibodies produced in
challenge also explains the basis of organ trans- the lifetime of a human did not have to have
plant rejection, autoimmunity, allergies, immuno- the equivalent number of physical genes on
deficiency, and potential future therapies. their chromosomes. From his work, it was de-
termined that the genes responsible for anti-
Key terms body synthesis are arranged in tandem seg-
apoptosis: cell death that is programmed as a ments on specific chromosomes relating to
natural consequence of growth and develop- specific parts of antibody structure. The amino
ment through normal cellular pathways or acids that form the two light polypeptide
through signals from neighboring cells chains and the two heavy polypeptide chains
cytokines: soluble intercellular molecules making up the IgG class of antibody are pro-
produced by cells such as lymphocytes that grammed by nucleotide sequences of DNA that
can influence the immune response exist on three different chromosomes. Light-
downstream: describes the left-to-right direc- chain genes are found on chromosomes 2 and
tion of DNA whose nucleotides are arranged 22. The specific nucleotide sequences code for
in sequence with the 5 carbon on the left light polypeptide chains, with half the chain
and the 3 on the right; the direction of RNA having a constant amino acid sequence and the
transcription of a genetic message with the other half having a variable sequence. The
beginning of a gene on the left and the end amino acid sequences of the heavy polypeptide
on the right chains are constant over three-quarters of their
haplotype: a sequential set of genes on a sin- length, with five basic sequences identifying
gle chromosome inherited together from five classes of human immunoglobulins: IgG,
one parent; the other parent provides a IgM, IgD, IgA, and IgE. The other quarter
matching chromosome with a different set length has a variable sequence that, together
of genes with the variable sequence of the light chain,
transposon: a sequence of nucleotides flanked forms the antigen-binding site. The nucleotide
by inverted repeats capable of being removed sequence coding for the heavy chain is part of
or inserted within a genome chromosome 14.
The actual light-chain locus is organized
Genes, B Cells, and Antibodies into sequences of nucleotides designated V, J,
The fundamental question that led to the and C segments. The multiple options for the
development of immunogenetics relates to different V and J segments and mixing the dif-
how scientists are able to make the thousands ferent V and J segments cause the formation of
of specific antibodies that protect people from many different DNA light-chain nucleotide se-
the thousands of organisms with which they quences and the synthesis of different antibod-
come in contact. Macfarlane Burnet proposed ies. The same type of rearrangement occurs be-
the clonal selection theory, which states that an tween a variety of nucleotide sequences related
antigen (that is, anything not self, such as an in- to the V, D, and J segments of the heavy-chain
vading microorganism) selects, from the thou- locus. The recombination of segments appears
sands of different B cells, the receptor on a par- to be genetically regulated by recombination
ticular B cell that fits it like a key fitting a lock. signal sequences downstream from the variable
That cell is activated to make a clone of plasma segments and recombination activating genes
cells, producing millions of soluble antibodies that function during B-cell development. Ge-
with attachment sites identical to the receptor netic recombination is complete with the im-
on that B-cell surface. The problem facing sci- mature B cell committed to producing one
entists who were interested in a genetic expla- kind of antibody. The diversity of antibody mol-
nation for this capability was the need for more ecules is explained by the fact that the mRNA
genes than the number that was believed to transcript coding for either the light polypep-
make up the entire human genome. tide chain or the heavy polypeptide chain is
It was Susumu Tonegawa who first recog- formed containing exons transcribed from re-
Immunogenetics 451
combined gene segments during B-cell differ- ing of the antigen to the specific B cell activates
entiation. The unique antigen receptor-binding its cell division and the formation of a clone of
site is formed when the variable regions of one plasma cells that produce a unique antibody. If
heavy and one light chain come together dur- this circulating B cell does not contact its spe-
ing the formation of the completed antibody cific antigen within a few weeks, it will die by
in the endoplasmic reticulum of the mature apoptosis. During plasma cell formation, the
B cell. The B-cell antigen receptor is an at- class of antibody protein produced normally
tached surface antibody of the IgM class. Bind- switches from IgM to IgG through the forma-
Antibody-mediated Nonspecific
immune response defense
response
Macrophages destroy
B bacteria through
cell phagocytosis
Helper
T Information is
cell provided to
Virgin B cells B helper T cells
are sensitized cell
Antibodies are
released into
the bloodstream
tion of an mRNA transcript containing the , DQ and , and DR and . These genes en-
exon nucleotide sequence made from IgG code for glycoprotein molecules that attach to
heavy-chain C segment rather than the heavy- the cell surface in and pairs. A child will in-
chain C segment for IgM. The intervening nu- herit the six genes as a group or haplotype,
cleotide sequence of the IgM constant segment three and glycoprotein gene pairs from
is deleted from the chromosome as an excised each parent. The child will also have glyco-
circle reminiscent of the transposon or plasmid protein molecules made from combinations
excision process. The result of this switch is the of the maternal and paternal and pairings
formation of an IgG antibody having the same during glycoprotein synthesis.
antigen specificity as the IgM antibody, because The Class II MHC molecules are found on
the variable regions of the light and heavy poly- the membranes of macrophages, B cells, and
peptide chains remain the same. Although the dendritic cells. These specialized cells capture
activation and development of B cells by some antigens and attach antigen peptides to the
antigens may not need T-cell involvement, it is three-dimensional grooves formed by com-
believed that class switching and most B-cell ac- bined and glycoprotein pairs. The antigen
tivity are influenced by T-cell cytokines. attached to the Class II groove is presented to
the T helper cell, with the receptor recognizing
Major Histocompatibility Genes the specific antigen in relation to the self anti-
In humans, the major histocompatibility gen. The specific T helper cell forms a specific
genes encoding self antigens are also called clone of effector cells and memory cells.
the HLA complex and are located on chromo-
some 6. The nucleotides that compose this Genes, T Helper Cells, and T Cytotoxic
DNA complex encode for two sets of cell sur- Cells
face molecules designated MHC Class I and The thousands of specific T-cell receptors
MHC Class II antigens. The Class I region con- (TCR) available to any specific antigen one
tains loci A, B, and C, which encode for MHC might encounter in a lifetime are formed in the
Class I A, B, and C glycoproteins on every nu- human embryonic thymus from progenitor T
cleated cell in the body. Because the A, B, and C cells. The TCR comprises two dissimilar poly-
loci comprise highly variable nucleotide se- peptide chains designated and or and .
quences, numerous kinds of A, B, and C glyco- They are similar in structure to immunoglobu-
proteins characterize humans. All people in- lins and MHC molecules, having regions of
herit MHC Class I A, B, and C genes as a variable amino acid sequences and constant
haplotype from each of their parents. Children amino acid sequences arranged in loops called
will have tissues with half of their Class I A, B, domains. This basic structural configuration
and C antigens like those of their mother and places all three types of molecules in a chemi-
half like those of their father. Siblings could cally similar grouping designated the immu-
have tissue antigens identical or totally dissimi- noglobulin superfamily. The genes of these
lar based on their MHC I glycoproteins. Body molecules are believed to be derived from a
surveillance by T lymphocytes involves T cells primordial supergene that encoded the basic
recognizing self glycoproteins. Cellular inva- domain structure.
sion by a virus or any other parasite results in The exons encoding the and polypep-
the processing of antigen and its display in the tides are designated V, J, and C gene segments
cleft of the MHC Class I glycoprotein. T cyto- in sequence and associate with recombination
toxic lymphocytes with T-cell receptors specific signal sequences similar to the immunoglobu-
for the antigen-MHC I complex will attach to lin light-chain gene. The and polypeptide
the antigen and become activated to clonal se- genes are designated VDJ and C exon segments
lection. Infected host cells are killed when acti- in sequence associating with recombination
vated cytotoxic T cells bind to the surface and signal sequences similar to the immunoglobu-
release perforins, causing apoptosis. lin heavy-chain genes. Just as there are multiple
MHC Class II genes are designated DP and forms for each of the immunoglobulin variable
Immunogenetics 453
16 to 17 days: Eggs
are examined to see
if they have been 14 to 15 days (immediately
fertilized and have before ovulation): Ripe eggs
started to develop are removed by laparoscopy
into embryos. If so, or by ultrasound-guided needle
several two- or four-cell aspiration through the vagina
embryos are placed or abdomen. Eggs are mixed
in the womans uterus. with sperm in a dish, which is
then incubated.
through the uterus and into each Fallopian In Vitro Fertilization and Embryo Transfer
tube in search of an ovum. During this trip, the Fertilization can also take place artificially in
sperm undergo changes called capacitation. laboratory culture dishes. Gametes are col-
To fuse with the ovum, a sperm must penetrate lected, brought together, and fertilized in a lab-
several surrounding barriers. After fusion of oratory. After the zygote develops into an em-
sperm and egg, the nuclear membranes of the bryo, it can then be transferred to a uterus for
two cells break down so that the paternal and continued development and eventual birth.
maternal chromosomes can congregate in a This procedure can be done for many species,
single nucleus. The resulting zygote divides including humans. The first human conceived
into two new diploid cells, the first cells of a ge- by in vitro fertilization (IVF), Louise Brown,
netically unique new being. was born on July 25, 1978, in England.
For women who do not produce any viable oocytes DNA. These transcription factors are contributed by
because of permanent failure of the ovaries, options the enucleated, donor egg, and they determine what
for having a child who contains genetic information genes will be active, in what cells, and for how long.
from the mother are limited. Nuclear transfer into Proteins contributed by the donor egg will control
an enucleated donor egg could address this limita- the early embryonic divisions. The donor egg also
tion. Since the 1980s, nuclei from relatively undif- contains RNA molecules that serve as templates to
ferentiated mammalian embryonic cells have been create the proteins needed for events in early em-
successfully transferred to donor eggs. In 1996 re- bryogenesis, essential to the development of the new
searchers at the Roslyn Institute in Scotland ad- organism. These molecules will influence how that
vanced nuclear transfer by taking a nucleus from an organism grows and develops and what genes are ex-
adult somatic cell and successfully transferring it pressed by its cells.
into an enucleated egg. The result of this work was The nucleus is not the only source of DNA in
the birth of the first vertebrate cloned from an adult the animal cell. The donor egg contains organelles
cell, Dolly the sheep. Since Dolly, nuclear transfer called mitochondria that contain their own DNA.
has been successfully performed in cows, pigs, cats, Mitochondria reproduce by a process much like bac-
and mice. teria, copying their own DNA and dividing within the
Adult somatic cells contain essentially the same cell. All of the mitochondria in an organism pro-
genetic information as the single fertilized egg that duced by nuclear transfer into a donor egg will be de-
gave rise to the adult organism. However, unlike the rived from the donor egg, not from the cell that do-
fertilized egg, most adult somatic cells are terminally nated the nucleus. Mitochondria are responsible for
differentiated and have lost the ability to produce cellular metabolism, and some metabolic diseases
any type of cell in the body, as a fertilized egg can. Nu- can be traced directly to mutations within mitochon-
clear transfer takes a nucleus from an adult somatic drial DNA.
cell and places it into an enucleated donor egg. In As might be anticipated, this reproductive tech-
the environment of the egg, the DNA in the trans- nique raises ethical questions, as only one parent
ferred nucleus can dedifferentiate and direct the can contribute a nucleus to the donor egg. More-
production of a new individual. Because this tech- over, it involves a great deal of manipulation in vi-
nique does not involve fertilization, the new individ- tro, and some suggest that developmental problems
ual is considered a clone of the adult organism that can result from such manipulation. Nevertheless, in
contributed the nucleus. 2003, as the first test-tube baby, Louise Brown, cele-
Is the new individual produced really a clone of brated her twenty-fifth birthday, many remarked on
the adult? The enucleated egg contributes the envi- how many children had been similarly brought into
ronment that directs the unfolding of the genetic the world since 1978 and how common the tech-
program that leads to the development of the new in- nique had become as an alternative for infertile cou-
dividual. Proteins called transcription factors con- ples.
trol the expression of individual genes within the Michele Arduengo
In Vitro Fertilization and Embryo Transfer 457
In humans IVF is usually used to overcome nancy through elective abortion becomes an
infertility caused by problems such as blocked option. Not only does abortion represent a
Fallopian tubes or low sperm count. IVF is also higher risk to the mother, it is an unacceptable
done in veterinary medicine and for scientific choice for many people because of ethical and
research. IVF also makes genetic diagnoses eas- moral concerns.
ier and could eventually lead to more effective Access to gametes prior to fertilization and
gene therapy. Mature sperm for IVF are easily to embryos prior to implantation also opens
obtained by masturbation. Mature ova are more the possibility of gene therapy. Gene therapy in
difficult to obtain. The female is given gonado- human embryos presents insurmountable eth-
tropin hormones to stimulate her to super- ical issues, at present, and has been banned
ovulate (that is, to produce ten or more mature pending more study. Genetic modification of
eggs rather than just one). Ova are later col- the embryos of other species, especially those
lected by inserting a small suction needle into of commercial interest, carries no such ethical
her pelvic cavity. The ova are inseminated with concerns and is routinely practiced.
laboratory-capacitated sperm. Two to four em- IVF also opens the possibility of genetic clon-
bryos are transferred into the uterus through a ing. Cloning is the process of creating multiple
catheter. Excess embryos can be saved by a individuals with identical genetic characteris-
freezing procedure called cryopreservation. tics. This can be accomplished by dividing an
These may be thawed for later attempts at im- early embryo, allowing each group of cells to
plantation should the first attempt fail or a sec- develop into a separate embryo. A few of these
ond pregnancy be desired. embryos can then be implanted, saving the oth-
ers for future attempts, or all can be implanted,
Impact and Applications using several different females as surrogate
Technology such as the polymerase chain mothers. Through the use of cryopreservation,
reaction (PCR) permits assessment of genetic these pregnancies could occur years apart. It is
information in the nucleus of a single cell, even possible to remove the nucleus from an
whether diploid or haploid. IVF gives physi- isolated cell and replace it with a nucleus taken
cians access to sperm, ova, and very early em- from an adult. The cell with the transplanted
bryos. One or two cells can be removed from an nucleus is able, using special procedures, to de-
eight-cell embryo without damaging the ability velop into an embryo that can be implanted.
of the remaining cells to develop normally fol- The offspring will be genetically identical to
lowing embryo transfer. Thus IVF permits ge- the adult source of the transplanted nucleus.
netic diagnosis at the earliest stages of human Most people recognize cloning technology as
development and even allows the possibility of inappropriate in human medicine, but it has
gene therapy. acceptable applications in agriculture and vet-
Preimplantation genetic diagnosis (PGD) is erinary medicine.
used clinically to help people with significant Armand M. Karow, updated by Bryan Ness
genetic risks to avoid giving birth to an abnor- See also: Amniocentesis and Chorionic Vil-
mal child that might die in infancy or early lus Sampling; Cloning; Genetic Counseling;
childhood. If tests show that the embryo is free Genetic Screening; Genetic Testing; Genetic
of genetic defects, it can be transferred to the Testing: Ethical and Economic Issues; Heredi-
uterus for implantation; if found defective it tary Diseases; Infertility; Prenatal Diagnosis;
can be destroyed. PGD is successful in avoiding Stem Cells; Totipotency; Turner Syndrome.
pregnancies with embryos that will develop cys-
tic fibrosis, Huntingtons disease, Lesch-Nyhan Further Reading
disease, Tay-Sachs disease, and other genetic Bonnicksen, Andrea L. In Vitro Fertilization:
abnormalities. Prior to the development of Building Policy from Laboratories to Legislature.
PGD, detection of genetic defects was possible Reprint. New York: Columbia University
only by prenatal diagnosis during pregnancy. If Press, 1991. Examines two facets of IVF: the
a defect is detected, termination of the preg- publics political, legal, and ethical concerns
458 Inborn Errors of Metabolism
the term inborn errors of metabolism to de- ter Garrod presented his ideas. In 1952, Von
scribe these conditions. Other investigators Gierkes disease was found to be caused by the
have studied more than three thousand addi- defective enzyme glucose-6 phosphatase. After
tional diseases that can be included in this cate- this discovery, many inborn errors of metabo-
gory. A few of these conditions occur at rela- lism were traced to defects in other enzymes.
tively high frequency in humans. In the U.S. Enzymes are proteins that catalyze biochemical
Caucasian population, cystic fibrosis occurs in reactions. They are responsible for increasing
about 1 in 2,000 births. Some conditions, such the rates of reactions that occur in all cells.
as phenylketonuria (PKU), are seen at moder- These reactions are important steps in meta-
ate frequency, about 1 in 10,000. Many of the bolic pathways that are responsible for pro-
inborn errors are rare, with frequencies less cesses such as utilization of nutrients, genera-
than 1 in 100,000. A generally accepted defini- tion of energy, cell division, and biosynthesis
tion of an inborn error of metabolism is any of substances that are needed by organisms.
condition with actual or potential health conse- There are many metabolic pathways that can be
quences that can be inherited in the fashion affected if one of the enzymes in the pathway is
described by Gregor Mendel in the nineteenth missing or malfunctions. In addition to en-
century. zymes, defective proteins with other functions
may also be considered as candidates for in-
Malfunctioning Proteins and Enzymes born errors of metabolism. For example, there
The biochemical causes of the inborn errors are many types of defective hemoglobin, the
of metabolism were discovered many years af- protein responsible for oxygen transport.
Nine-year-old Andy Burgy in 2003. He suffers from an incurable inborn metabolic error known as epidermolysis bullosa, which
makes his skin blister at the touch. (AP/Wide World Photos)
460 Inborn Errors of Metabolism
These defective hemoglobins are the causes of Huntingtons disease are manifested as domi-
diseases such as sickle-cell disease and thalas- nant genetic traits. Only one copy of the defec-
semia. tive gene is necessary for manifestations of the
abnormal condition. There are some inborn
Genetic Basis of Inborn Errors errors of metabolism that are sex-linked. Dis-
The cause of these defects in enzymes and eases that involve mutations carried on the X
proteins has been traced to mutations in the chromosome may be severe in males because
genes that code for them. Alterations in the they have only one X chromosome but less se-
structure or nucleotide composition of DNA vere or nonexistent in females because females
can have various consequences for the struc- carry two X chromosomes.
ture of the protein coded for by the DNA. Some
of the genetic alterations affecting metabolism Diagnosis and Treatment
simply represent normal variation within the Significant progress has been made in the di-
population and are asymptomatic. An example agnosis of inborn errors of metabolism. Prior
of such a genetic alteration is the ability of to 1980, much of the diagnosis for metabolic
some individuals to experience a bitter taste af- defects relied on symptoms detected during
ter exposure to chemical derivatives of thio- clinical examination. Biochemical tests are used
urea. Some asymptomatic variations may lead to detect various substances that accumulate or
to complications after environmental condi- are missing when an enzymatic defect is pres-
tions are changed. There are a few inborn er- ent. The commonly used screening for phenyl-
rors that can be induced by certain drugs. An- ketonuria (PKU) relies on detection of phenyl-
other class of alterations may be minor, with the ketones in the blood of newborns. For cases in
resulting protein having some degree of func- which the genetic defect is known, DNA can of-
tion. Individuals with such alterations may live ten be used for the purpose of genetic testing.
long lives but will occasionally experience a Genetic counselors will help parents determine
range of problems associated with their condi- their chances of having a child with a severe de-
tions. Depending on the exact nature of the fect when parents are identified as carriers.
mutation, some of the alterations in the result- Small samples of cells can be used as a source of
ing protein structure can lead to a completely DNA, and such cells may even be obtained
nonfunctional protein or enzyme. Conse- from amniotic fluid by amniocentesis. This al-
quences of this type of mutation can be quite lows diagnosis to be made prenatally. Some par-
severe and may result in death. ents choose abortion when their fetus is diag-
Many of the inborn errors of metabolism are nosed with a lethal or debilitating defect.
inherited as autosomal recessive traits. Individ- Although strides have been made in diagno-
uals are born with two copies of the gene. If one sis, the problem of treatment still remains. For
copy is defective and the second copy is nor- some inborn errors of metabolism such as
mal, enough functioning protein or enzyme phenylketonuria, dietary modification will of-
can be made to prevent the individual from ex- ten prevent the serious symptoms of the disease
hibiting any symptoms of the disease. Such in- condition. Individuals with phenylketonuria
dividuals will be classified as carriers for the de- must limit their intake of the amino acid phe-
fect since they can pass on the defective gene to nylalanine during the critical stages of brain
their offspring. About one in twenty Cauca- development, generally the first eight years of
sians in the U.S. is a carrier for the cystic fibrosis life. Treatment of other inborn errors may in-
gene, and about one in thirty individuals of volve avoidance of certain environmental con-
Eastern Jewish descent carries the gene for the ditions. For example, individuals suffering
lethal Tay-Sachs disease. When an individual from albinism, a lack of pigment production,
inherits two defective copies of the gene, the must avoid the sun. For other inborn errors of
manifestations of the disease can be much metabolism, there are no simple cures on the
more severe. horizon. Since the early 1990s, some medical
Some inborn errors of metabolism such as pioneers have been involved in clinical trials of
Inbreeding and Assortative Mating 461
gene therapy, an attempt to replace a defective Scriver, Charles, et al., eds. The Metabolic and
gene by insertion of a normal, functioning ver- Molecular Bases of Inherited Disease. 8th ed. 4
sion. Although theoretically promising, gene vols. New York: McGraw-Hill, 2001. These
therapy has not met with significant success. In authoritative volumes on genetic inheri-
addition, there are many ethical issues raised tance, by some of the biggest names in the
when gene therapy trials are proposed before field, survey all aspects of genetic disease, in-
potential hazards have been completely elimi- cluding metabolic disorders. The eighth edi-
nated. Nevertheless, scientists are looking more tion has been thoroughly updated; more
and more toward genetic cures to genetic prob- than half of the contents are new.
lems such as those manifested as inborn errors
of metabolism. Web Sites of Interest
Barbara Brennessel Children Living with Inherited Metabolic Dis-
See also: Amniocentesis and Chorionic Vil- eases (CLIMB). http://www.climb.org.uk. A
lus Sampling; Biochemical Mutations; Com- national British organization supporting
plementation Testing; Cystic Fibrosis; Genetic families and research on a host of inherited
Screening; Genetic Testing; Genetics, Histori- metabolic disorders; includes information
cal Development of; Hereditary Diseases; Hun- and links to sites on specific disorders.
tingtons Disease; Phenylketonuria (PKU); Tay- Society for Inherited Metabolic Disorders.
Sachs Disease. http://www.simd.org. A nonprofit profes-
sional organization promoting worldwide
Further Reading advancement of research and medical treat-
Econs, Michael J., ed. The Genetics of Osteoporosis ment of inherited disorders of metabolism.
and Metabolic Bone Disease. Totowa, N.J.: Includes a searchable database of detailed
Humana Press, 2000. International experts descriptions and diagnoses for specific in-
discuss the genetic and molecular dimen- born errors.
sions of their own research into various as-
pects of the clinical features and pathophysi-
ology of metabolic bone disease.
Lee, Thomas F. The Human Genome Project: Inbreeding and Assortative
Cracking the Genetic Code of Life. New York: Ple- Mating
num Press, 1991. The diagnosis of inborn er-
rors of metabolism, development of molecu- Field of study: Population genetics
lar methods for diagnosis of these genetic Significance: Most population genetic models as-
defects, and prospects for treatment of these sume that individuals mate at random. One com-
conditions by gene therapy are highlighted mon violation of this assumption is inbreeding, in
within the context of the Human Genome which individuals are more likely to mate with rel-
Project. atives, resulting in inbreeding depression, a reduc-
ORahilly, S., and D. B. Dunger, eds. Genetic In- tion in fitness. Another violation of random mat-
sights in Paediatric Endocrinology and Metabo- ing is assortative mating, or mating based on
lism. Bristol, England: BioScientifica, 1999. phenotype. Many traits of organisms, including
Examines endocrine and metabolic diseases pollination systems in plants and dispersal in ani-
among infants, children, and adolescents. Il- mals, can be understood as mechanisms that re-
lustrated. duce the frequency of inbreeding and the cost of in-
Pacifici, O. G. M., Julio Collado-Vides, and Ralf breeding depression.
Hofestadt, eds. Gene Regulation and Metabo-
lism: Postgenomic Computational Approaches. Key terms
Cambridge: MIT Press, 2002. Explores cur- allele: any of a number of possible genetic
rent computational approaches to under- variants of a particular gene locus
standing the complex networks of metabolic assortative mating: mating that occurs when
and gene regulatory capabilities of the cell. individuals make specific mate choices
462 Inbreeding and Assortative Mating
based on the phenotype or appearance of which egg cell combine is expected to be unre-
others lated to the specific allele each gamete is carry-
heterozygote: a diploid genotype that con- ing, so the union is said to be random. In cases
sists of two different alleles in which males and females form pairs and pro-
homozygote: a diploid genotype that consists duce offspring, it is assumed that individuals
of two identical alleles find mates without reference to the particular
inbreeding: mating between genetically re- gene under examination. In humans, people
lated individuals do not choose potential mates at random, but
inbreeding depression: a reduction in the they do mate at random with respect to most
health and vigor of inbred offspring, a com- genetic variation. For instance, since few peo-
mon and widespread phenomenon ple know (or care) about the blood type of po-
random mating: a mating system in which tential partners, people mate at random with
each male gamete (sperm) is equally likely respect to blood-type alleles.
to combine with any female gamete (egg) Inbreeding and assortative mating are viola-
tions of this basic Hardy-Weinberg assumption.
Random Mating and the Hardy- For inbreeding, individuals are more likely to
Weinberg Law mate with relatives than with a randomly drawn
Soon after the rediscovery of Gregor Men- individual (for outbreeding, the reverse is
dels rules of inheritance in 1900, British math- true). Assortative mating occurs when individ-
ematician Godfrey Hardy and German physi- uals make specific mate choices based on the
cian Wilhelm Weinberg published a simple phenotype or appearance of others. Each has
mathematical treatment of the effect of sexual somewhat different genetic consequences.
reproduction on the distribution of genetic When either occurs, the Hardy-Weinberg pre-
variation. Both men published their ideas in dictions are not met, and the relative propor-
1908 and showed that there was a simple rela- tions of homozygotes and heterozygotes are
tionship between allele frequencies and geno- different from what is expected.
typic frequencies in populations. An allele is
simply a genetic variant of a particular gene; for The Genetic Effects of Inbreeding
example, blood type in humans is controlled by When relatives mate to produce offspring,
a single gene with three alleles (A, B, and O). the offspring may inherit an identical allele
Every individual inherits one allele for each from each parent, because related parents
gene from both their mother and father and share many of the same alleles, inherited from
has a two-allele genotype. In the simplest case their common ancestors. The closer the ge-
with only two alleles (for example, A and a), netic relationship, the more alleles two individ-
there are three different genotypes (AA, Aa, uals will share. Inbreeding increases the num-
aa). The Hardy-Weinberg predictions specify ber of homozygotes for a particular gene in a
the frequencies of genotypes (combinations of population because the offspring are more
two alleles) in the population: how many will likely to inherit identical alleles from both par-
have two copies of the same allele (homozy- ents. Inbreeding also increases the number of
gotes such as AA and aa) or copies of two differ- different genes in an individual that are homo-
ent alleles (heterozygotes such as Aa). zygous. In either case, the degree of inbreeding
One important assumption that underlies can be measured by the level of homozygosity
the Hardy-Weinberg predictions is that gametes (the percentage or proportion of homozygotes
(sperm and egg cells) unite at random to form relative to all individuals).
individuals or that individuals pair randomly to Inbreeding is exploited by researchers who
produce offspring. An example of the first case want genetically uniform (completely homozy-
is marine organisms such as oysters that release gous) individuals for experiments: Fruit flies or
sperm and eggs into the water; zygotes (fertil- mice can be made completely homozygous by
ized eggs) are formed when a single sperm repeated brother-sister matings. The increase
finds a single egg. Exactly which sperm cell and in the frequency of homozygotes can be calcu-
Inbreeding and Assortative Mating 463
Two children in the Indian state of Bihar in July, 2000. Many children in the area suffer from deformities. Activists blame uranium
mining in the area, whereas government officials blame inbreeding, malnutrition, and unsanitary conditions. (AP/Wide World
Photos)
lated for different degrees of inbreeding. Self- deleterious recessive alleles. These alleles pro-
fertilization is the most extreme case of in- duce negative consequences for the individual
breeding, followed by sibling mating, and so when homozygous, but when they occur in a
forth. Sewall Wright pioneered computational heterozygote, their negative effects are masked
methods to estimate the degree of inbreed- by the presence of the other allele. Because in-
ing in many different circumstances. For self- breeding increases the relative proportion of
fertilization, the degree of homozygosity in- homozygotes in the population, many of these
creases by 50 percent each generation. For alleles are expressed, yielding reduced health
repeated generation of brother-sister matings, and vigor. In some cases, the effects can be
the homozygosity increases by about 20 per- quite severe. For example, when researchers
cent each generation. wish to create homozygous lines of the fruit fly
Drosophila melanogaster by repeated brother-sis-
Inbreeding Depression ter matings, 90 percent or more of the lines fail
Inbreeding commonly produces inbreeding because of widespread genetic problems.
depression. This is characterized by poor
health, lower growth rates, reduced fertility, Assortative Mating
and increased incidence of genetic diseases. Al- In assortative mating, the probability of par-
though there are several theoretical reasons ticular pairings is affected by the phenotype of
why inbreeding depression might occur, the the individuals. In positive assortative matings,
major effects are produced by uncommon and individuals are more likely to mate with others
464 Inbreeding and Assortative Mating
of the same phenotype, while in negative assor- must often consider inbreeding depression. In
tative mating, individuals are more likely to very small populations such as species main-
mate with others that are dissimilar. In both tained in captivity (zoos) or in isolated natural
cases, the primary effect is to alter the expected populations, inbreeding may be hard to avoid.
genotypic frequencies in the population from Inbreeding has been blamed for a variety of
those expected under the Hardy-Weinberg law. health defects in cheetahs and Florida pan-
Positive assortative mating has much the same thers.
effect as inbreeding and increases the relative Paul R. Cabe
frequency of homozygotes. Negative assorta- See also: Consanguinity and Genetic Dis-
tive mating, as expected, has the opposite ef- ease; Genetic Load; Hardy-Weinberg Law; He-
fect and increases the relative proportion of redity and Environment; Hybridization and In-
heterozygotes. Positive assortative mating has trogression; Lateral Gene Transfer; Mendelian
been demonstrated for a variety of traits in hu- Genetics; Natural Selection; Polyploidy; Popu-
mans, including height and hair color. lation Genetics; Punctuated Equilibrium;
Quantitative Inheritance; Sociobiology; Speci-
Impact and Applications ation.
The widespread, detrimental consequences
of inbreeding are believed to shape many as- Further Reading
pects of the natural history of organisms. Many Avise, John, and James Hamrick, eds. Conserva-
plant species have mechanisms developed tion Genetics: Case Histories from Nature. New
through natural selection to increase outbreed- York: Chapman and Hall, 1996. Examines
ing and avoid inbreeding. The pollen (male ga- case studies of germ plasm resources and
mete) may be released before the ovules (fe- population genetics, focusing in one chap-
male gametes) are receptive, or there may be a ter on inbreeding in cheetahs and panthers.
genetically determined self-incompatibility to Hartl, Daniel. A Primer of Population Genetics.
prevent self-fertilization. In most animals, self- Rev. ed. Sunderland, Mass.: Sinauer Associ-
fertilization is not possible, and there are often ates, 2000. Covers genetic variation, the
behavioral traits that further reduce the proba- causes of evolution, molecular population
bility of inbreeding. In birds, males often breed genetics, and the genetic architecture of
near where they were born, while females dis- complex traits.
perse to new areas. In mammals, the reverse is Hedrick, Philip. Genetics of Populations. 2d ed.
generally true, and males disperse more widely. Boston: Jones and Bartlett, 2000. For those
Humans appear to be an exception among the with quantitative experience in the field, this
mammals, with a majority of cultures showing text integrates empirical and experimental
greater movement by females. These sex-biased approaches with theory, describing methods
dispersal patterns are best understood as mech- for estimating population genetics parame-
anisms to prevent inbreeding. ters as well as other statistical tools used for
In humans, individuals are unlikely to marry population genetics.
others with whom they were raised. This pre- Krebs, J., and N. Davies. An Introduction to Be-
vents the potentially detrimental consequences havioral Ecology. Malden, Mass.: Blackwell,
of inbreeding in matings with close relatives. 1991. Discusses inbreeding avoidance and
This has also been demonstrated in some birds. kin recognition.
Domestic animals and plants may become in- Laikre, Linda. Genetic Processes in Small Popula-
bred if careful breeding programs are not fol- tions: Conservation and Management Consider-
lowed. Many breeds of dogs exhibit a variety ations with Particular Focus on Inbreeding and
of genetic-based problems (for example, hip Its Effects. Stockholm: Division of Popula-
problems, skull and jaw deformities, and ner- tion Genetics, Stockholm University, 1996.
vous temperament) that are likely caused by Aimed at conservation biologists and ad-
inbreeding. Conservation biologists who man- dresses the management of inbreeding in
age endangered or threatened populations small populations. Illustrated.
Incomplete Dominance 465
Soul, Michael, ed. Conservation Biology: The Sci- Incomplete vs. Complete Dominance
ence of Scarcity and Diversity. Sunderland, Diploid organisms have two copies of each
Mass.: Sinauer Associates, 1986. Good dis- gene locus and thus two alleles at each locus.
cussions of inbreeding in birds and mam- Each locus can have either a homozygous geno-
mals, the effects of inbreeding depression in type (two of the same alleles, such as AA, aa, or
plants and animals, and issues related to the a+a+) or a heterozygous genotype (two different
conservation of natural heritage. alleles, such as Aa or a+a). The phenotype of an
Thornhill, Nancy Wilmsen, ed. The Natural His- organism that is homozygous for a particular
tory of Inbreeding and Outbreeding: Theoretical gene is usually easy to predict. If a pea plant has
and Empirical Perspectives. Chicago: Univer- two tall alleles of the height locus, the plant is
sity of Chicago Press, 1993. Researchers from tall; if a plant has two dwarf alleles of the height
several disciplines provide a comprehensive locus, it is small. The phenotype of a heterozy-
review of ideas and observations on natural gous individual may be harder to predict. In
inbreeding and outbreeding, among both most circumstances, one of the alleles (the
wild and captive populations. Illustrated. dominant) is able to mask or cover the other
(the recessive). The phenotype is determined
by the dominant allele, so a heterozygous pea
plant, with one tall and one dwarf allele, will be
tall. When Gregor Mendel delivered the results
Incomplete Dominance of his pea-plant experiments before the Natu-
Field of study: Classical transmission ral Sciences Society in 1865 and published
genetics them in 1866, he reported one dominant and
Significance: In most allele pairs, one allele is dom- one recessive allele for each gene he had stud-
inant and the other recessive; however, other rela- ied. Later researchers, starting with Carl
tionships can occur. In incomplete dominance, one Correns in the early 1900s, discovered alleles
allele can only partly dominate or mask the other. that did not follow this pattern.
Some very important human genes, such as the When a red snapdragon or four-oclock
genes for pigmentation and height, show incom- plant is crossed with a white snapdragon or
plete dominance of alleles. four-oclock, the offspring are neither red nor
white. Instead, the progeny of this cross are
pink. Similarly, when a chinchilla (gray) rabbit
Key terms is crossed with an albino rabbit, the progeny
allele: one of the alternative forms of a gene are neither chinchilla nor albino but an inter-
codominance: the simultaneous expression of mediate shade called light chinchilla. This phe-
two different (heterozygous) alleles for a nomenon is known as incomplete dominance,
trait partial dominance, or semidominance.
complete dominance: expression of an allele If the flower-color locus of peas is compared
for a trait in an individual that is heterozy- with the flower-color locus of snapdragons, the
gous for that trait, determining the pheno- differences and similarities can be seen. The
type of the individual two alleles in peas can be designated W for the
heterozygous: having two different alleles at purple allele and w for the white allele. Peas
a gene locus, often symbolized Aa or a+a that are WW are purple, and peas that are ww
homozygous: having two of the same alleles at are white. Heterozygous peas are Ww and ap-
a gene locus, often symbolized AA, aa, or a+a+ pear purple. In other words, as long as one
phenotype: the expression of a genotype, as dominant allele is present, enough purple pig-
observed in the outward appearance or bio- ment is made to make the plants flower color
chemical characteristics of an organism phenotype purple. In snapdragons, R is the red
recessive trait: a genetically determined trait allele and r is the white allele. Homozygous RR
that is expressed only if an organism receives plants have red flowers and rr plants have white
the gene for the trait from both parents flowers. The heterozygous Rr plants have the
466 Incomplete Dominance
same kind of red pigment as the RR plants but crossing two heterozygous individuals will pro-
not enough to make the color red. Instead, the duce the following results: Ww Ww 1 4WW +
less pigmented red flower is designated as pink. 1 Ww + 1 ww. Since both WW and Ww look the
2 4
Because neither allele shows complete domi- same, the 1 4WW and the 1 2Ww can be added to-
nance, other symbols are sometimes used. The gether to give 3 4 purple. In other words, when
red allele might be called cR or C1, while the two heterozygotes are crossed, the most com-
white allele might be called cW or C2. mon result is to have 3 4 of the progeny look like
the dominant and 1 4 look like the recessive
The Enzymatic Mechanism of Incomplete the standard 3:1 ratio. With incomplete domi-
Dominance nance, each genotype has its own phenotype,
To understand why incomplete dominance so when two heterozygotes are crossed (for ex-
occurs, metabolic pathways and the role of en- ample, Rr Rr), 1 4 of the progeny will be RR and
zymes must be understood. Enzymes are pro- look like the dominant (in this case red), 1 4 will
teins that are able to increase the rate of chemi- be rr and look like the recessive (in this case
cal reactions in cells without the enzymes white), but 1 2 will be Rr and have an intermedi-
themselves being altered. Thus an enzyme can ate appearance (in this case pink)a 1:2:1 ratio.
be used over and over again to speed up a par-
ticular reaction. Each different chemical re- Codominance
action in a cell needs its own enzyme. Each One type of inheritance that can be con-
enzyme is composed of one or more polypep- fused with incomplete dominance is codomi-
tides, each of which is coded by a gene. Look- nance. In codominance, both alleles in a heter-
ing again at flower color in peas, the W allele ozygote are expressed simultaneously. Good
codes for an enzyme in the biochemical path- examples are the A and B alleles of the human
way for production of purple pigment. When- ABO blood system. ABO refers to chemicals, in
ever a W allele is present, this enzyme is also this case short chains of sugars called antigens,
present. The w allele has been changed (mu- that can be found on the surfaces of cells.
tated) in some way so that it no longer codes Blood classified as A has A antigens on the sur-
for a functional enzyme. Thus ww plants have face, B blood has B antigens, and AB blood has
no functional enzyme and cannot produce any both A and B antigens. (O blood has neither A
purple pigment. Since many biochemicals such nor B antigens on the surface.)
as fibrous polysaccharides and proteins found Genetically, individuals that are homozy-
in plants are opaque white, the color of a ww gous for the A allele, I AI A, have A antigens on
flower is white by default. In a Ww plant, there is their cells and are classified as type A. Those
only one copy of the allele for a functional en- homozygous for the B allele, I BI B, have B anti-
zyme. Since enzymes can be used over and over gens and are classified as type B. Heterozygotes
again, one copy of the functional allele pro- for these alleles, I AI B, have both A and B anti-
duces sufficient enzyme to make enough pig- gens and are classified as type AB. This is called
ment for the flower to appear purple. In snap- codominance because both alleles are able to
dragons the R allele, like the W allele, codes produce enzymes that function. When both en-
for a functional enzyme, while the r allele does zymes are present, as in the heterozygous I AI B
not. The difference is in the enzyme coded by individual, both antigens will be formed. The
the R allele. The snapdragon enzyme is not progeny ratios are the same for codominance
very efficient, which leads to a deficiency in the and incomplete dominance, because each ge-
amount of red pigment. Flowers with the re- notype has its own phenotype.
duced amount of red pigment appear pink. Whether an allele is called completely domi-
nant, incompletely dominant, or codominant
Phenotypic Ratios often depends on how the observer looks at the
Phenotypic ratios in the progeny from con- phenotype. Consider two alleles of the hemo-
trolled crosses are also different than for sim- globin gene: H A (which codes for normal he-
ple Mendelian traits. For Mendelian traits, moglobin) and H S (which codes for sickle-cell
Incomplete Dominance 467
hemoglobin). To the casual observer, both AAbbccddee, aaBbccDdee, and other individuals
H AH A homozygotes and H AH S heterozygotes with two incompletely dominant alleles at 20
have normal-appearing blood. Only the H SH S percent above the minimum; all the way up to
homozygote shows the sickling of blood cells AABBCCDDEE individuals that show the maxi-
that is characteristic of the disease. Thus H A is mum (100 percent above the minimum)
dominant to H S. Another observer, however, height. The greater the number of genes with
may note that under conditions of oxygen incompletely dominant alleles that affect a
deprivation, the blood of heterozygotes does phenotype, the more the distribution of phe-
sickle. This looks like incomplete dominance. notypes begins to look like a continuous distri-
The phenotype is intermediate between never bution. Human skin, hair, and eye pigmenta-
sickling, as seen in the normal homozygote, tion phenotypes are also determined by the
and frequently sickling, as seen in the H SH S ho- additive effects of several genes with incom-
mozygote. A third way of observing, however, pletely dominant alleles.
would be to look at the hemoglobin itself. In
normal homozygotes, all hemoglobin is nor- Incomplete Dominance and Sex Linkage
mal. In H SH S homozygotes, all hemoglobin is In many organisms, sex is determined by the
abnormal. In the heterozygote, both normal presence of a particular combination of sex
and abnormal hemoglobin is present; thus, the chromosomes. Human females, for example,
alleles are codominant. have two of the same kind of sex chromosomes,
called X chromosomes, so that all normal hu-
Incomplete Dominance and Polygenes man females have the XX genotype. Human
In humans and many other organisms, sin- males have two different sex chromosomes;
gle characteristics are often under the genetic thus, all normal human males have the XY ge-
control of several genes. Many times these notype. The same situation is also seen in the
genes function in an additive manner so that a fruit fly Drosophila melanogaster. When genes
characteristic such as height is not determined with incompletely dominant alleles are located
by a single height gene with just two possible al- on the X chromosome, only the female with
ternatives, as in tall and dwarf peas. There can her two X chromosomes can show incomplete
be any number of these genes that determine dominance. The apricot (w a) and white (w) al-
the expression of a single characteristic, and leles of the eye color gene in D. melanogaster are
very often the alleles of these genes show in- on the X chromosome, and w a is incompletely
complete dominance. dominant to w. Male flies can have either of two
Suppose one gene with an incompletely genotypes, w aY or wY, and appear apricot or
dominant allele determined height. Three ge- white, respectively. Females have three possible
notypes of height could exist: HH, which codes genotypes: w a w a, w a w, and ww. The first is apri-
for the maximum height possible (100 percent cot and the third is white, but the second geno-
above the minimum height), Hh, which codes type, waw, is an intermediate shade often called
for 50 percent above the minimum height, and light apricot.
hh, which codes for the minimum height. If two In birds and other organisms in which the
height genes existed, there would be five possi- male has two of the same kind of sex chromo-
ble heights: AABB (maximum height); AaBB or somes and the female has the two different sex
AABb (75 percent above minimum); AAbb, chromosomes, only the male can show incom-
AaBb, or aaBB (50 percent above minimum); plete dominance. A type of codominance can
Aabb or aaBb (25 percent above minimum); also be seen in genes that are sex linked. In do-
and aabb (minimum). If there were five genes mestic cats, an orange gene exists on the X
involved in height, there would be aabbccddee chromosome. The alleles are orange (XO) and
individuals with minimum height; Aabbccddee, not orange (X+). Male cats can be either black
aaBbccddee, and other individuals having geno- (or any color other than orange, depending on
types with only one of the incompletely domi- other genes that influence coat color) when
nant alleles at 10 percent above the minimum; they are X+Y, or they can be orange (or light or-
468 Infertility
X, and pentasomy. These syndromes are the fe- tersection of biology, the environment, and
male counterparts of Klinefelter syndrome and culture.
can be associated with mental retardation. Jansen, Robert, and D. Mortimer, eds. Towards
At least 60 percent of miscarriages or preg- Reproductive Certainty: Fertility and Genetics Be-
nancy losses are caused by chromosomal ab- yond 1999. Boca Raton, Fla.: CRC Press,
normalities. Most babies with these abnormali- 1999. Surveys the status of conception in
ties would not survive even if they were born. controlled circumstances outside the body,
Chromosomal problems are more common if including ethical, medical, and psychologi-
the mother is older and has a history of requir- cal considerations.
ing longer than a year to conceive. Men who Lewis, Ricki. Human Genetics: Concepts and Ap-
are older or who have a history of being sub- plications. 5th ed. New York: McGraw-Hill,
fertile can also contribute to genetic abnormal- 2003. An introductory text for undergradu-
ities. After the age of thirty-five, the structure ates with sections on fundamentals, trans-
within a womans eggs is more likely to become mission genetics, DNA and chromosomes,
damaged. Men over the age of forty-five have population genetics, immunity and cancer,
an increased risk of damage to the structure of and the latest genetic technology.
the chromosomes in their sperm. McElreavey, Ken, ed. The Genetic Basis of Male In-
Scientists believe that as their understand- fertility. New York: Springer, 2000. Explores
ing of the genetic basis of infertility problems medical progress in understanding the ge-
increases, new therapies will be developed to netics of spermatogenesis and male infertil-
treat them. Most infertility cases are treated ity. Illustrated.
with drugs or surgery to repair the reproduc- Marrs, Richard, et al. Dr. Richard Marrs Fertility
tive organs. No treatment is available to correct Book. New York: Dell, 1997. Covers advances
sex chromosomal abnormalities such as Turner in reproductive technology, how emotions
syndrome. However, some women with Turner can delay or stop ovulation, male sperm
syndrome can have children. For women who count that is borderline or subnormal, which
cannot conceive, possible procedures include fertility drugs work best and the associated
in vitro fertilization (fertilizing a womans egg side effects, chances of multiple births, and
with sperm outside the body) and embryo trans- when to change doctors or see a specialist.
fer (moving the fertilized egg into a womans Rosenthal, M. Sara. The Fertility Sourcebook: Ev-
uterus). Adoption is another option for infer- erything You Need to Know. 2d ed. Los Angeles:
tile men and women. Lowell House, 1998. Addresses advances in
Fred Buchstein fertility treatments, including issues for same-
See also: Amniocentesis and Chorionic Vil- sex partners, ethical considerations, and ba-
lus Sampling; Cloning; Genetic Counseling; sic information about treatment options.
Genetic Screening; Genetic Testing; Genetic
Testing: Ethical and Economic Issues; Heredi- Web Sites of Interest
tary Diseases; In Vitro Fertilization and Embryo American Association of Reproductive Medi-
Transfer; Prenatal Diagnosis; Stem Cells; Steril- cine. http://www.asrm.org. Site includes in-
ization Laws; Totipotency; Turner Syndrome; formation on infertility and reproduction.
X Chromosome Inactivation; XYY Syndrome. International Council on Infertility Informa-
tion Dissemination. http://www.inciid.org.
Further Reading Site provides fact sheets on in vitro fertil-
Bentley, Gillian R., and C. G. Nicholas Mascie- ization.
Taylor. Infertility in the Modern World: Present National Institutes of Health, National Libary
and Future Prospects. New York: Cambridge of Medicine. http://www.nlm.nih.gov/
University Press, 2000. Discusses changes in medlineplus/infertility.html. Provides in-
human reproduction brought on by the in- formation on all aspects of infertility.
Insurance 471
are possible as cases like these become more tions for which no effective preventive treat-
common. They could choose to cover prophy- ment exists. Alzheimers disease provides a par-
lactic treatments as a way to cut long-term costs ticularly poignant example. As of the late
associated with development of the genetic dis- 1990s, the connection between genes identi-
ease, or they could choose to exclude such con- fied as appearing in some early-onset Alzhei-
ditions under a preexisting condition argu- mers disease patients and the disease itself was
ment. So far the trend has been toward trying still unclear. People who underwent genetic
to exclude treatment, by the latter approach, screening to discover if they carried that partic-
including considering the later development ular genetic marker could spend many decades
of the full-blown disease as a preexisting condi- worrying needlessly about their own risk of de-
tion. This is a disturbing trend, as it would tend veloping Alzheimers disease while knowing
to discourage genetic screening, ruining the that there was no way to prevent it. At the same
opportunity for preventive measures. If the time, the identification of the genetic marker
courts decide to require that insurers must would have identified the patient as a high risk
fund prophylactic or preventive treatments, for medical insurance. Huntingtons disease
then another quandary occurs: At what per- represents an even more serious case, in which
centage predisposition will insurers be re- the test is nearly 100 percent predictive. A posi-
quired to cover the costs? A predisposition of tive test is essentially a guaranteed prediction
50 percent seems like a reasonable number, but of early death. Tests like these may provide no
what about 45 percent, also high? Covering any benefit to affected individuals, and may even
level of predisposition would be unreasonable, cause harm if the information is freely available
as it would bankrupt the system, so a line must to insurers.
be drawn, but where? Much more information On the other hand, in some cases the bene-
will be needed before such lines can be drawn fits of genetic screening may outweigh its po-
without being arbitrary. tential costs. For example, certain cancers have
In the case of degenerative disorders such as long been recognized as running in some fami-
Alzheimers disease or Huntingtons disease, lies. Doctors routinely counsel women with a
for which there is no prophylactic treatment family history of breast cancer to have annual
available, patients may live for many years fol- mammograms and even, in cases where the risk
lowing the initial diagnosis of the disease while seems particularly high, to undergo prophylac-
they become progressively more helpless and tic mastectomy or lumpectomy. The discovery
eventually require extended hospitalization or of genetic markers for breast cancer suggests
custodial care. An insurance company that that women who are concerned that they are at
wrote plans to cover nursing-home care could higher-than-average risk for the disease can al-
decide to exclude people identified as carrying lay their fears through genetic screening rather
a gene putting them at risk of developing Alz- than subjecting themselves to disfiguring sur-
heimers disease. The insurance companys rea- gery. Still, the very act of screening could be-
soning would be that because Alzheimers suf- come a double-edged sword. A positive test not
ferers may require many more years of custodial only would confirm a womans worst fears but
care than the average nursing-home resident, it also could result in her being denied high in-
would be unprofitable to insure known future surance coverage. Many patients with a high-
Alzheimers sufferers. Such people would be risk family profile fear that even if the screen-
seen as simply being too high-risk. ing turns out negative, simply requesting the
A number of geneticists and other analysts test will serve as a flag to health insurers, and
have suggested that another inherent difficulty they, too, will be assessed higher premiums or
with genetic screening is that it opens the door denied coverage based on their family histories.
for possible restriction of access to health insur- In a climate of rising medical costs and ef-
ance while not holding out any hope of a treat- forts by both traditional insurance providers
ment or cure for the patient. It is now possible and health maintenance organizations to re-
to detect the genetic markers for many condi- duce expenses, many people feel there is good
Insurance 473
reason to fear that genetic screening will serve sions of hiring and continued employment.
primarily as a tool to restrict access to health However, in an op-ed piece for The Wall Street
insurance. In response to these concerns, a Journal (December 20, 2002), William R.
number of government studies have been un- Brody, president of The Johns Hopkins Univer-
dertaken to assess potential remedies. Some sity, sounded an ominous yet potentially posi-
possible solutions include making the results of tive note. In view of the inevitable discovery
all genetic tests confidential, available to insur- that nearly all disease conditions have some ge-
ers and employers only with permission from netic basis, he predicted that, given the diffi-
the individual; passing laws that prohibit dis- culty private insurers will soon face in discrimi-
crimination of individuals with genetic pre- nating among conditions, they might also be
dispositions by insurers and employers; and facing their own demise as medical insurers:
universal health coverage with clearly defined
guidelines based on extensive research. A num- If legislatures pass laws banning insurers from us-
ber of states have already enacted laws prohibit- ing genetic screening data, those companies will
ing insurance companies from denying cover- protect themselves by continually raising premi-
age to individuals with genetic defects. It is also ums to consumers. Some may even go bankrupt
because purchasers of insurance will be the more
possible that the Americans with Disabilities
knowledgeable in the transaction. Yet if we allow
Act could be cited against genetic discrimina- insurers to use genetic data, many more individ-
tion. uals will be left without coverage because they
will be deemed too high-risk to warrant insur-
Impact of Medical Genomics ance at affordable prices. Given this conun-
With the mapping of the human genome drum, there is only one solution that can pre-
completed in 2003, it suddenly became clear serve the concept of health insurance: universal
that nearly all human diseasefrom complex coverage.
chronic conditions such as cancer, Alzhei-
mers, and diabetes to the predisposition for in- Based on the concept of community rating,
fectious disease and even traumahas some such coverage would spread risk across a large
genetic basis. Although genome sequences are group of individuals (now confined to smaller
essentially the same among all individuals, groups), and hence cost would spread across a
what variation there is accounts for many of the national pool, allowing individual traits and
differences in disease susceptibility and other hence risks to be diluted. Brody predicts that
health-related differences. All of this has made that day is coming sooner than many people
the drive to study human genomics as it affects imagine.
human health a burgeoning new field, medical Nancy Farm Mnnikk and Bryan Ness
genomics, that promises to affect every medi- See also: Aging; Alzheimers Disease; Bio-
cal field. The basis for this discipline will be ethics; Bioinformatics; Breast Cancer; Congen-
data gleaned from large, well-designed and ital Defects; Eugenics; Eugenics: Nazi Ger-
controlled clinical studies that are being devel- many; Forensic Genetics; Gene Therapy; Gene
oped and implemented in several nations to Therapy: Ethical and Economic Issues; Genetic
provide information on how genes influence a Counseling; Genetic Screening; Genetic Test-
wide range of traits, from disease states to be- ing; Genetic Testing: Ethical and Economic Is-
havior. sues; Genomic Libraries; Genomics; Hereditary
Given the dangers outlined above, it would Diseases; Human Genetics; Icelandic Genetic
seem that such studies pose an increased con- Database; Prenatal Diagnosis; Race; Sickle-Cell
cern regarding issues of privacy, discrepancies Disease; Sterilization Laws.
in access to health care, and even threats to in-
dividuals jobs, as more and more employers Further Reading
have been forced to self-insureessentially Brody, William R. A Brave New Insurance.
becoming insurers themselves and thus being The Wall Street Journal, December 20, 2002. In
forced to consider employees health in deci- this op-ed article, Brody addresses the im-
474 Intelligence
pact that swift progress and refinement of garding genetic testing and does so in an
genetic screening and testing will have on easy-to-understand way.
the insurance industry in the United States.
Hubbard, Ruth, and Elijah Wald. Exploding the Web Site of Interest
Gene Myth: How Genetic Information Is Produced National Human Genome Research Institute,
and Manipulated by Scientists, Physicians, Em- Health Insurance in the Age of Genetics.
ployers, Insurance Companies, Educators, and http://www.nhgri.nih.gov/news/insurance.
Law Enforcers. Boston: Beacon Press, 1999. Discusses the need for health insurance reg-
Argues against genetic determinism and ulation at the federal level to prevent dis-
biotechnology and attacks scientists who cite crimination against individuals because of
DNA sequences as the presumed basis for a their genetic makeup.
genetic tendency to cancer, high blood pres-
sure, alcoholism and criminal behavior.
Orin, Rhonda D. Making Them Pay: How to Get
the Most from Health Insurance and Managed Intelligence
Care. New York: St. Martins Press, 2001. A
consumer guide to health insurance and Field of study: Human genetics and social
managed care programs that explains how issues
to read and understand a health plan and Significance: The study of the genetic basis of intel-
how to work with insurance companies to ligence is one of the most controversial areas in hu-
get the benefits to which one is entitled. man genetics. Researchers generally agree that
Rifkin, Jeremy. The Biotech Century: Harnessing mental abilities are genetically transmitted to some
the Gene and Remaking the World. New York: extent, but there is disagreement over the relative
Jeremy P. Tarcher/Putnam, 1998. Discusses roles of genes and environment in the development
a variety of concerns regarding biotechnol- of mental abilities. There is also disagreement over
ogy and shows how genetic screening fits whether different mental abilities are products of a
into a much wider area of debate in modern single ability known as intelligence and disagree-
science. ment over how to measure intelligence.
U.S. Congress. Senate. Committee on Health,
Education, Labor, and Pensions. Fulfilling the Key terms
Promise of Genetics Research: Ensuring Nondis- dizygotic organism: an organism developed
crimination in Health Insurance and Employment. from two separate ova; fraternal twins are di-
Washington, D.C.: Government Printing Of- zygotic
fice, 2001. Committee formed to explore intelligence quotient (IQ): the most com-
possible connections between genetics re- mon measure of intelligence; it is based on
search and health insurance and job dis- the view that there is a single capacity for
crimination, and to ensure against discrimi- complex mental work and that this capacity
nation in these areas. can be measured by testing
_______. Protecting Against Genetic Discrimina- monozygotic organism: developed from a
tion: The Limits of Existing Laws. Washington, single ovum (egg); identical twins are mono-
D.C.: U.S. Government Printing Office, zygotic because they originate in the womb
2002. Examines existing laws and proposed from a single fertilized ovum that splits in two
legislation to prevent genetic discrimination psychometrician: one who measures intellec-
in the form of health insurance loss or de- tual abilities or other psychological traits
nial or losing ones job.
Zallen, Doris Teichler. Does It Run in the Family? Evidence for Genetic Links to Intelligence
A Consumers Guide to DNA Testing for Genetic Much of the research into the connection
Disorders. New Brunswick, N.J.: Rutgers Uni- between genes and intelligence has focused on
versity Press, 1997. Provides readers with the attempting to determine the relative roles of bi-
knowledge they need to make decisions re- ological inheritance and social influence in de-
Intelligence 475
A genetically engineered smart mouse performs a learning and memory test. Researchers hope to find causes and cures for Alzheimers
disease, and possibly ways to increase human intelligence. (AP/Wide World Photos)
veloping intelligence. Such attempts have usu- they will be in intelligence. Studies have indi-
ally involved a combination of four methods: cated that fraternal twins are only slightly more
associations of parental intelligence with the similar to each other than are nontwin siblings.
intelligence of offspring, associations of the in- Identical twins, developing from a single egg
telligence of siblings (brothers and sisters), with identical genetic material, have even more
comparisons of dizygotic (fraternal) twins and in common. Bouchard and McGue found that
monozygotic (identical) twins, and adoption there was an overlap of about 74 percent in the
studies. intellectual abilities of identical twins and an
To the extent that mental qualities are inher- overlap of about 36 percent in the intellectual
ited, one should expect blood relatives to share abilities of fraternal twins.
these qualities with each other more than with Family members may be similar because
nonrelatives. In an article published in 1981 in they live in similar circumstances, and identical
the journal Science, T. J. Bouchard, Jr., and Matt twins may be similar because they receive
McGue examined studies that looked at statisti- nearly identical treatment. However, studies of
cal relationships of intellectual abilities among adopted children show that the intellectual
family members. These studies did reveal abilities of these children were more closely re-
strong associations between mental capacities lated to those of their biological parents than to
of parents and children and strong associations those of their adoptive parents. Studies of iden-
among the mental capacities of siblings. Fur- tical twins who were adopted and raised apart
ther, if genes are involved in establishing men- from each other indicate that these twins have
tal abilities, one should expect that the more about 62 percent of their intellectual abilities
genes related people share, the more similar in common.
476 Intelligence
Twin studies, in particular, have helped to es- tent to which general intellectual ability may
tablish that heredity is involved in a number of be genetic in character. Intelligence quotient
intellectual traits. Memory, number ability, per- (IQ), the measure of intelligence most com-
ceptual skills, psychomotor skills, fluency in monly used to study genetic links to intellectual
language use, and proficiency in spelling are ability, is based on the view that there is a great
only a few of the traits in which people from deal of overlap among various mental traits. Al-
common genetic backgrounds tend to be simi- though a given individual may be skilled at mu-
lar to each other. However, psychometricians sic or writing and poor at mathematics, on the
have not reached agreement on the extent to average, people who are proficient in one area
which mental abilities are products of genes also tend to be talented in other areas. Propo-
rather than of environmental factors such as nents of IQ measures argue that this overlap ex-
upbringing and opportunity. Some researchers ists because there is a single, underlying, gen-
estimate that only 40 percent of intellectual eral intelligence that affects how people score
ability is genetic; others set the estimate as high on tests of various kinds of mental abilities. The
as 80 percent. opponents of IQ measures counter that even
It is important to keep in mind that even if if one can speak of intelligence rather than
most differences in mental abilities among hu- intelligences, it is too complex to be reduced
man beings were caused by genetics, members to one number.
of families would still show varied abilities. If,
for example, there is a gene for high mathe- Impact and Applications
matical ability (gene A) and a gene for low The passing of mental abilities from parents
mathematical ability (gene a), it is quite possi- to children by genetic inheritance is a politi-
ble that a woman who has inherited each gene cally controversial issue because genetic theo-
(Aa) from her parents will marry a man who ries of intelligence may be used to justify exist-
has inherited each gene (Aa) from his parents. ing social inequalities. Social and economic
In this case, there is a 1 in 4 probability that they inequalities among racial groups, for example,
will have a child who is mathematically gifted have been explained as differences among
(AA) and a 1 in 4 probability that they will have groups in inherited intelligence levels. During
a child who is mathematically slow (aa). This the nineteenth century, defenders of slavery
example, although grossly simplified, gives an claimed that black slaves were by nature less in-
idea of the effect of variation in the genes in- telligent than the white people who held them
herited. in slavery. After World War I, the Princeton
University psychologist C. C. Brigham con-
The Problem of Defining and Measuring cluded from results of army IQ tests that south-
Intelligence ern European immigrants had lower levels of
Debates over genetic links to intelligence inherited intelligence than native-born Ameri-
are complicated by the problem of precisely de- cans and that blacks had even more limited
fining and accurately measuring intelligence. intelligence. White supremacists and segrega-
It may be that abilities to build houses, draw, tionists used Brighams results to justify limit-
play music, or understand complex mathemat- ing the access of blacks to higher education
ical procedures are inherited as well as learned. and other opportunities for advancement. In
Which of these abilities, however, constitute in- 1969, Berkeley psychologist Arthur R. Jensen
telligence? Because of this debate, some people, touched off a storm of debate when he pub-
such as Harvard psychologist Howard Gardner, lished an article that suggested that differences
have argued that there is no single quality of in- between black and white children in educa-
telligence but rather multiple forms of intelli- tional success were caused in part by genetic
gence. variations in mental ability.
If there is no single ability that can be la- Wealth and poverty, even within racial and
beled intelligence, this means that one can- ethnic groups, have been explained as conse-
not measure intelligence or determine the ex- quences of inherited intelligence. Harvard psy-
Intelligence 477
chologist Richard Herrnstein and social critic can social system and a genetically limited
Charles Murray have argued that American so- lower class at the bottom.
ciety has become a competitive, information- Scientific truth cannot be established by ac-
based society in which intellectual ability is the cusing theories of being inconvenient for so-
primary basis of upward mobility. They have cial policies of equal opportunity. Neverthe-
maintained, furthermore, that much of intel- less, it is not clear that genetic differences in
lectual ability is genetic in character and that intelligence are necessarily connected to so-
people tend to marry and reproduce within cial status. Even those who believe that inher-
their own social classes. Therefore, in their ited intelligence affects social position gener-
view, social classes also tend to be intellectual ally recognize that social status is affected by
classes: a cognitive elite at the top of the Ameri- many other factors such as parental wealth, ed-
Genetics and IQ
The genetics of intelligence continues to prompt aration, and divorce have all been shown to influ-
controversy and often emotional debate centering ence the development of intelligence by as much as
on the relative roles of genetics and environment in 40 percent, leading some environmentalists and so-
shaping intelligence and multiple intelligence. The ciologists to claim that culture is the major factor in
dictionary defines intelligence as the capacity to ac- intelligence. It is precisely because of the influence
quire knowledge, process information by reasoning, of such environmental factors in shaping intelli-
and make rational decisions. It follows that some in- gence that performance gains can be increased
dividuals may have a greater facility for acquiring somewhat.
and analyzing information than others. Even the Support for the genetic contribution to intelli-
concept of multiple intelligence implies that some gence comes primarily from studies of identical and
individuals are more intelligent than others. This is fraternal twins, siblings, and family groupings. For
not to say, however, that individuals with a higher example, the correlation of intelligence between
level of intelligence will always be more successful identical twins (monozygotic twins) reared together
while individuals with lower levels of intelligence will is consistently well over 0.8 (1.0 being the highest
always be failures. That is, the abilities conferred by correlation), with highest scores measured at 0.86.
higher levels of inherited intelligence are probabi- Scores of fraternal (dizygotic) twins and siblings are
listic rather than determinate and are shaped by lower but still higher than less closely related kin
many factors other than genetics alone. such as cousins and uncles. Furthermore, intelli-
Out of the enormous amount of debate certain gence measures of adopted siblings show lower cor-
facts have emerged about the inheritance of intelli- relations compared to intelligence correlations be-
gence in humans. First, geneticists, behavioral genet- tween or among natural siblings. Thousands of such
icists, and neurobiologists have consistently demon- data have led most authorities to suggest that be-
strated that there is a significant genetic contribution tween 40 and 80 percent of an individuals intelli-
to intelligence, although the exact genes that code gence is shaped by genetics.
for intelligence have not yet been discovered. Em- The basic genetic mechanisms underlying these
bedded within this inheritance pattern, however, is observations are not, as yet, well understood. Geneti-
the undeniable and at times substantial contribution cists, behavioral geneticists, and neurobiologists ar-
of the social environment in development of intelli- gue that genes code for brain size, number of brain
gence in individuals. cells, and number of connections, all of which proba-
The role of environment in shaping intelligence bly play roles in determining intellectual ability,
has also been consistently demonstrated to be a vital though the relative contributions of each remain
factor in shaping intelligence. This is most clearly unclear. Further evidence for the role of genetics
shown where environmental factors adversely influ- comes from cases of chromosomal deletions, tri-
ence growth and development of the central ner- somy, and other genetic abnormalities.
vous system. Low birth rate, anoxia, malnutrition, Dwight G. Smith
childhood trauma, income, occupation, parent sep-
478 Intelligence
ucational opportunity, and cultural attitudes. Fish, Jefferson M., ed. Race and Intelligence: Sepa-
It seems evident that there are genetic links rating Science from Myth. Mahwah, N.J.: Law-
to mental ability. At the same time, however, rence Erlbaum, 2002. An interdisciplinary
the extent to which genes shape intellectual ca- collection disputing race as a biological cate-
pacities, whether these capacities should be gory and arguing that there is no general or
combined into one dimension called intelli- single intelligence and that cognitive ability
gence, and the validity of measures of intelli- is shaped through education. Bibliography,
gence remain matters of debate. The scientific index.
debate, moreover, is difficult to separate from Fraser, Steven, ed. The Bell Curve Wars: Race,
social and political debates. Intelligence, and the Future of America. New
Carl L. Bankston III York: Basic Books, 1995. Brief, critical re-
See also: Aging; Biological Determinism; sponse to the book by Herrnstein and Mur-
Chromosome Mutation; Congenital Defects; ray by scholars from a variety of disciplines
Criminality; Developmental Genetics; Down and backgrounds. Bibliography.
Syndrome; Eugenics; Eugenics: Nazi Germany; Gardner, Howard. Frames of Mind: The Theory of
Fragile X Syndrome; Genetic Counseling; Ge- Multiple Intelligences. 10th anniversary ed.
netic Screening; Genetic Testing; Genetic Test- New York: Basic Books, 1993. Argues that
ing: Ethical and Economic Issues; Hereditary there is no single mental ability to be inher-
Diseases; Heredity and Environment; Human ited. New introduction, bibliography, index.
Genetics; Human Growth Hormone; Kline- Gould, Stephen Jay. The Mismeasure of Man.
felter Syndrome; Nondisjunction and Aneu- New York: Norton, 1996. An influential criti-
ploidy; Phenylketonuria (PKU); Prader-Willi cism of IQ as a measure of intelligence and
and Angelman Syndromes; Prenatal Diagnosis; of the idea that intellectual abilities are in-
Race; Twin Studies; X Chromosome Inactiva- herited. Bibliography, index.
tion; XYY Syndrome. Herrnstein, Richard J., and Charles Murray.
The Bell Curve: Intelligence and Class Structure
Further Reading in America. New York: Free Press, 1994. The
Bock, Gregory R., Jamie A. Goode, and Kate authors maintain that IQ is a valid measure
Webb, eds. The Nature of Intelligence. New of intelligence, that intelligence is largely a
York: John Wiley & Sons, 2001. Presents the product of genetic background, and that dif-
debate between evolutionary psychologists, ferences in intelligence among social classes
who argue against general intelligence and play a major part in shaping American soci-
for an intelligence that develops and evolves ety. Illustrations, bibliography, index.
based on particular, extraspecies domains, Heschl, Adolf. The Intelligent Genome: On the Ori-
and behavior geneticists, who believe gen- gin of the Human Mind by Mutation and Selec-
eral intelligence is fundamental and who fo- tion. Drawings by Herbert Loserl. New York:
cus their work on intraspecies differences. Il- Springer, 2002. Chapters include Learning:
lustrations, bibliography, index. Appearances are Deceptive, The Wonder
Cooper, Colin. Intelligence and Abilities. New of Language, How to Explain Conscious-
York: Routledge, 1999. Discusses the origins ness, and The Cultural Struggle of Genes.
of intelligence and the question of genes ver- Scientific American 9, no. 4 (Winter, 1998). A spe-
sus environment in determining intellectual cial issue on Exploring Intelligence.
abilities. Illustrations, bibliography, index.
Devlin, Bernie, et al. Intelligence, Genes, and Suc- Web Site of Interest
cess: Scientists Respond to The Bell Curve. New Human Genome Project Information, Behav-
York: Springer, 1997. Presents a scientific ioral Genetics. http://www.ornl.gov/tech
and statistical reinterpretation of The Bell resources/human_genome/elsi/behavior
Curves claims about the heritability of intel- .html. Behavioral genetics information that
ligence and about IQ and social success. Bib- includes the study of the genetic basis of in-
liography, index. telligence.
Klinefelter Syndrome male. Sometimes Klinefelter syndrome is the
Field of study: Diseases and syndromes result of mosaicism, with males having both
Significance: Klinefelter syndrome is a sex chromo- normal (XY) karyotypes in some cells and ab-
some disorder in which males have an extra X normal karyotypes (usually with an extra X
chromosome. It accounts for ten out of every one chromosome) in others. Individuals with sex
thousand institutionalized mentally retarded chromosome complements of XXYY, XXXY, or
adults in industrialized nations and is one of the XX can also be diagnosed with Klinefelter syn-
more common chromosomal aberrations. drome. Individuals with Klinefelter syndrome
that have a sex chromosome complement of
Key terms XX are male because although an entire Y
azoospermia: the absence of spermatozoa chromosome is not present, a portion of a Y
from the semen chromosome is often attached to another chro-
cytogenetics: the study of chromosome num- mosome. This condition can sometimes be di-
ber and structure, including identification agnosed by a careful karyotype analysis.
of abnormalities
gynecomastia: a condition characterized by Signs and Symptoms
abnormally large mammary glands in the The classic type of Klinefelter syndrome usu-
male that sometimes secrete milk ally becomes apparent at puberty, when the sec-
hypogonadism: a condition resulting in ondary sex characteristics develop. The testes
smaller than normal testicles in males fail to mature, causing primary hypogonad-
karyotype: a pictorial or verbal description of ism. In this classic type, degenerative testicular
the chromosomes of a single cell changes begin that eventually result in irrevers-
mosaicism: a condition in which an individual ible infertility. Gynecomastia is often present,
has two or more cell populations derived and it is usually associated with learning disabil-
from the same fertilized ovum, or zygote, as ities, mental retardation, and violent, antisocial
in sex chromosome mosaics in which some behavior. Other common symptoms include
cells contain the usual XY chromosome pat- abnormal body proportions (disproportionate
tern and others contain extra X chromo- height relative to arm span), chronic pulmo-
somes nary disease, varicosities of the legs, and diabe-
tes mellitus (which occurs in 8 percent of those
Definition and Diagnosis afflicted with Klinefelters). Another 18 per-
Klinefelter syndrome is a relatively common cent exhibit impaired glucose tolerance. Most
genetic abnormality named after Harry Kline- people affected also have azoospermia (no
felter, Jr., an American physician. The funda- spermatozoa in the semen) and low testoster-
mental chromosomal defect associated with one levels. However, men with the mosaic form
the syndrome is the presence of one or more of Klinefelter syndrome may be fertile.
extra X chromosomes. The normal human Congenital hypogonadism appears as de-
male karyotype (array of chromosomes) con- layed puberty. Men with hypogonadism experi-
sists of twenty-two pairs of chromosomes, called ence decreased libido, erection dysfunction,
autosomes, plus the XY pair, called sex chromo- hot sweats, and depression. Genetic testing and
somes. The female also has twenty-two auto- careful physical examination may reveal Kline-
some pairs but with an XX pair in place of the felter syndrome to be the reason for the primary
XY pair for the sex chromosomes. Klinefelter complaint of infertility. Mental retardation is a
syndrome affects 1 in every 500 to 600 men. frequent symptom of congenital chromosomal
The incidence is relatively high in the mentally aberrations such as Klinefelter syndrome be-
retarded population. cause of probable coincidental defective devel-
Because individuals with Klinefelter syn- opment of the central nervous system. Early
drome have a Y chromosome, they are always spontaneous abortion is a common occurrence.
480 Klinefelter Syndrome
disorder, was the focus of much of the early atic examination of the role played by these
work with the knockout technology. The meth- genes. It has also proven useful in understand-
odology has permitted the creation of previ- ing memory, learning, and behavior, as knock-
ously unknown animal models for cystic fibro- out mice with abnormalities in these areas can
sis, Alzheimers disease, and sickle-cell disease, also survive if human intervention can com-
which will stimulate research into new thera- pensate for their deficiencies. Knockout mice
pies for these diseases. Knockout mice have have been created that cannot learn simple lab-
also been developed to study atherosclerosis, oratory tests, cannot remember symbols or
cancer susceptibility, and obesity, as well as im- smells, lack nurturing behavior, or exhibit ex-
munity, memory, learning, behavior, and devel- treme aggression, which have implications for
opmental biology. the fields of education, psychology, and psychi-
Knockout mice are particularly appropriate atry.
for studying the immune system because im- Developmental biology has also benefited
mune-compromised animals can survive if kept from knockout technology. Animals with mi-
isolated from pathogens. More than fifty genes nor developmental abnormalities can be stud-
are responsible for the development and oper- ied with relative ease, whereas those with highly
ation of B and T lymphocytes, the two main deleterious mutations may be maintained in
types of cells that protect the body from infec- the heterozygous state, with homozygotes gen-
tion. Knockout technology permits a system- erated only as needed for study. The genera-
tion of conditional knockouts is facili-
tating study of the genes responsible for
controlling the development of various
tissues (lung, heart, skeleton, and mus-
cle) during embryonic development.
These genes can be explored methodi-
cally with knockout technology.
By 1997, more than one thousand
different knockout mice had been cre-
ated worldwide. A primary repository
for such animals is the nonprofit Jack-
son Laboratory in Bar Harbor, Maine,
where more than two hundred so-called
induced mutant strains are available to
investigators. Other strains are avail-
able from the scientists who first de-
rived them or commercial entities li-
censed to generate and sell them.
two separate single knockout mice to produce One of the originators of the technology de-
double mutant offspring. Consequences of scribes the steps involved and examples of its
both mutations can then be examined simulta- utility.
neously. Crawley, Jacqueline N. Whats Wrong with My
Some single knockout mice are deleteri- Mouse? Behavioral Phenotyping of Transgenic
ously affected during embryonic development and Knockout Mice. New York: Wiley-Liss,
and do not survive to birth. This has led to the 2000. Discusses transgenic technology and
generation of conditional knockout mice, in the mouse genome. Illustrations, bibliogra-
which the gene is functional until a particular phy, index.
stage of life or tissue development triggers its Gilbert, Scott F. Developmental Biology. 6th ed.
inactivation. The approach is to generate ani- Sunderland, Mass.: Sinauer Associates, 2000.
mals with two mutations: The first is the addi- Includes a discussion of the knockout meth-
tion of a new gene that causes a marked seg- odology. Bibliography.
ment of a gene to be deleted in response to a Mak, Tak W., et al., eds. The Gene Knockout Facts-
temporal or tissue signal, and the second is to book. 2 vols. San Diego: Academic Press, 1998.
mark the gene that has been selected to be ex- Covers six hundred gene knockouts, includ-
cised. In these animals, the latter gene remains ing their general descriptions, constructs,
functional until signaled to be removed. and phenotypes. Bibliography, index.
Knockout methodology involves generation Mestel, Rosie. The Mice Without Qualities.
of loss-of-function or null mutations. Its rever- Discover 14 (March, 1993). Briefly reports on
sal would permit the function of an inoperative the creation of knockout mice and their use
gene to be restored. This reversal has been suc- in understanding the role of the missing
cessfully accomplished in mice with the correc- gene.
tion of the Lesch-Nyhan defect. Further ex- Weaver, Robert F., and Philip W. Hedrick. Ge-
perimentation may permit it to be applied to netics. 3d ed. New York: McGraw-Hill, 1997.
humans and other animals. Such targeted res- Explains the technique and various appli-
toration of gene function would be the most di- cations, including understanding tumor-
rect way for gene therapy (the process of intro- suppressor genes. Illustrations, bibliography,
ducing a functional gene into an organisms index.
cells) to cure inherited diseases.
James L. Robinson
See also: Cloning; Developmental Genet- Web Site of Interest
ics; Genetic Engineering; Genetic Engineer- TBASE: The Transgenic/Targeted Mutation
ing: Medical Applications; Genomics; Model Database, Jackson Laboratory, Bar Harbor,
Organism: Caenorhabditis elegans; Model Organ- Maine. http://tbase.jax.org. Database of
ism: Mus musculus; Model Organisms; Trans- information about transgenic animals gen-
genic Organisms. erated worldwide, searchable by species,
technique, DNA construct, phenotype, lab-
Further Reading oratory. Features the Knockout Model of
Capecchi, Mario. Targeted Gene Replace- the Montha discussion of new animal
ment. Scientific American 270 (March, 1994). modelsand a glossary.
Lactose Intolerance The metabolism (breaking down) of lactose
Field of study: Diseases and syndromes to glucose and galactose takes place via a specific
Significance: Lactose intolerance is a common dis- enzyme called lactase, which is produced by the
order associated with the digestion of milk sugar. It mucosal cells of the small intestine. Because
affects a large portion of the human population lactase activity is rate-limiting for lactose absorp-
and creates unpleasant intestinal effects. Its un- tion, any deficiency in the enzyme is directly re-
derstanding has led to the commercial availability flected in a diminished rate of the sugar absorp-
of alternative products that supplement the lack of tion. This irregularity should not be confused
dairy products in the diet. with intolerance to milk resulting from a sensi-
tivity to milk proteins such as beta-lactoglobulin.
Key terms
congenital deficiency: a deficiency that is at- Consequences of Lactase Deficiency
tributed to inherited genetic causes often There are three types of lactase deficiency:
apparent at birth inherited deficiency, secondary low-lactase ac-
galactosemia: a disease attributed to the ac- tivity, and primary low-lactase activity. In inher-
cumulation of galactose in the blood, caused ited lactase deficiency, the symptoms of intoler-
by a lack of the enzyme that metabolizes ga- ance develop very soon after birth, as indicated
lactose; galactosemia is not related to lactose by the presence of lactose in the urine. Patients
intolerance, which is attributed to the lack of are recommended a lactose-free diet as well as
the lactase enzyme the consumption of live-culture yogurt, which
lactase: an enzyme that breaks down lactose to provides the enzyme beta-galactosidase that at-
the monosaccharides glucose and galactose tacks the small amounts of lactose that may be
in the small intestine during the metabolic in the diet. Beta-galactosidase preparations are
process; its deficiency is responsible for the also commercially available. Secondary low-
ill effects associated with lactose intolerance lactase activity can be a side effect of peptic ul-
lactose: a sugar, also known as milk sugar, that cer surgery or can occur for a variety of reasons.
constitutes 2 to 8 percent of milk content and It may also be present during intestinal dis-
makes up about 40 percent of an infants diet eases such as colitis, gastroenteritis, kwashior-
kor, and sprue. Individuals sometimes develop
The Function of Lactose and Lactase primary low-lactase activity as they get older. A
Milk is the primary source of nutrition for in- large number of adults, estimated at almost
fants. One pint of cows summer milk provides 20 percent, gradually exhibit lactose intoler-
about 90 percent of the calcium, 30 to 40 per- ance, caused by the gradual inability to synthe-
cent of the riboflavin, 25 to 30 percent of the size an active form of lactase. Susceptible indi-
protein, and 10 to 20 percent of the calories viduals may start developing lactose intolerance
needed daily. Lactose, also known as milk as early as four years old.
sugar, exists in the milk of humans, cows, and As a result of lactose intolerance, relatively
other mammals. About 7.5 percent of human large quantities of the unhydrolyzed (unbro-
milk consists of lactose, while cows milk is ken) lactose pass into the large intestine, which
about 4.5 percent lactose. This sugar is also one causes the transfer of water from the interstitial
of the few carbohydrates exclusively associated fluid to the lumen by osmosis. At the same time,
with the animal kingdom; its biosynthesis takes the intestinal bacteria produce organic acids as
place in the mammary tissue. It is produced well as gases such as carbon dioxide, methane,
commercially from whey, which is obtained as a and hydrogen, which lead to nausea and vom-
by-product during the manufacture of cheese. iting. The combined effect also produces
Its so-called alpha form is used as an infant cramps and abdominal pains.
food. Its sweetness is about one-sixth that of su- Definitive diagnosis of the condition is estab-
crose (table sugar). lished by an assay for lactase content in the in-
Lamarckianism 485
testinal mucosa. Such a test requires that the in- Hill, John, et al. Chemistry and Life: An Introduc-
dividuals drink 50 grams of lactose in 200 tion to General, Organic, and Biological Chemis-
milliliters of water. Blood specimens are then try. 6th ed. New York: Prentice Hall, 2000. In-
taken after 30, 60, and 120 minutes for glucose cludes a section on lactose intolerance.
analysis. An increase of blood glucose by 30 mil- Ouellette, Robert J. Organic Chemistry. 4th ed.
ligrams per deciliter is considered normal, New York: Prentice Hall, 1996. Contains a
while an increase of 20 to 30 milligrams per section on lactose metabolism.
deciliter is borderline. A smaller increase indi- Siezen, Roland J., et al., eds. Lactic Acid Bacteria:
cates lactase deficiency. This test, however, may Genetics, Metabolism, and Applications. 7th ed.
still show deficiency results with individuals Boston: Kluwer Academic, 2002. Presents re-
who have a normal lactase activity. search from a conference held every three
Lactase deficiency displays remarkable ge- years. Illustrations (some color).
netic variations. The condition is more preva- Srinivasan, Radhika, and Anil Minocha. When
lent among infants of Middle Eastern, Asian to Suspect Lactose Intolerance. Postgradu-
(especially Chinese and Thai), and African de- ate Medicine 104 (September, 1998). Focuses
scent (such as the Ibo, Yoruba, and other tribes on particular populations in the United
in Nigeria and the Hausa in Sudan). On the States, including Asians, African Americans,
other hand, Europeans (especially northern) and Native Americans. Discusses lactase de-
appear to be statistically less susceptible to the ficiency, symptoms, and treatment.
deficiency. Similarly, the Fula tribe in Sudan Why Does Milk Bother Me? NIH Publication 98-
raises the fulani breed of cattle, and the Eastern 2751 4006187742, DHHS Publication 98-
African Tussi, who own cattle in Rundi, appear 2751 4008061199. Bethesda, Md.: National
to be rarely affected. It is estimated that 10 to Digestive Diseases Information Clearing-
20 percent of American Caucasians and about house, 1998. An illustrated, twelve-page
75 percent of African Americans are affected. pamphlet aimed at those suffering from lac-
The ill effects disappear as long as the diet tose intolerance.
excludes milk altogether. Often people who ex-
hibit partial lactose intolerance can still con- Web Sites of Interest
sume dairy products, including cheese and yo- American Gastroenterological Association.
gurt, if the food is processed or partially http://www.gastro.org. Site provides a guide
hydrolyzed. This may be accomplished by heat- to lactose intolerance, including discussion
ing or partially fermenting milk. Some com- of causes, diagnostics, and treatment, and
mercial products, such as Lactaid, are designed links to related resources.
for lactose-intolerant people because they in- National Institute of Diabetes & Digestive &
clude the active form of the lactase enzyme in Kidney Diseases. http://www.niddk.nih.gov.
either liquid or tablet form. This arm of the National Institutes of Health
Soraya Ghayourmanesh offers resources and links to research on lac-
See also: Aging; Hereditary Diseases; In- tose intolerance.
born Errors of Metabolism.
Further Reading
Auricchio, Salvatore, and G. Semenza, eds.
Common Food Intolerances 2: Milk in Human
Lamarckianism
Nutrition and Adult-Type Hypolactasia. New Field of study: Evolutionary biology; History
York: Karger, 1993. Discusses the health risks of genetics
associated with not consuming milk. Illustra- Significance: Although some aspects of Lamarck-
tions, bibliography, index. ianism have been discredited, the basic premises of
Buller, H. A., and R. J. Grant. Lactose Intoler- nineteenth century French biologist Jean-Baptiste
ance. Annual Reviews of Medicine 141 (1990). Lamarcks philosophy have become widely accepted
A thorough overview of lactose intolerance. tenets of evolutionary theory. Lamarckianism be-
486 Lamarckianism
came intellectually suspect following fraudulent abuses of his ideas. In the most egregious cases,
claims by the Soviet scientist Trofim Lysenko that researchers in the late nineteenth and early
he could manipulate the heredity of plants by twentieth centuries claimed that deliberate
changing their environment; by the 1990s, how- mutilations of animals could cause changes in
ever, scientists had become more willing to ac- succeeding generationsfor example, they be-
knowledge the influence of Lamarckianism in evo- lieved that if they cut the tails off a population
lutionary biology. of mice, succeeding generations would be born
without tails. During the twentieth century, the
Key terms Soviet agronomist Trofim Lysenko claimed to
acquired characteristic: a change in an or- have achieved similar results in plants. Such
ganism brought about by its interaction with claims have been thoroughly disproved.
its environment
Lysenkoism: a theory of transformation that Who Was Lamarck?
denied the existence of genes Such gross distortions of his natural philoso-
transformist theory of evolution: a nine- phy would probably have appalled Lamarck.
teenth century theory that animals gradu- Essentially an eighteenth century intellectual,
ally changed over time in response to their Lamarck was one of the last scientists who saw
perceived needs himself as a natural philosopher. He was born
August 1, 1744, in Picardy, and as the youngest
Lamarckianism Defined of eleven children was destined originally for
The term Lamarckianism has for many the church. The death of his father in 1759
years been associated with intellectually disrep- freed Lamarck to leave the seminary and enlist
utable ideas in evolutionary biology. Originally in the military, but an injury forced him to re-
formulated by the early nineteenth cen-
tury French scientist Jean-Baptiste-Pierre-
Antoine de Monet, chevalier de Lamarck
(1744-1829), Lamarckianism had two
components that were often misinter-
preted by scholars and scientists. The
first was the transformist theory that ani-
mals gradually changed over time in re-
sponse to their perceived needs. Many
critics interpreted this to mean that spe-
cies could adapt by wanting to change
in other words, that giraffes gradually
evolved to have long necks because they
wanted to reach the leaves higher in the
trees or that pelicans developed pouched
beaks because they wanted to carry more
fish. Where Lamarck had suggested only
that form followed functionfor exam-
ple, that birds that consistently relied on
seeds for food gradually transformed to
have beaks that worked best for eating
seedscritics saw the suggestion of ac-
tive intent or desire.
The second component of Lamarck-
ianism, that changes in one generation
of a species could be passed on to the
next, also led to misinterpretations and Jean-Baptiste Lamarck (Library of Congress)
Lamarckianism 487
Lysenkoism
Although Lamarckian evolutionary theories never in a warm environment sprout and bloom and can
enjoyed wide acceptance, a century after Lamarcks thereby be forced to blossom midwinter if desired.
death a Russian agronomist, Trofim Denisovich Ly- Lysenko claimed that seeds from vernalized wheat
senko (1898-1976), promoted similar theories of would sprout early without undergoing vernaliza-
heritability of acquired characteristics. Lysenko, tion themselves. Several ensuing years of good wheat
born in Ukraine, earned a doctorate in agricultural production seemed to validate Lysenkos claims.
science from the Kiev Agricultural Institute in 1925. Unfortunately for both Soviet science and Soviet
Lysenko claimed that changing the environment agriculture, before it could become evident that
in which plants grew made it possible to alter the Lysenkos seeming successes resulted from good
fruit they bore, and those alterations would be pres- growing conditions rather than from his theories,
ent in the plants grown from their seed. Unlike Lysenko proved more adept at politics than he was at
Lamarck, who posited gradual change over many biology. He and his supporters denounced Darwin-
generations, Lysenko suggested that dramatic alter- ian evolutionary theories as bourgeois, contrary to
ations were possible immediately. One of his more the fundamental principles of Marxism and dialecti-
outlandish claims was that wheat grown under condi- cal materialism as practiced in the Soviet Union. By
tions suited for rye would yield rye seeds, a notion as politicizing science, Lysenko made it impossible for
biologically impossible as the idea that feeding cat other Russian scientists to pursue research that con-
food to a dog would result in its giving birth to kittens tradicted Lysenkos pet theories. As director of the
instead of puppies. Institute of Genetics of the Academy of Sciences
Lysenkos ideas were based on results achieved by from 1940 to 1965, Lysenko wielded tremendous
an uneducated but successful horticulturalist, Ivan power within the Soviet scientific community. Scien-
V. Michurin (1855-1935). Michurin developed hun- tists who challenged his theories not only risked los-
dreds of varieties of berries and fruit trees. He cred- ing their academic positions and research funding
ited his achievements to inheritance of acquired but also could be charged with crimes against the
characteristics rather than to selective breeding. Ly- state. In the 1940s several of Lysenkos critics were
senko believed similar success was possible with ce- found guilty of anti-Soviet activity, resulting in either
real grains, primarily wheat, upon which the Soviet their execution or exile to Siberian prison camps.
Union relied. By the 1950s it was clear that Lysenkos theories
Lysenko used vernalization of wheat as proof that did not work. Wheat production consistently failed
acquired characteristics were heritable. Vernaliza- to achieve promised yields. Agronomists quietly
tion involves forcing seeds into responding to the stopped using Lysenkos methods as Lysenkos influ-
changing of seasons earlier than they would under ence faded, but Lysenko managed to retain his ad-
natural conditions. Bulbs of tulips, for example, ministrative positions for another decade.
when refrigerated for a short time and then placed Nancy Farm Mnnikk
sign his commission in 1768. He sampled a vari- When the garden was reorganized as the Mu-
ety of possible vocations before deciding to seum National dHistoire Naturelle in 1794,
pursue a career in science. twelve professorships were created; Lamarck
His early scientific work was in botany. He became a professor of what would now be
devised a system of classification of plants and called invertebrate zoology.
in 1778 published a guide to French flowers. In Lamarck demonstrated through his lectures
1779, at the age of thirty-five, Lamarck was and published works that he modeled his career
elected to the Acadmie des Sciences. Re- on that of his mentor, Buffon. He frequently
nowned naturalist Georges-Louis Leclerc, went beyond the strictly technical aspects of
comte de Buffon, obtained a commission for natural science to discuss philosophical issues,
Lamarck to travel in Europe as a botanist of the and he was not afraid to use empirical data as a
king. In 1789, Lamarck obtained a position at basis for hypothesizing. Thus, he often specu-
the Jardin du Roi as keeper of the herbarium. lated freely on the transformation of species.
488 Lamarckianism
Philosophie Zoologique (Zoological Philosophy), into evolutionary theory and scientific dis-
now considered his major published work, was course. Researchers in microbiology have de-
issued in two volumes in 1809. In it, Lamarck scribed processes that have been openly de-
elaborated upon his theories concerning the scribed as Lamarckian, while other scholars
evolution of species through adaptation to began to recognize that Lamarcks ideas did in-
changes in their environments. An essentially deed serve as an important influence in devel-
philosophical work, Zoological Philosophy is to- oping theories about the influence of environ-
day remembered primarily for Lamarcks two ment on both plants and animals.
laws: Nancy Farm Mnnikk
See also: Central Dogma of Molecular Biol-
First Law: In every animal which has not passed ogy; Chromosome Theory of Heredity; Classi-
the limit of its development, a more frequent cal Transmission Genetics; DNA Structure and
and continuous use of any organ gradually Function; Evolutionary Biology; Genetic Code,
strengthens, develops and enlarges that organ Cracking of; Genetic Engineering: Historical
and gives it a power proportional to the length of Development; Genetics, Historical Develop-
time it has been so used; while the permanent ment of; Genetics in Television and Films;
disuse of any organ imperceptibly weakens and Genomics; Human Genome Project; Mendel-
deteriorates it, and progressively diminishes its
ian Genetics.
functional capacity, until it finally disappears.
early twentieth century French evolutionary Frederick Griffith with pneumonia-causing bac-
science. Bibliography, index. teria in the 1920s. Griffith discovered the pro-
Steele, Edward J., Robyn A. Lindley, and Robert cess of bacterial transformation, by which the
V. Blanden. Lamarcks Signature: How Retro- organism acquires genetic material from its en-
genes Are Changing Darwins Natural Selection vironment and expresses the traits contained
Paradigm. Reading, Mass.: Perseus Books, on the DNA in its own cells. Bacteria may also
1998. Argues that some acquired character- acquire foreign genetic material by the process
istics and immunities (environmental influ- of transduction. In transduction a bacterio-
ence), and not just unchanging genetic pre- phage picks up a piece of host DNA from one
dispositions, as widely believed, can be passed cell and delivers it to another cell, where it inte-
on from generation to generation. Illustra- grates into the genome. This material may then
tions, bibliography, index. be expressed in the same manner as any of the
other of the hosts genes. A third mechanism,
conjugation, allows two bacteria that are con-
nected by means of a cytoplasmic bridge to ex-
change genetic information.
Lateral Gene Transfer With the development of molecular biology,
evidence has been accumulated that supports
Field of study: Population genetics the lateral movement of genes between prokar-
Significance: Lateral gene transfer is the movement yotic species. In the case of Escherichia coli, one
of genes between organisms. It is also sometimes of the most heavily researched bacteria on the
called horizontal gene transfer. In contrast, verti- planet, there is evidence that as much as 20 per-
cal gene transfer is the movement of genes between cent of the organisms approximately 4,403
parents and their offspring. Vertical gene transfer genes may have been transferred laterally into
is the basis of the study of transmission genetics, the species from other bacteria. This may ex-
while lateral gene transfer is important in the plain the ability of E. coli, and indeed many
study of evolutionary genetics, as well as having other prokaryotic species, to adapt to new envi-
important implications in the fields of medicine ronments. It may also explain why in a given
and agriculture. bacterial genus some members are pathogenic
while others are not. Rather than evolving
Key terms pathogenic traits, bacteria may have acquired
gene transfer: the movement of fragments of genetic sequences from other organisms and
genetic information, whole genes, or groups then exploited their new abilities.
of genes between organisms It is also now possible to screen the genomes
genetically modified organism (GMO): an of bacteria for similarities in genetic sequences
organism produced by using biotechnology and use this information to reassess previously
to introduce a new gene or genes, or new established phylogenetic relationships. Once
regulatory sequences for genes, into it for again, the majority of this work has been done
the purpose of giving the organism a new in prokaryotic organisms, with the primary fo-
trait, usually to adapt the organism to a new cus being on the relationship between the do-
environment, provide resistance to pest spe- mains Archaea and Bacteria. Several researchers
cies, or enable the production of new prod- have detected evidence of lateral gene transfer
ucts from the organism between thermophilic bacteria and Archaea
transposons: mobile genetic elements that prokaryotes. Although the degree of gene
may be responsible for the movement of ge- transfer between these domains is under con-
netic material between unrelated organisms tention, there is widespread agreement that
the transfer of genes occurred early in their
Gene Transfer in Prokaryotes evolutionary history. The fact that there was lat-
The fact that genes may move between bac- eral gene transfer has complicated accurate de-
teria has been known since the experiments of terminations of divergence time and order.
490 Lateral Gene Transfer
overs to occur. Double crossovers give the same (A, B, and C) that are arranged in that order on
result as no crossover, and are therefore not de- the chromosome. Suppose that the AB distance
tected. Thus, the greater the distance between on the physical map is exactly the same as the
two loci, the more the distance will be under- BC distance. If the crossover frequency be-
estimated. tween A and B is higher than between B and C,
Once a large number of genes on the same then the AB linkage map distance will be larger
chromosome have been mapped, the linkage than the BC linkage map distance. It is com-
map is redrawn with map positions rather than mon to find small discrepancies between link-
map distances. For example, if many other ex- age maps and physical maps all along the chro-
periments provided more information about mosome. Large discrepancies are usually
linked genes, the following linkage map might limited to loci close to centromeres. Crossover
emerge: frequencies are generally very low near centro-
meres, apparently due to the structural charac-
p q a c b r s teristics of centromeres. If two loci are on oppo-
site sides of a centromere, they will appear
0 6 14 21 32 39 49
farther apart on the physical map and much
closer on the linkage map.
The A and C loci are still 7 cM apart (21 14 = James L. Farmer, updated by Bryan Ness
7), and the other distances on the first map are See also: Chromosome Structure; Chromo-
also still the same. some Theory of Heredity; Classical Transmis-
Very detailed linkage maps have been con- sion Genetics; Complete Dominance; Dihybrid
structed for some plants, animals, fungi, and Inheritance; Gene Families; Genomics; Men-
protists that are of particular value to medicine, delian Genetics; Mitosis and Meiosis; Model
agriculture, industry, or scientific research. Organism: Drosophila melanogaster; Model Or-
Among them are Zea mays (maize), Drosophila ganism: Neurospora crassa.
melanogaster (fruit fly), and Saccharomyces cerevis-
iae (bakers yeast). The linkage map of Homo sa-
piens (humans) is not very detailed because it is Further Reading
unethical and socially impossible to arrange all Liu, Ben-Hui. Statistical Genomics: Linkage, Map-
of the desired crosses that would be necessary ping, and QTL Analysis. Boca Raton, Fla.:
to construct one. Other techniques have al- CRC Press, 1998. Covers the quantitative
lowed the construction of very detailed physi- and theoretical aspects of genomics, includ-
cal maps of human chromosomes. ing linkage map construction and merging.
Illustrations, glossary, bibliography, index.
Genetic Linkage Maps and the Structure Ott, Jurg. Analysis of Human Genetic Linkage. 3d
of Chromosomes ed. Baltimore: Johns Hopkins University
It should be emphasized that the linkage Press, 1999. Introductory text that presents
map is not a scale model of the physical chro- basic methods for linkage analysis. Illustra-
mosome. It is generally true that the relative or- tions.
der of genes on the linkage map and the physi- Terwilliger, Joseph Douglas, and Jurg Ott.
cal chromosome map are the same. However, Handbook of Human Genetic Linkage. Balti-
the relative distances between genes on the more: Johns Hopkins University Press, 1994.
linkage map may not be proportionately the Emphasizes computer-based analyses. Illus-
same on the physical map. Consider three loci trations, bibliography, index.
Mendelian Genetics earned just enough from tutoring to get by. At
Field of study: Classical transmission times, however, the pressure became too much
genetics; History of genetics for him. He suffered a breakdown in 1839 and
Significance: Gregor Mendel was a monk and a returned home for several months to recuper-
science teacher in Moravia when he wrote his fa- ate. He was to have several more of these stress-
mous paper about experimental crosses of pea related illnesses, but no precise information is
plants. Little note was taken of it when it was pub- available about their causes and symptoms.
lished in 1866, but it provided concepts and meth- In 1840, Mendel completed Gymnasium, as
ods that catalyzed the growth of modern genetics af- the elite secondary schools were called, and en-
ter 1900 and earned Mendel posthumous renown tered the University of Olomouc for the two-
as the founder of the new science. year program in philosophy that preceded
higher university studies. He had trouble sup-
Key terms porting himself in Olomouc, perhaps because
gametes: reproductive cells that unite during there was less demand for German-speaking tu-
fertilization to form an embryo; in plants, tors, and his Czech was not good enough for
the pollen cells and egg cells are gametes teaching. He suffered another breakdown in
hybrid: a plant form resulting from a cross be- 1841 and retreated to Hyn5ice during spring
tween two distinct varieties exams.
independent assortment: the segregation of That summer, Mendel decided once more
two or more pairs of genes without any ten- against staying and taking over the farm. Since
dency for certain genes to stay together his father could not work, the farm was sold to
segregation: the process of separating a pair his elder sisters husband. Johanns share of the
of Mendelian hereditary elements (genes), proceeds was not enough to see him through
one from each parent, and distributing
them at random into the gametes
Early Life
Born Johann Mendel on July 22, 1822, the
future teacher, monk, abbot, botanist, and me-
teorologist grew up in a village in Moravia, a
province of the Austrian Empire that later be-
came part of Czechoslovakia (1918) and the
Czech Republic (1993). His parents were peas-
ant farmers and belonged to the large, German-
speaking minority in this predominantly Czech
province. Like most places in Moravia, Men-
dels hometown had two names: Hyn5ice in
Czech and Heinzendorf in German.
Johann Mendel was an exceptional pupil,
but no local schooling was available for him be-
yond the age of ten. In 1833, he persuaded his
parents to send him to town to continue his ed-
ucation. They were reluctant to let him go be-
cause they could ill afford to dispense with his
help on the farm or finance his studies. In
1838, Mendels father was partially disabled in
a logging accident, and Johann, then sixteen
and still at school, had to support himself. He Gregor Mendel. (National Library of Medicine)
Mendelian Genetics 495
the Olomouc program, especially since he had These exams were very demanding and nor-
to repeat a year because of the missed exams. mally required more preparation than Men-
However, his twelve-year-old sister sacrificed dels two years at Olomouc. Mendel failed, but
part of her future dowry so that he could con- one examiner advised the abbot to let him try
tinue. (He repaid her years later by putting her again after further study. The abbot took this
three sons through Gymnasium and university.) advice and sent Mendel to study in Vienna for
Upon finishing at Olomouc in 1843, Mendel two years (1851-1853). There he took courses
decided to enter the clergy. The priesthood in biology, physics, and meteorology with some
filled his need for a secure position and held of the best-known scientists of his day, includ-
out possibilities for further learning and teach- ing physicist Christian Doppler and botanist
ing, but Mendel did not seem to be called to it. Franz Unger.
Aided by a professors recommendation, Men- For unknown reasons, Mendel returned to
del was accepted into the Augustinian monas- Moravia to resume substitute teaching and did
tery in Brno, the capital of Moravia, where he not go to Vienna for the exams until 1856. This
took the name Gregor. In 1847, after four years time he was too nervous to finish. After writing
of preparation at the monastery, he was or- one essay, he fell ill and returned to Brno. De-
dained a priest. spite this failure, he was allowed to teach regu-
lar classes until 1868 even though he was tech-
Priesthood and Teaching nically only a substitute.
The Brno monastery was active in the com-
munity and provided highly qualified instruc- Scientific Work
tors for Gymnasia and technical schools During his teaching career, Mendel per-
throughout Moravia. Several monks, including formed his famous experiments on peas in a
the abbot, were interested in science, and they garden at the monastery. He published the re-
had experimental gardens, a herbarium, a min- sults in an 1866 article, which introduced fun-
eralogical collection, and an extensive library. damental concepts and methods of genetics.
Mendel found himself in learned company The first set of experiments involved fourteen
with opportunities for research in his spare varieties of pea plant, each with a single distin-
time. guishing trait. These traits made up seven con-
Unfortunately, Mendels nerves failed him trasting pairs, such as seeds that were either
when he had to minister to the sick and dying. round or wrinkled in outline or seed colors that
Assigned to a local hospital in 1848, he was so were green or yellow. Upon crossing each pair,
upset by it that he was bedridden himself within Mendel obtained hybrids identical to one par-
five months. However, his abbot was sympa- ent variety. For example, the cross of round
thetic and let him switch to teaching. A letter with wrinkled peas yielded only round peas; the
survives in which the abbot explains this deci- cross of green with yellow peas yielded only yel-
sion to the bishop: [Mendel] leads a retiring, low peas. He referred to traits that asserted
modest and virtuous religious life . . . and he de- themselves in the hybrids as dominant. The
votes himself diligently to scholarly pursuits. others were recessive because they receded
For pastoral duties, however, he is less suited, from view. The effect was the same regardless of
because at the sick-bed or at the sight of the sick whether he fertilized the wrinkled variety with
or suffering he is seized by an insurmountable pollen from the round or the round variety
dread, from which he has even fallen danger- with pollen from the wrinkled. This indicated
ously ill. to Mendel that both pollen cells and egg cells
Mendel taught Latin and Greek, German lit- contributed equally to heredity; this was a sig-
erature, math, and science as a substitute at the nificant finding because the details of plant re-
Gymnasium and was found to be very good at production were still unclear.
teaching. Therefore, he was sent to Vienna in Mendel next allowed the seven hybrids to
1850 to take the licensing examinations so that pollinate themselves, and the recessive traits re-
he could be promoted to a regular position. appeared in the second generation. For in-
496 Mendelian Genetics
stance, the round peas, which were hybrids of the pollen a and egg a combination, which ex-
round and wrinkled peas, yielded not only cludes the A element. For similar reasons,
more round peas but also some wrinkled ones. plants with the dominant trait bred true one-
Moreover, the dominant forms outnumbered third of the time, depending on whether they
the recessives three to one. Mendel explained were the pure forms from the pollen A and egg
the 3:1 ratio as follows. He used the symbols A A combination or the hybrids from the pollen
for the dominant form, a for the recessive, and A and egg a or pollen a and egg A combina-
Aa for the hybrid. A hybrid, he argued, could tions.
produce two types of pollen cell, one contain- Mendels hereditary elements sound like
ing some sort of hereditary element corre- the modern geneticists genes or alleles, and
sponding to trait A and the other an element Mendel usually receives credit for introducing
corresponding to trait a. Likewise, it could pro- the gene concept. Like genes, Mendels ele-
duce eggs containing either A or a elements. ments were material entities inherited from
This process of dividing up the hereditary fac- both parents and transmitted to the gametes.
tors among the gametes became known as seg- They also retained their integrity even when re-
regation. cessive in a hybrid. However, it is not clear
The gametes from the Aa hybrids could whether he pictured two copies of each ele-
come together in any of four combinations: ment in every cell, one copy from each parent,
pollen A with egg A, pollen A with egg a, pollen and he certainly did not associate them with
a with egg A, and pollen a with egg a. The first chromosomes.
three of these combinations all grew into plants In a second set of experiments, Mendel
with the dominant trait A; only the fourth pro- tested combinations of traits to see whether
duced the recessive a. Therefore, if all four they would segregate freely or tend to be inher-
combinations were equally common, one could ited together. For example, he crossed round,
expect an average of three plants exhibiting A yellow peas with wrinkled, green ones. That
for every one exhibiting a. cross first yielded only round, yellow peas, as
Allowing self-pollination to continue, Men- could be expected from the dominance rela-
del found that the recessives always bred true. tionships. Then, in the second generation, all
In other words, they only produced more four possible combinations of traits segregated
plants with that same recessive trait; no domi- out: not only the parental round yellow and
nant forms reappeared, not even in subse- wrinkled green peas but also new round green
quent generations. Mendels explanation was and wrinkled yellow ones. Mendel was able to
that the recessives could only have arisen from explain the ratios as before, based on equally
Round wrinkled seeds All round 5,474 round : 1,850 wrinkled 2.96 : 1
Yellow green seeds All yellow 6,022 yellow : 2,001 green 3.01 : 1
Gray white seedcoats All gray 705 gray : 224 white 3.15 : 1
Inflated pinched pods All inflated 882 inflated : 299 pinched 2.95 : 1
Green yellow pods All green 428 green : 152 yellow 2.82 : 1
Axial terminal flowers All axial 651 axial : 207 terminal 3.14 : 1
Long short stems All long 787 long : 277 short 2.84 : 1
Mendelian Genetics 497
he proposed the genic or sex balance theory, males occurs in the female parent during meio-
which defined the relationship between sex sis I.
chromosomes and autosomes (A) for sex de- Fertilization of an egg carrying two X chro-
termination. According to this theory, the fol- mosomes by an X-bearing (22A + 1X = 23)
lowing ratios of sex chromosomes and number sperm results in an individual with 44A + 3X =
of sets of autosomes determine what sex phe- 47 chromosomes, or a metafemale. The extra
notype will emerge in humans. For example, X chromosome is not usually transmitted to
XX + 2 sets of autosomes (2X:2A ratio = 1.0) = the children. Thus, metafemales can have nor-
normal female; XY + 2 sets of autosomes mal children. Triple X, triplo-X, trisomy X, and
(1X:2A ratio = 0.5) = normal male; and XXX + 47 XXX are also the names given to the meta-
2 sets of autosomes (3X:2A ratio = 1.5) = meta- female phenotype. This genetic condition has
female, or superfemale. also been referred to as extra X aneuploidy
The term metafemale was first applied to or multiple X syndrome.
the XXX (triple X) condition by Curt Stern
around 1959. The frequency of metafemale
phenotype in the general human population is Social Issues
approximately one in one thousand to fifteen The IQ of metafemales is usually low normal
hundred newborn girls. The XXX females are to normal. In some studies, IQ was found to be
characterized by the presence of two Barr bod- lower by 30 points than that of their normal sib-
ies in their cells. They have a total of 47 chro- lings; only a few had an IQ lower than 70. Lan-
mosomes instead of the normal complement guage learning in XXX children is usually de-
of 46. layed. Emotional maturation may also be
Metafemales have variable fertility, ranging delayed. These delays in development are pre-
from normal to sterile. They may be pheno- ventable by providing increased psychological,
typically normal but are often slightly taller social, and motor stimulation both at home
than average, with longer legs. These individu- and at school. Tutoring is often needed at some
als may have widely spaced nipples and a time during development.
webbed neck. Studies have shown that most The 47 XXX condition can put some af-
metafemales lead a normal sexual life and have fected individuals at risk for speech disorders,
normal children. In some cases, menstruation learning disabilities, and neuro-motor deficits,
may begin at an older age, menstrual cycles which ultimately could lead to decreased psy-
may be irregular or temporarily interrupted, chosocial adaptation, especially during ado-
and menopause may begin earlier compared to lescence. One study found young females with
normal XX women. 47 XXX to be less well adapted in both their
teen and adult years; they described their lives
Genetic Cause as more stressful. On average, they experienced
The basic causes of XXX females are best ex- more work, social, and relationship problems
plained through meiosis, the cell division that than their siblings. Metafemales may encoun-
halves the number of chromosomes in ga- ter behavioral problems, including mild de-
metes, and nondisjunction. From a single hu- pression, conduct disorder, immature behav-
man cell (46 chromosomes) designated for ior, and socializing problems. Good parenting
sexual reproduction, meiosis produces four and a supportive home may assure a better so-
cells, each with 23 chromosomes. Thus, normal cial and behavioral development.
human eggs carry one-half (22A + 1X = 23) of Manjit S. Kang
the total number of chromosomes (44A + 2X = See also: Behavior; Biological Clocks; Gen-
46). Occasionally, a mistake occurs during mei- der Identity; Hermaphrodites; Homosexuality;
osis, called nondisjunction. Nondisjunction Human Genetics; Pseudohermaphrodites; Ste-
during meiosis I or meiosis II can produce eggs roid Hormones; Testicular Feminization Syn-
with 2X chromosomes (22A + 2X = 24). Usually drome; X Chromosome Inactivation; XYY Syn-
the nondisjunction that gives rise to XXX fe- drome.
Miscegenation and Antimiscegenation Laws 501
tries around the world, including the United Yancey, George. An Analysis of Resistance to
States, are now racially heterogeneous societ- Racial Exogamy. Journal of Black Studies 31
ies. Genetic studies indicate that perhaps 20 to (May, 2001). A look at opposition to interra-
30 percent of the genes in most African Ameri- cial marriage and at South Carolinas at-
cans are a result of admixture of white genes tempt in 1998 to legalize interracial mar-
from mixed matings since the introduction of riage through state referendum.
slavery to the Americas more than three hun-
dred years ago. Miscegenation has been wide- Web Site of Interest
spread throughout the world, and there may Cold Spring Harbor Laboratory, Image Ar-
not even be such a thing as a pure race. No ad- chive on the American Eugenics Movement.
verse biological effects can be attributed to mis- http://www.eugenicsarchive.org/eugenics.
cegenation. Comprehensive and extensively illustrated
Donald J. Nash site that covers the eugenics movement in
See also: Biological Determinism; Eugen- the United States, including miscegenation
ics; Eugenics: Nazi Germany; Evolutionary Bi- and antimiscegenation laws.
ology; Genetic Engineering: Social and Ethical
Issues; Heredity and Environment; Intelli-
gence; Race; Sociobiology; Sterilization Laws.
for the cells and harbor their own genetic not. Organs also require different amounts of
material adenosine triphosphate (ATP), the cells en-
mitochondrial DNA (mtDNA): genetic ma- ergy source produced in mitochondria. If the
terial found uniquely in mitochondria, lo- population of mutated mitochondria grows to
cated outside the nucleus and therefore sep- outnumber the unmutated forms, most cells in
arate from the nuclear DNA a particular organ may appear diseased. This
replicative segregation: a mechanism by process has been called replicative segregation,
which individual mtDNAs carrying different and a mitochondrial disease is the result. Loss
mutations can come to predominate in any of mtDNA also occurs with increasing age, es-
one mitochondrion pecially in the brain and heart.
set of experiments has worked on cells in tissue debilitating diseases. Analysis of the mitochon-
culture but has not been used on humans. drial DNA sequence of different human popula-
These approaches aim to alter the competitive tions has also provided information relevant to the
ability of undamaged genes to exist in a cellular understanding of human evolution.
environment that normally favors damaged
genes. Further advances in treatment will also Key terms
require better understanding of the natural adenosine triphosphate (ATP): the mole-
ability of mtDNA to undergo genetic recombi- cule that serves as the major source of en-
nation and DNA repair. ergy for the cell
Rebecca Cann ATP synthase: the enzyme that synthesizes
See also: Aging; Extrachromosomal Inheri- ATP
tance; Hereditary Diseases; Human Genetics; cytochromes: proteins found in the electron
Mitochondrial Genes. transport chain
electron transport chain: a series of pro-
Further Reading tein complexes that pump H+ ions out of the
Jorde, Lynn, et al. Medical Genetics. Rev. 2d ed. mitochondria as a way of storing energy that
St. Louis, Mo.: Mosby, 2000. Presents a sim- is then used by ATP synthase to make ATP
ple discussion of these diseases in the con- mitochondrial DNA (mtDNA): genetic ma-
text of other genetic syndromes that are sex- terial found uniquely in mitochondria, lo-
linked or sex-limited in their inheritance cated outside the nucleus and therefore sep-
patterns. Illustrations, bibliography, index. arate from the nuclear DNA
Lestienne, Patrick, ed. Mitochondrial Diseases: ribosomes: organelles that function in protein
Models and Methods. New York: Springer, 1999. synthesis and are made up of a large and a
Focuses on mitochondrial tRNA structure small subunit composed of proteins and ri-
and its mutations. Illustrated (some color). bosomal RNA (rRNA) molecules
Raven, Peter H., and George B. Johnson. Biol- spacers: long segments of DNA rich in ade-
ogy. 6th ed. New York: W. H. Freeman/Worth, nine-thymine (A-T) base pairs that separate
1999. Helps clarify mitochondria and how exons and introns, although most of the
they interact with a cells nucleus. Illustra- spacer DNA is transcribed but is not trans-
tions, maps, index. lated messenger RNA (mRNA)
At Londons Natural History Museum in 1997, anthropologist Chris Stringer displays the nine-thousand-year-old skull of Cheddar
Man (named for the southwestern English town), to whom he traced a modern relative by comparing DNA samples from the skull
with samples from a living, forty-two-year-old schoolteacher. This is possible because mitochondrial DNA is passed unchanged from
generation to generation down the maternal line. (AP/Wide World Photos)
similarity led to the endosymbiont hypothesis order to store energy. Another protein that is
developed by Lynn Margulis, which proposes embedded in the inner mitochondrial mem-
that mitochondria arose from bacteria that took brane is an enzyme called adenosine triphos-
up residence in the cytoplasm of the ancestor phate (ATP) synthase. This enzyme allows the
to eukaryotes. H+ ions to travel back into the matrix. When
Embedded in the inner mitochondrial this happens, energy is released that is then
membrane is a series of protein complexes that used by the synthase enzyme to make ATP. Cells
are known collectively as the electron trans- use ATP to provide energy for all of the biologi-
port chain. These proteins participate in a de- cal work they perform, including movement
fined series of reactions that begin when en- and synthesis of other molecules. The concept
ergy is released from the breakdown of glucose of linking the production of a proton gradient
and end when oxygen combines with 2H+ ions to ATP synthesis was developed by Peter Mitch-
to produce water. The net result of these reac- ell in 1976 and is referred to as the chemios-
tions is the movement of H+ ions (also called motic hypothesis.
protons) from the matrix into the intermem-
brane space. This establishes a proton gradient Mitochondrial Genes
in which the intermembrane space has a more The mitochondrial chromosome is a circu-
positive charge and is more acidic than the ma- lar DNA molecule that varies in size from about
trix. Thus mitochondria act as tiny batteries 16,000 base pairs (bp) in humans to more than
that separate positive and negative charges in 100,000 base pairs in certain species of plants.
Mitochondrial Genes 507
Despite these size differences, mitochondrial bosomal RNA (rRNA) and proteins. Genes that
DNA (mtDNA) contains only a few genes that play a role in mitochondrial protein synthesis
tend to be similar over a wide range of organ- include two rRNA genes designated 16S rRNA
isms. This discussion will focus on genes located and 12S rRNA, indicating the RNA for the large
on the human mitochondrial chromosome that and small subunits respectively. Also in this first
has been completely sequenced. These genes category are genes for mitochondrial transfer
fall into two broad categories: those that play a RNA. Transfer RNA (tRNA) is an L-shaped
role in mitochondrial protein synthesis and molecule that contains the RNA anticodon at
those involved in electron transport and ATP one end and an amino acid attached to the
synthesis. other end. The tRNA anticodon pairs with the
Mitochondria have their own set of ribo- codon of the messenger RNA (mRNA) and
somes that consist of a large and a small sub- brings the correct amino acid into position to
unit. Each ribosomal subunit is a complex of ri- be added to the growing protein chain. Thus
The mitochondria of plants, animals, and fungi in- ing sequences between segments consisting of func-
clude their own DNA genomes, mitochondrial DNA tioning genes.
(mtDNA). The mtDNA genome typically consists of Despite the size differences, plant and animal
a bacteria-like circular loop of DNA located in highly mtDNA usually carry the same thirty-seven coding
condensed structures called nucleoids within the mi- genes: twenty-two genes coding for transfer RNA
tochondrial matrix. However, the mtDNA of the molecules, two ribosomal RNA genes, and thirteen
yeast Hansenula, the protozoans Tetrahymena and Par- genes coding for proteins involved in mitochon-
amecium, and the alga Chlamydomonas are chainlike drial respiration. Again, certain organisms differ.
or linear rather than circular, while that of proto- Marchantia mtDNA, for example, includes an addi-
zoan parasites such as Trypanosoma, Leishmania, and tional sixteen genes that code for ribosomal proteins
Crithidia is organized into a network of several hun- and twenty-nine genes that code for proteins of un-
dred maxicircles about 21-31 kilobase pairs (kb) known function.
long, interlocked with several thousand minicircles, Translation of mtDNA is consistent with the uni-
each about 0.5-2.5 kb. versal genetic code, with notable departures. For ex-
The size of each mtDNA varies greatly among or- ample, both AGA and AGG specify the amino acid
ganisms. Most animals have small mtDNA genomes arginine in the universal genetic code but are stop
ranging from about 6 to 20 kb, such as the 6-kb codes in animal mtDNA. In ciliated protozoans the
mtDNA genome of the protozoan parasite Plas- mtDNA code for glutamine is UAA and UAG, which
modium falciparium, which causes malaria, and the specifies stop in the universal genetic code. In yeast
14.3-kb mtDNA of free-living Ascaris roundworms. the mtDNA codes CUU, CUA, CUC, and CUG spec-
The mtDNA genome of humans is about 16.5 kb and ify the amino acid threonine instead of leucine,
comprises about 0.3 percent of the total genome. as specified by the universal genetic code. Presum-
The mtDNA genomes of most plants and fungi are ably, all of these mtDNA coding departures from the
larger: The mtDNA of the yeast Saccharomyces cerevis- universal genetic code result from mutations that oc-
iae is 86 kb, that of the common pea Sativa is 110 kb, curred subsequent to the endosymbiotic incorpora-
that of the liverwort Marchantia is 186 kb, and that of tion of the original mitochondria into early eukary-
the muskmelon Cucumis melo is a gigantic 2,400 kb. otic cells.
Much of the size variation is due to the presence of Inheritance patterns of mtDNA differ for some
long segments of noncoding sequences embedded plants and animals as well. In animals the mtDNA ge-
within the genome, which seem to be especially nome is transmitted primarily through the female
abundant in plants and fungi but not in animal egg to the offspring, but in Chlamydomonas algae and
mtDNA. More than half of the mtDNA of yeasts, for yeasts male and female gametes are nearly equal in
example, is formed by long segments of spacers, size and contribute mtDNA genome to the offspring.
while another quarter consists of introns, interven- Dwight G. Smith
508 Mitochondrial Genes
the tRNA molecule serves as a bridge between tions can be wide-ranging and debilitating, if
the information in the mRNA molecule and not fatal. If the mutation occurs in a gene that
the sequence of amino acids in the protein. Mi- plays a role in mitochondrial protein synthesis,
tochondrial tRNAs are different from those in- the ability of the mitochondria to perform pro-
volved in protein synthesis in the cytoplasm. In tein synthesis is affected. Consequently, pro-
fact, cytoplasmic tRNAs would not be able to teins that are translated on mitochondrial ribo-
function on mitochondrial ribosomes, nor somes such as cytochrome b or the NADH
could mitochondrial tRNAs work with cytoplas- dehydrogenase subunits cannot be made, lead-
mic ribosomes. Thus, mtDNA contains a com- ing to defects in electron transport and ATP
plete set of twenty-two tRNA genes. synthesis. Mutations in mitochondrial tRNA
Genes involved in electron transport fall genes, for example, have been shown to be the
into the second category of mitochondrial cause of several degenerative neuromuscular
genes. The electron transport chain is divided disorders. Genes involved in electron transport
into a series of protein complexes, each of and ATP synthesis have a more directly nega-
which consists of a number of different pro- tive effect when mutated. Douglas C. Wallace
teins, a few of which are encoded by mtDNA. and coworkers identified a mutation within the
The NADH dehydrogenase complex (called NADH dehydrogenase subunit 4 gene, for ex-
complex I) contains about twenty-two different ample, that was the cause of a maternally inher-
proteins. In humans, only six of these proteins ited form of blindness and was one of the first
are encoded by genes located on the mitochon- mitochondrial diseases to be identified.
drial chromosome. Cytochrome c reductase Of further interest is the study of nuclear
(complex III) contains about nine proteins, in- genes that contribute to mitochondrial func-
cluding cytochrome b, which is the only one tion. Included in this list of nuclear genes are
whose gene is located on mtDNA. Cytochrome those encoding proteins involved in mtDNA
oxidase (complex IV) contains seven proteins, replication, repair, and recombination; en-
three of which are encoded by mitochondrial zymes involved in RNA transcription and pro-
genes. About sixteen different proteins com- cessing; and ribosomal proteins and the ac-
bine to make up the mitochondrial ATP cessory factors required for translation. It is
synthase, and only two of these are encoded by presumed that a mutation in any of these genes
mtDNA. could have negative effects upon the ability of
All of the proteins not encoded by mito- the mitochondria to function. Understanding
chondrial genes are encoded by genes located how nuclear genes contribute to mitochon-
on nuclear chromosomes. In fact, more than drial activity is an essential part of the search
90 percent of the proteins found in the mito- for effective treatments for mitochondrial dis-
chondria are encoded by nuclear genes. These eases.
genes must be transcribed into mRNA in the Human evolutionary studies have also been
nucleus, then the mRNA must be translated affected by the understanding of mitochon-
into protein on cytoplasmic ribosomes. Finally, drial genes and their inheritance. Researchers
the proteins are transported into the mito- Allan C. Wilson and Rebecca Cann, knowing
chondria where they function. By contrast, that mitochondria are inherited exclusively
genes located on mtDNA are transcribed in the through the female parent, hypothesized that a
mitochondria and translated on mitochon- comparison of mitochondrial DNA sequences
drial ribosomes. in several human populations would enable
them to trace the origins of the ancestral hu-
Impact and Applications man population. These studies led to the con-
Any mutation occurring in a mitochondrial clusion that a female living in Africa about
gene has the potential to reduce or prevent mi- 200,000 years ago was the common ancestor for
tochondrial ATP synthesis. Because human all modern humans; she is referred to as mito-
cells are dependent upon mitochondria for chondrial Eve.
their energy supply, the effects of these muta- Bonnie L. Seidel-Rogol
Mitosis and Meiosis 509
See also: Aging; Ancient DNA; Extrachro- daughter cells: cells resulting from the divi-
mosomal Inheritance; Hereditary Diseases; sion of a parent cell
Human Genetics; Mitochondrial Diseases; diploid cells: cells containing two sets of ho-
RNA World. mologous chromosomes
haploid cells: cells containing one set of
Further Reading chromosomes; eggs and sperm are haploid
Hartwell, L. H., L. Hood, M. L. Goldberg, A. E. cells
Richards, L. M. Silver, and R. C. Veres. Genet-
ics: From Genes to Genomes. Boston: McGraw- Cellular Reproduction
Hill, 2003. Chapter 15 provides an excellent Organisms must be able to grow and repro-
summary of mitochondrial DNA. duce. Prokaryotes, such as bacteria, duplicate
Pon, Liza, and Eric A. Schon, eds. Mitochondria. DNA and divide by splitting in two, a process
San Diego: Academic Press, 2001. Discusses called binary fission. Cells of eukaryotes, in-
the effects of impaired mitochondrial func- cluding those of animals, plants, fungi, and
tion. protists, divide by one of two methods: mitosis
Scheffler, Immo E. Mitochondria. New York: or meiosis. Mitosis produces two cells, called
John Wiley & Sons, 1999. Comprehensive, daughter cells, with the same number of chro-
concise discussion of mitochondria bio- mosomes as the parent cell, and is used to pro-
chemistry, genetics, and pathology. duce new somatic (body) cells in multicellular
Wallace, Douglas C. Mitochondrial DNA in eukaryotes or new individuals in single-celled
Aging and Disease. Scientific American, Au- eukaryotes. In sexually reproducing organisms,
gust, 1997. Gives a detailed explanation of cells that produce gametes (eggs or sperm) di-
human mitochondrial diseases, aimed at vide by meiosis, producing four cells, each with
nonspecialists. half the number of chromosomes possessed by
Wilson, Allan C., and Rebecca L. Cann. The the parent cell.
Recent African Genesis of Humans. Scien-
tific American, April, 1992. Describes how Chromosome Replication
studies of mitochondrial genes have led to All eukaryotic organisms are composed of
information about human origins. cells containing chromosomes in the nucleus.
Chromosomes are made of DNA and proteins.
Most cells have two complete sets of chromo-
somes, which occur in pairs. The two chromo-
Mitosis and Meiosis somes that make up a pair are homologous,
and contain all the same loci (genes control-
Field of study: Cellular biology ling the production of a specific type of prod-
Significance: Mitosis is the process of cell division uct). These chromosome pairs are usually re-
in multicellular eukaryotic organisms. Meiosis is ferred to as homologous pairs. An individual
the process of cell division that produces haploid chromosome from a homologous pair is some-
gametes in sexually reproducing eukaryotic organ- times called a homolog. For example, typical
isms. lily cells contain twelve pairs of homologous
chromosomes, for a total of twenty-four chro-
Key terms mosomes. Cells that have two homologous chro-
binary fission: reproduction of a cell by divi- mosomes of each type are called diploid. Some
sion into two parts cells, such as eggs and sperm, contain half the
centromere: a region on the chromosome normal number of chromosomes (only one of
where chromatids join each homolog) and are called haploid. Lily egg
chromatid: one-half of a replicated chromo- and sperm cells each contain twelve chromo-
some somes.
cytokinesis: division of the cytoplasm to form DNA must replicate before mitosis or meio-
new cells sis can occur. If daughter cells are to receive a
510 Mitosis and Meiosis
Mitosis
Mitosis consists of five stages:
prophase, prometaphase, meta-
phase, anaphase, and telophase.
Although certain events identify
each stage, mitosis is a continu-
ous process, and each stage grad-
ually passes into the next. Identi- (1) Early prophase I (2) Prophase I
fication of the precise state is
therefore difficult at times.
During prophase, the chro-
matin becomes more tightly
coiled and condenses into chro-
mosomes that are clearly visible
under a microscope, the nucleo-
lus disappears, and the spindle
apparatus begins to form in the
cytoplasm. In prometaphase the
nuclear envelope breaks down,
(3) Late prophase I (4) Metaphase I
and the spindle apparatus is now
able to invade the nuclear re-
gion. Some of the spindle fibers
attach themselves to a region
near the centromere of each
chromosome called the kineto-
chore. The spindle apparatus is
the most obvious structure of
the mitotic apparatus. The nu-
clear region of the cell has oppo-
site poles, like the North and
South Poles of the earth. Spin- (5) Anaphase I (6) Metaphase II
dle fibers reach from pole to
pole, penetrating the entire nu-
clear region.
During metaphase, the cells
chromosomes align in a region
called the metaphase plate, with
the sister chromatids oriented
toward opposite poles. The met-
aphase plate traverses the cell,
much like the equator passes
through the center of the earth.
Sister chromatids separate dur- (7) Anaphase II (8) Late telophase II
ing anaphase. The sister chro-
matids of each chromosome split (Kimberly L. Dawson Kurnizki)
512 Mitosis and Meiosis
apart, and the spindle fibers pull each sister falls apart, and a nuclear envelope re-forms
chromatid (now a separate chromosome) from around each of the two haploid nuclei. Because
each pair toward opposite poles, much as a the number of chromosomes in each of the
rope-tow pulls a skier up a mountain. Telo- telophase I nucleus is half the number in the
phase begins as sister chromatids reach oppo- parent nucleus, meiosis I is sometimes called
site poles. Once the chromatids have reached the reductional division.
opposite poles, the spindle apparatus falls apart, Meiosis II is essentially the same as mitosis,
and the nuclear membrane re-forms. Mitosis is dividing the two haploid nuclei formed in mei-
complete. osis I. Prophase II, metaphase II, anaphase II,
and telophase II are essentially identical to the
Meiosis stages of mitosis. Meiosis II begins with two hap-
Meiosis is a more complex process than mi- loid cells and ends with four haploid daughter
tosis and is divided into two major stages: meio- cells.
sis I and meiosis II. As in mitosis, interphase
precedes meiosis. Meiosis I consists of pro- Nuclear Division and Cytokinesis
phase I, metaphase I, anaphase I, and telo- Mitosis and meiosis result in the division of
phase I. Meiosis II consists of prophase II, meta- the nucleus. Nuclear division is nearly always
phase II, anaphase II, and telophase II. In some coordinated with division of the cytoplasm.
cells, an interphase II occurs between meiosis I Cleaving of the cytoplasm to form new cells is
and meiosis II, but no DNA replication occurs. called cytokinesis. Cytokinesis begins toward
During prophase I, the chromosomes con- the middle or end of nuclear division and in-
dense, the nuclear envelope falls apart, and the volves not just the division of the cytoplasm but
spindle apparatus begins to form. Homolo- also the organelles. In plants, after nuclear divi-
gous chromosomes come together to form tet- sion ends, a new cell wall must be formed be-
rads (a tetrad consists of four chromatids, two tween the daughter nuclei. The new cell wall
sister chromatids for each chromosome). The begins when vesicles filled with cell wall mate-
arms of the sister chromatids of one homolog rial congregate where the metaphase plate was
touch the arms of sister chromatids of the other located, producing a structure called the cell
homolog, the contact points being called chias- plate. When the cell plate is fully formed, cyto-
mata. Each chiasma represents a place where kinesis is complete. Following cytokinesis, the
the arms have the same loci, so-called homolo- cell returns to interphase. Mitotic daughter
gous regions. During this intimate contact, the cells enlarge, reproduce organelles, and re-
chromosomes undergo crossover, in which the sume regular activities. Following meiosis, ga-
chromosomes break at the chiasmata and swap metes may be modified or transported in the
homologous pieces. This process results in re- reproductive system.
combination (the shuffling of linked alleles,
the different forms of genes, into new combi- Alternation of Generations
nations), which results in increased variability Meiotic daughter cells continue develop-
in the offspring and the appearance of charac- ment only if they fuse during fertilization. Mito-
ter combinations not present in either parent. sis and meiosis alternate during the life cycles
Tetrads align on the metaphase plate dur- of sexually reproducing organisms. The life-
ing metaphase I, and one spindle fiber attaches cycle stage following mitosis is diploid, and the
to the kinetochore of each chromosome. In stage following meiosis is haploid. This process
anaphase I, instead of the sister chromatids is called alternation of generations. In plants,
separating, they remain attached at their cen- the diploid state is referred to as the sporo-
tromeres, and the homologous chromosomes phyte generation, and the haploid stage as the
separate, each homolog from a tetrad moving gametophyte generation. In nonvascular plants,
toward opposite poles. Telophase I begins as the gametophyte generation dominates the life
the homologs reach opposite poles, and similar cycle. In other words, the plants normally seen
to telophase of mitosis, the spindle apparatus on the forest floor are made of haploid cells.
Model Organism: Arabidopsis thaliana 513
The sporophytes, which have diploid cells, are John, Bernard. Meiosis. New York: Cambridge
small and attached to the body of the gameto- University Press, 1990. Review and discus-
phyte. In vascular plants, sporophytes are the sion of meiosis, the antithesis of fertilization.
large, multicellular individuals (such as trees Discusses the scheduling, mechanisms, bio-
and ferns) whereas gametophytes are very small chemistry, and the genetic control of the
and either are embedded in the sporophyte or events in meiosis.
are free-living, as are ferns. The genetic varia- Keeton, William T., and James L. Gould. Biologi-
tion introduced by sexual reproduction has a cal Science. 5th ed. New York: W. W. Norton,
significant impact on the ability of species to 1993. The chapter Cellular Reproduction
survive and adapt to the environment. Alterna- discusses in detail the stages of mitosis and
tion of generations allows sexual reproduction meiosis. Excellent diagrams allow visualiza-
to occur without changing the chromosome tion of cell division.
number characterizing the species.
Joyce A. Corban and Randy Moore
See also: Cell Culture: Animal Cells; Cell
Culture: Plant Cells; Cell Cycle, The; Cell Divi- Model Organism:
sion; Cytokinesis; Gene Regulation: Eukary- Arabidopsis thaliana
otes; Polyploidy; Totipotency.
Field of study: Techniques and
Further Reading methodologies
Alberts, Bruce, Dennis Bray, Julian Lewis, Mar- Significance: Arabidopsis thaliana, also known
tin Raff, Keith Roberts, and James D. Wat- as mouse-ear cress, can grow from seed to maturity
son. Molecular Biology of the Cell. 4th ed. New and back to thousands of seeds again in about six
York: Garland, 2002. The chapter How weeks. Its short reproduction cycle and simple, low-
Cells Are Studied gives extensive informa- cost cultivation allow genetic experiments with
tion regarding study methods in cell biology. tens of thousands of plants and make it a popular
Light and electron microscopy are discussed and convenient organism to use as a model or-
as well as staining techniques and tissue cul- ganism.
ture.
Audesirk, Teresa, Gerald Audesirk, and Bruce Key terms
E. Myers. Biology: Life on Earth. 6th ed. Upper Brassicaceae: the mustard family, a large, cos-
Saddle River, N.J.: Prentice Hall, 2001. The mopolitan family of plants with many wild
chapter Cellular Reproduction and the species, some of them common weeds, in-
Life Cycles of Organisms is a brief overview cluding widely cultivated edible plants like
of mitosis, meiosis, and the cell cycle. In- cabbage, cauliflower, radish, rutabaga, tur-
cludes excellent discussion of alternation of nip, and mustard
generations. genetic map: a map showing distances be-
Campbell, Neil A., and Jane B. Reece. Biology. tween genes in terms of recombination fre-
6th ed. San Francisco: Benjamin Cummings, quency
2002. The chapter Reproduction of Cells
provides extensive information regarding Natural History
mitosis and the cell cycle. The phases of mi- Although common as an introduction into
tosis, the mitotic spindle, cytokinesis, con- America and Australia, Arabidopsis thaliana (of-
trol mechanisms, and abnormal cell division ten referred to simply by its genus name, Arabi-
are discussed in detail. The chapter Meiosis dopsis) is found in the wild throughout Europe,
and Sexual Life Cycles addresses the stages the Mediterranean, the East African highlands,
of meiosis, sexual life cycles, and a compari- and Eastern and Central Asia (which is proba-
son of mitosis and meiosis. This text is in- bly where it originated). Since Arabidopsis is a
tended for use in introductory biology and is low winter annual (standing about 1.5 deci-
very readable and informative. meters), it flowers in disturbed habitats from
514 Model Organism: Arabidopsis thaliana
March through May. Arabidopsis was first de- melanogaster, long a favorite model organism
scribed by Johannes Thal (hence the thaliana among geneticists). Yet in comparison to the
as the specific epithet) in the sixteenth century genome of corn (Zea mays), for example, Arabi-
in Germanys Harz Mountains, but he named it dopsis has a genome that is ten times smaller.
Pilosella siliquosa at the time. Undergoing sys- Furthermore, Arabidopsis is easily transformed
tematic revisions and several name changes, using the standard vector Agrobacterium tumefa-
the little plant was finally called Arabidopsis thal- ciens. There are also a large number of mutant
iana in 1842. lines and genomic resources available for Arabi-
Several characteristics of Arabidopsis make it dopsis at stock centers, and a cooperative multi-
useful as a model organism: First, it has a short national research community of academic, gov-
life cycle; it goes from seed to seed in only about ernment, and industry laboratories exists, all
three months, and each individual plant is pro- working with Arabidopsis.
lific, yielding thousands of seeds. Second, the
plants are small, easy to grow and to manipu- History of Experimental Work with
late, so that many genetic screens can be done Arabidopsis
on petri dishes with a thousand seedlings exam- The earliest report of a mutant probably
ined inside just one dish. Also, the genome of was made in 1873 by A. Braun, and Freidrich
Arabidopsis is relatively small, with 120 million Laibach first compiled the unique characteris-
base pairs (Mbp), 25,000 genes, and five chro- tics of Arabidopsis thaliana as a model organism
mosomes containing all the requisite informa- for genetics in 1943 (publishing the correct
tion to encode an entire plant (similar to the chromosome number of five much earlier, in
functional complexity of the fruit fly Drosophila 1907, later confirmed by other investigators).
Model Organism: Arabidopsis thaliana 515
Erna Reinholz (a student of Laibach) submit- vide an important resource for map-based gene
ted her thesis in 1945, published in 1947, on cloning and genome analysis. The Arabidopsis
the first collection of X-ray-induced mutants. Genome Initiative, an international effort to
Peter Langridge established the usefulness of sequence the complete Arabidopsis genome,
Arabidopsis in the laboratory in the 1950s, as was created in the mid-1990s, and the results of
did George Redei and other researchers, in- this massive undertaking were published on
cluding J. H. van der Veen in the Netherlands, December 14, 2000, in Nature.
J. Veleminsky in Czechoslovakia, and G. Rob-
belen in Germany in the 1960s. Comparative Genomics
Maarten Koorneef and his coworkers pub- With full sequencing of the genome of Arabi-
lished the first detailed genetic map for Arabi- dopsis completed, the first catalog of genes in-
dopsis in 1983. A genetic map allows researchers volved in the life cycle of a typical plant is now
to observe approximate positions of heritable available, and the investigational emphasis has
factors (genes and regulatory elements) on shifted to functional and comparative ge-
chromosomes. The 1980s saw the first steps in nomics. Scientists began looking at when and
analysis of the genome of Arabidopsis. Tagged where specific genes are expressed in order to
mutant collections were developed. Physical learn more about how plants grow and develop
maps, with distances between genes in terms of in general, how they survive in the changing
DNA length, based on restriction fragment environment, and how the gene networks are
length polymorphisms (RFLPs), were also controlled or regulated. Potentially this re-
made in this time period. The physical maps al- search and work can lead to improved crop
low genes to be located and characterized, even plants that are more nutritious, more resistant
if their identities remained unknown. to pests and disease, less vulnerable to crop fail-
The 1990s saw scientists outlining long- ure, and capable of producing higher yields
range plans for Arabidopsis through the Multi- with less damage to the natural environment.
national Coordinated Arabidopsis Genome Re- Since many more people die from malnutri-
search Project, which called for genetic and tion in the world than from diseases, the Arabi-
physiological experimentation necessary to dopsis genome takes on a much more impor-
identify, isolate, sequence, and understand tant consideration than one might think. Of
Arabidopsis genes. In the United States, the Na- course, plants are fundamental to all ecosys-
tional Science Foundation (NSF), U.S. Depart- tems, and their energy input into those systems
ment of Energy (DOE), and Agricultural Re- is essential and critical.
search Service (ARS) funded work done at Already the genetic research on Arabidopsis
Albany directed by Athanasios Theologis. NSF has boosted production of staple crops such as
and DOE funds went also to Stanford, Philadel- wheat, tomatoes, and rice. The genetic basis for
phia, and four other U.S. laboratories. World- every economically important trait in plants
wide communication among laboratories and whether pest resistance, vegetable oil produc-
the creation of shared databases (particularly tion, or even wood quality in paper products
in the United States, Europe, and Japan) were is under intense scrutiny in Arabidopsis.
established. Transformation methods have be- Although Arabidopsis is considered a weed
come much more efficient, and a large number throughout its ecological range on the planet,
of Arabidopsis mutant lines, gene libraries, and it is closely related to a number of vegetables,
genomic resources have been made and are including broccoli, cabbage, brussels sprouts,
now available to the scientific community and cauliflower, which are very important to
through public stock centers. The expression humans nutritionally and economically. For
of multiple genes has been followed, too. example, a mutation observed in Arabidopsis
Teresa Mozo provided the first comprehensive has resulted in its floral structures assuming the
physical map of the Arabidopsis genome, pub- basic shape of a head of cauliflower. This muta-
lished in 1999; she used overlapping fragments tion in Arabidopsis, not surprisingly, is referred
of cloned DNA. These fundamental data pro- to simply as cauliflower and was isolated by
516 Model Organism: Caenorhabditis elegans
Martin Yanofskys laboratory. The analogous See also: Cell Culture: Plant Cells; Extra-
gene from the cauliflower plant was examined, chromosomal Inheritance; Model Organisms.
and it was discovered the cauliflower plant al-
ready had a mutation in this gene. From the Further Reading
study of Arabidopsis, therefore, researchers have Bowman, John L. Arabidopsis: An Atlas of Mor-
uncovered why a head of cauliflower looks the phology and Development. New York: Springer-
way it does. Verlag, 1993. Contains images and descrip-
In plants there is an ethylene-signaling path- tions of normal and mutant Arabidopsis
way (ethylene is a plant hormone) that regu- plants.
lates fruit ripening, plant senescence, and leaf Russell, Peter J. Genetics. San Fransisco, Calif.:
abscission. The genes necessary for the ethyl- Benjamin Cummings, 2002. Good genetic
ene-signaling pathway have been identified in textbook with specific references to genetic
Arabidopsis, including genes coding for the eth- duplications, genome sequences, homeotic
ylene receptors. As expected, a mutation in genes, model organism considerations, and
these ethylene receptors would also cause the the regulation of development in Arabi-
Arabidopsis plant to be unable to sense ethyl- dopsis.
ene. Ethylene receptors have now been uncov- Wilson, Zoe A. Arabidopsis: A Practical Approach.
ered from other plant species from the knowl- New York: Oxford University Press, 2000.
edge gained from Arabidopsis. Harry Klees Provides an introduction to techniques re-
laboratory, for example, has found a tomato quired for the use of Arabidopsis as an experi-
mutation in the ethylene receptor, which pre- mental system. Provides strategies for the
vents ripening. When the mutant Arabidopsis identification, mapping, and characteriza-
receptor is expressed in other plants, more- tion of mutants by microscopy, molecular cy-
over, the transformed plants also exhibit this togenetics, and gene expression analysis.
insensitivity to ethylene and the lack of ensu-
ing processes associated with it. Therefore, the Web Site of Interest
mechanism of ethylene perception would seem The Arabidopsis Information Resource (TAIR).
to be conserved in plants, and modifying ethyl- http://www.arabidopsis.org. The gateway to
ene receptors can induce change in a plant. the Arabidopsis Genome Initiative (AGI), de-
Advances in evolutionary biology and medi- signed for the scientific community, consists
cine are expected from Arabidopsis research, of a searchable relational database with many
too. Robert Martienssen of Cold Spring Har- different data types that can be viewed, ana-
bor Laboratory has referred to the completion lyzed, and downloaded. Also has pages for
of the Arabidopsis genome sequence as having news, lab protocols, and links.
major impact on human health as well as plant
biology and agriculture. Surprisingly, some of
the newly identified Arabidopsis genes are ex-
tremely similar or even identical to human Model Organism:
genes linked to certain illnesses. No doubt
there are many more mysteries to unravel with
Caenorhabditis elegans
the proteome analysis of Arabidopsis (analysis of Field of study: Techniques and
how proteins function in the plant), and the bi- methodologies
ological role of all the twenty-five thousand Significance: The roundworm Caenorhabditis
genes will keep scientists busy for some time to elegans has helped scientists understand develop-
come. For example, this relatively simple lit- ment of multicellular organisms. For their work
tle plant has surprised workers with its amazing using C. elegans to identify apoptosis, or pro-
genetic duplication where more than 70 per- grammed cell death, three scientists received the
cent of its DNA is copied at least once some- Nobel Prize. The C. elegans genome project has
where else on its genome. enabled scientists to develop much of the technology
F. Christopher Sowers that was used to sequence the human genome. Re-
Model Organism: Caenorhabditis elegans 517
search with this organism has also contributed to hundred fertilized eggs in the first four days of
understanding genetics of the nervous system, ag- adulthood; hermaphrodites that mate with
ing, and even learning. males will continue to lay eggs as long as sperm
are present.
Key terms Caenorhabditis elegans eggs begin develop-
cell differentiation: a process during which ment within the uterus. They hatch as small L1
a cell specifically expresses certain genes, ul- larvae and molt four times as they proceed
timately adopting its final cell fate to become through the easily recognizable larval stages of
a specific type of cell, such as a neuron, or L2, L3, L4, and adult. The adult hermaphro-
undergoing programmed cell death (apop- dite is a little larger than the adult male and can
tosis) be distinguished by the presence of fertilized
model organism: an organism well suited for eggs lined up in the uterus. The smaller males
genetic research because it has a well-known have specialized tails that contain structures for
genetic history, a short life cycle, and genetic mating called copulatory spicules.
variation between individuals in the popula-
tion A Model Organism
Because of its small size and simple diet (bac-
The Organism teria), C. elegans is easily adapted to laboratory
The nematode Caenorhabditis elegans (C. ele- culture conditions. The worms are grown on
gans) has been the subject of intense analysis by small agar-filled petri plates that are seeded
biologists around the world. Nematodes, or with E. coli. The worms live comfortably at
roundworms, are simple metazoan animals room temperature, but elevating or lowering
that have cells specialized to form tissues and the temperature can speed up or slow down de-
organs such as nerve tissue and digestive tissue. velopment, and changes in temperatures can
Analysis of genetic control of the events that even reveal conditional phenotypes of some ge-
lead to the formation of the tissues in C. elegans netic mutations.
has revealed biological mechanisms that also One unmated hermaphrodite will produce
control the differentiation of tissues and or- three hundred progeny over the first four days
gans in more complex organisms such as hu- of adulthood. Additionally, C. elegans has a
mans. short generation time of approximately three
Caenorhabditis elegans is a microscopic, 1-mil- weeks. Obtaining large numbers of progeny al-
limeter-long roundworm that lives in soils and lows thorough statistical analysis of the way a
eats bacteria from decaying materials. It be- mutation is segregated within a population. Be-
longs to the phylum Nematoda (the round- cause researchers can screen large numbers of
worms), which includes many significant plant worms in a short period of time, extremely rare
and animal parasites. Caenorhabditis elegans, mutations are likely to be revealed. Genetically
however, is free-living (nonparasitic) and does pure strains are also quickly produced.
not cause any human diseases. It exists as two Hermaphrodite genetics also provides ad-
sexes, males (containing a single X chromo- vantages. Because hermaphrodites are self-
some) and hermaphrodites (containing two X fertile, getting homozygous mutations is not
chromosomes). Both male and hermaphrodite difficult. A hermaphrodite that is heterozygous
worms have five pairs of autosomal (non-sex) for a given mutation (has one wild-type copy of
chromosomes. The hermaphrodites are self- a gene and one mutated copy of a gene) will
fertile. They produce sperm first, which they produce progeny, one-fourth containing two
store, and later switch gonads to begin pro- mutated copies of the gene (homozygotes).
ducing eggs. These eggs may be fertilized by Additionally, for researchers studying mutations
the hermaphrodites own sperm, or if the her- that affect reproduction or mating behavior,
maphrodite mates with a male, sperm from the having self-fertile hermaphrodites allows them
male will fertilize the eggs. A hermaphrodite to maintain mutations that affect processes such
that is not mated will lay approximately three as sperm production. A hermaphrodite that
518 Model Organism: Caenorhabditis elegans
cannot make its own sperm can be mated to a have 1,021. Because the entire cell lineage for
wild-type male, and the mutation causing the the worm is known and the worm is transpar-
defect can be maintained. This is not possible ent, researchers can use a laser to destroy a sin-
in organisms that are strictly male/female or gle, specific cell and observe how loss of one
that are strictly hermaphroditic. cell affects development of the worm. These
Another strength of C. elegans is that the ge- kinds of studies have contributed to the under-
netic strains can be frozen in liquid nitrogen standing of how neurons find target cells and
and maintained indefinitely. Even fruit flies how one cell can direct the fate of another.
have to be constantly mated or passaged to
maintain the genetic stocks for a laboratory. Embryonic Development: Asymmetric
Caenorhabditis elegans strains are maintained in Divisions
a central location, giving all scientists access to Research on C. elegans has revealed how pro-
the same well-characterized genetic stocks. grammed genetic factors (autonomous devel-
Caenorhabditis elegans is a transparent worm, opment) and cell-cell interactions guide devel-
ideally suited for microscopic analysis. The ori- opment of an organism from egg to adult. The
gin and ultimate fate of every cell in the worm very first division of the fertilized egg (zygote)
(the cell lineage) has been mapped and traced in C. elegans is asymmetric (uneven) and creates
microscopically. Adult hermaphrodites have the first difference in the cells of the organism
959 somatic (non-sex) cell nuclei, and males that is reflected in the adult. This division pro-
H. Robert Horvitz points to an image of the nematode Caenorhabditis elegans. Working with this organism, he, Sydney Brenner,
and John E. Sulston won the 2002 Nobel Prize in Physiology or Medicine for discovering genes regulating organ development and
leading to apoptosis (programmed cell death)discoveries with significant implications for cancer therapies. (AP/Wide World
Photos)
Model Organism: Caenorhabditis elegans 519
duces two daughter cells called P and AB. AB is thought of as resulting from uncontrolled pro-
a large cell that gives rise to tissues such as mus- liferation of cells, but it can also result when
cle and digestive tract. P is a much smaller cell cells that should die during development fail to
that ultimately produces the cells that become die. Scientists are looking at ways to specifically
the gonads (sex cell-producing tissues). The activate apoptosis in tumor cells in order to kill
difference in P and AB is determined by the tumors. The clues for what genes to target for
segregation of small P granules in the cell. The such treatments come from studies of the apop-
location of these granules and the asymmetry tosis pathway in organisms such as C. elegans.
of this initial division are determined by the
point of entry of the sperm. Until the eight-cell A Molecular Tool
stage, there is no genetic activity by the embryo; The first metazoan genome that was se-
the first few divisions are directed by the mater- quenced was C. elegans. Many of the technol-
nal gene products. This is one example of how ogies (automated machines, chemistries for
maternal gene products can influence the early isolating and preparing DNA) that were devel-
development of an embryo. oped in the course of the C. elegans genome-
sequencing project were directly applied to the
Neural Development human genome sequencing project, and many
One of the areas of later development that is of the scientists involved in sequencing the C.
particularly well understood in C. elegans is the elegans genome contributed expertise to the
development of the nervous system. The ner- Human Genome Project as well.
vous system has been completely reconstructed The green fluorescent protein, which is a
with serial electron micrographs that reveal protein that was first used to trace neurons in C.
precisely how one neuron connects to another. elegans, is now used in experiments with a wide
Some neurons migrate to assume their final variety of organisms or cell cultures to follow
cell fate and function. These migrations are specific cells or specific proteins during devel-
easily studied in the worm because of its trans- opment. RNA interference, a technique that
parency, and a single neuron can be visualized uses RNA specifically to knock out gene expres-
by marking it with green fluorescent protein. sion of a target gene, was first described in
Many genes and their encoded proteins that worms. This technique enables scientists to
have been identified as important for directing knock out gene expression at the RNA level
the growth, connectivity, and migration of C. rather than requiring laborious genetic engi-
elegans neurons are highly conserved in evolu- neering of DNA. This technique promises to be
tion and control axon guidance in the verte- particularly useful for researchers working with
brate spinal cord. human or other mammal cell culture systems.
Caenorhabditis elegans research identified the
Apoptosis: Programmed Cell Death first presenilin, a class of proteins later impli-
The 2002 Nobel Prize in Physiology or Medi- cated in Alzheimers disease. Research on the
cine was awarded to Sydney Brenner, H. Robert worm has led to a greater understanding of cer-
Horvitz, and John E. Sulston for identifying ge- tain proteins that are involved in cellular aging.
netically controlled cell death in worms. Cell Studies in C. elegans are even contributing to a
death is an important part of development in better understanding of learning and behavior.
plants and animals. For instance, human em- Most C. elegans scientists are studying the worm
bryos have webbing between fingers and toes. because it provides a tool for answering many
This webbing is composed of cells that die in of the hows and whys of biology that cannot be
the course of normal development before a hu- answered easily in more complex systems. The
man baby is born. The death of these cells oc- answers to seemingly esoteric questions, such
curs because of a genetic program in the cells, as how C. elegans sperm move, will shed light on
apoptosis. The genes that control apoptosis are fundamental biological processes shared by all
highly conserved throughout evolution. Apop- organisms.
tosis also plays a role in cancer. Often cancer is Michele Arduengo
520 Model Organism: Chlamydomonas reinhardtii
See also: Aging; Antisense RNA; Comple- spond to genes but lack introns that are pres-
mentation Testing; Human Genome Project; ent in the actual genome
Model Organism: Chlamydomonas reinhardtii; cosmid: a cloning vector, a hybrid of bacterial
Model Organisms; Noncoding RNA Molecules. plasmid and bacteriophage vectors, that re-
lies on bacteriophage capsules to infect bac-
Further Reading teria; these are constructed with selectable
Lewin, Benjamin. Genes VII. New York: Oxford markers from plasmids and two regions of
University Press, 2001. Contains articles lambda phage DNA known as cos (for cohe-
about many of the processes researched in sive end) sites
the worm, including apoptosis. insertional mutagenesis: the generation of
Wood, W. B., et al. The Nematode Caenorhabditis a mutant by inserting several nucleotides
elegans. Cold Spring Harbor, N.Y.: Cold into a genome
Spring Harbor Laboratory Press, 1988. The microarray: a flat surface on which 10,000 to
first worm book contains an excellent 100,000 tiny spots of DNA molecules fixed
overview of worm development and an in- on glass or another solid surface are used for
troductory letter from Nobel laureate Syd- hybridization with a probe of fluoresent
ney Brenner. DNA or RNA
model organism: an organism well suited for
Web Site of Interest genetic research because it has a well-known
Caenorhabditis elegans Web ser ver. http:// genetic history, a short life cycle, and genetic
elegans.swmed.edu. Contains links to major variation between individuals in the popula-
worm labs around the world and to intro- tion
ductory information about the worm. In- transformation: a change in both genotype
cludes access to WormBase, a repository of and phenotype resulting from the uptake of
mapping, sequencing and phenotypic infor- exogenous DNA
mation.
The Organism
Chlamydomonas reinhardtii is the best-re-
searched member of the green algal genus
Chlamydomonas (Greek chlamys, a cloak, plus
Model Organism: monas, solitary). Chlamydomonas reinhardtii is
Chlamydomonas reinhardtii unicellular with a definite cell wall that con-
sists of glycoproteins rich in the amino acid
Field of study: Techniques and hydroxyproline. A large, solitary chloroplast
methodologies folded into a cup shape dominates most of the
Significance: Chlamydomonas reinhardtii is a cytoplasm. The presence of this chloroplast al-
unicellular green alga that has been extremely use- lows autotrophic growth, although C. reinhard-
ful as a genetics model organism. It has a simple tii is capable of using acetate as an external car-
life cycle, is easily mutable, and is accessible for mo- bon source. A circular body that is prominent
lecular genetic studies. within the chloroplast is referred to as the
pyrenoid. It is the site of carbohydrate synthe-
Key terms sis during the light-independent reactions of
bacterial artificial chromosome (BAC): a photosynthesis. The chloroplast also contains a
vector used to clone large fragments of DNA red eyespot with a rhodopsin-like pigmented
(up to 500 kb) that can be readily inserted in photoreceptor, called the stigma, that permits
a bacterium, such as Escherichia coli phototaxis. Chlamydomonas reinhardtii cells dis-
complementary DNA (cDNA): a DNA mole- play positive phototaxis (that is, swimming to-
cule that is synthesized using messenger ward light) in moderate light and negative
RNA (mRNA) as a template and the enzyme phototaxis in intense light.
reverse transcriptase; these molecules corre- The cell nucleus is visible with light micros-
Model Organism: Chlamydomonas reinhardtii 521
copy and predominates cross-sectional images mating types are placed in a nitrogen-free me-
in electron microscopy, along with the nucleo- dium. The zygote formed from such a mating
lus. Electron microscopy also indicates sixteen can produce four unordered tetrads on appro-
or more chromosomes, which is consistent with priate media. Sometimes an additional mitotic
the seventeen linkage groups defined by cyto- event generates eight haploid products that are
genetic analysis. The cells anterior end con- easy to recover. These features have made C.
sists of two contractile vacuoles, and mitochon- reinhardtii extremely useful as an experimental
dria are dispersed throughout the cytosol. Two organism.
long, whiplike flagella extend from basal bod-
ies, which are also located at the anterior end of Mutagenesis and Transmission Genetics
the cell. Chlamydomonas reinhardtii swims using Research in the 1950s led to the isolation of
a breaststroke motion. Internally the flagella mutants displaying defects in the ability to pho-
consist of a central pair of microtubules sur- tosynthesize. Since then mutants have been de-
rounded by nine doublets. Each doublet con- veloped that affect every structure, function,
sists of arms made of the protein dynein. The and behavior of C. reinhardtii. Ultraviolet or
dynein interacts with adjacent doublets by chemical methods can be used to induce mu-
pressing and sliding against the neighboring tants. One of the first mutants isolated was resis-
microtubule when adenosin triphosphate tant to the antibiotic streptomycin (designated
(ATP) is hydrolyzed. This brings about the sr). These cells are able to grow on media sup-
flagellar beat and allows the organism to swim. plemented with streptomycin as well as media
Chlamydomonas reinhardtii reproduces asexu- free of streptomycin. Wild-type cells (desig-
ally by mitotic divisions. Parental cells can pro- nated ss) are unable to grow on media contain-
duce as many as sixteen progeny cells by succes- ing the antibiotic. Reciprocal crosses with cells
sive divisions within the cell wall. Each progeny of these distinct phenotypes resulted in segre-
cell secretes a cell wall and generates flagella. gation patterns that departed significantly
The new cells escape by secreting autolytic en- from Mendelian expectations. The sr pheno-
zymes that digest the parental cell wall. type was clearly transmitted only through mt+
cells. Further study has shown that resistance
Mating and Laboratory Analysis passed through the mt+ chloroplast. The chlo-
The vegetative form of C. reinhardtii is hap- roplast contains more than fifty copies of a cir-
loid and exists as one of two genetically distinct cular, double-stranded DNA molecule. Unipa-
mating types (mt+) and (mt). When deprived rental inheritance has been demonstrated for
of nitrogen, cells of each mating type differen- the mitochondrial genome, too. This genome
tiate into gametes. Gametes of opposite mating contains fewer genes than the chloroplast, but
types come into contact with each other by way antibiotic resistant mutations have been gener-
of their flagella. The gametes fuse, thereby ated, along with other types. It is interesting to
forming a zygote. The zygote secretes a heavy note that mitochondrial inheritance of antibi-
wall and becomes a zygospore. Zygospores can otic resistance appears to be transmitted by way
remain dormant and viable in soils for several of mt cells.
years. Light and nitrogen can bring about Mutational analysis has elucidated aspects of
zygospore germination. Four biflagellated nuclear inheritance, also. The mating type
cells, known as zoospores, are released. In phenotype segregates in a 1:1 ratio in accor-
some strains, meiosis occurs prior to the release dance with Mendelian principles. With the ad-
of zoospores, followed by a mitotic division. vent of molecular techniques, insertional mu-
The result is the release of eight zoospores tagenesis has resulted in a wide array of
rather than four. mutants, including nonphotosynthetic, non-
Cells of C. reinhardtii are easy to culture. motile, antibiotic resistant, herbicide resistant,
They grow copiously in defined culture media and many more. This type of analysis has re-
under var ying environmental conditions. sulted in mapping nearly two hundred nuclear
Mating can be induced when cells of opposite loci.
522 Model Organism: Drosophila melanogaster
Key terms
linked genes: genes, and traits they specify,
that are situated on the same chromosome
and tend to be inherited together
model organism: an organism well suited for
genetic research because it has a well-known
genetic history, a short life cycle, and genetic
variation between individuals in the popula-
tion
sex chromosomes: The X and Y chromosomes,
which determine sex in many organisms; in
Drosophila, a female carries two X chromo-
somes and a male carries one X and one Y
chromosome
lated to its sex, and he located the eye-color Linked Genes and Chromosome Maps
gene to the X chromosome of the fruit fly. The Many genes are located on each chromo-
X chromosome is one of the sex chromosomes. some. Genes, and the traits they specify, that
Because a female fly has two X chromosomes are situated on the same chromosome tend to
and a male has one X and one Y chromosome, be inherited together. Such genes are referred
and because the Y chromosome does not carry to as linked genes. Morgan performed a vari-
genes corresponding to those on the X chro- ety of genetic crosses with linked genes and de-
mosome, any gene on the males X chromo- veloped detailed maps of the positions of the
some is expressed as a trait, even if it is normally genes on the chromosomes based on his re-
recessive. This interesting and unusual exam- sults. Morgan did his first experiments with
ple of the first mutant gene in flies was called a linked genes in Drosophila that specified body
sex-linked trait because the trait was located color and wing type. In fruit flies, a brown body
on the X chromosome. is the wild type and a black body is a mutant
This important discovery attracted many type. In wild flies wings are very long, while one
students to Morgans laboratory, and before mutant variant has short, crinkled wings re-
long they found many other unusual inherited ferred to as vestigial wings. When Morgan
traits in flies and determined their inheritance mated wild-type females with black-bodied, ves-
patterns. One of the next major discoveries by tigial-winged males, the next generation con-
members of the fly lab was that of genes exist- sisted of all wild-type flies. When he then mated
ing on the same chromosome, information females from this new generation with black-
that was used to map the genes to individual bodied, vestigial-winged males, most of the
chromosomes. progeny were either brown and normal winged
A. X X X Y B. X X X Y
+
and
Red-eyed Red-eyed
females males
+
Morgans experiments discovered such results as the following: A. A red-eyed female is crossed with a white-eyed male. The red-eyed
progeny interbreed to produce offspring in a red to white ratio. All the white-eyed flies are male. B. A white-eyed male is crossed
with its red-eyed daughter, giving red-eyed and white-eyed males and females in equal proportions. (Electronic Illustrators
Group)
Model Organism: Drosophila melanogaster 525
cals were used to generate new mutations for gle one will truncate the rest of development,
study in Drosophila, and researchers realized resulting in a severely mutated fly. It was found
that in many cases they could correlate a partic- that conserved regions of DNA outside of the
ular gene with a physical band along a chromo- developmental genes received the signals to
some. Also noted were chromosome abnormal- turn on. Such sequences were found to be
ities, including deletions of pieces, inversions present in all animals studied. These control re-
of chromosome sections, and the translocation gions were termed homeoboxes after the ho-
of a portion of one chromosome onto another meotic genes that control the overall body plan
chromosome. The pioneering techniques of of an organism in early development.
linkage mapping through recombination of Many other aspects of Drosophila were found
traits and physical mapping of genes to chro- to be useful in understanding the structure and
mosome sections provided detailed genetic function of the DNA of all organisms. It was
maps of Drosophila. Similar techniques have found that in Drosophila, large pieces of DNA
been used to construct gene maps of other or- will, under certain circumstances, pop out of
ganisms, including humans. the chromosome and reinsert themselves at an-
other site. One such element, called a P ele-
Control of Genes at the Molecular Level ment, was used by scientists to introduce nonfly
This seminal genetic work on Drosophila was DNA into the fruit fly embryo, thus providing
unparalleled in providing insights into the information on how DNA is expressed in ani-
mechanisms of inheritance. Most of the inheri- mals. This work also provided early clues into
tance patterns discovered in the fruit flies were the successful creation of transgenic animals
found to be applicable to nearly all organisms. commonly used in research to study cancer and
However, the usefulness of Drosophila as a re- other diseases.
search organism did not end with classical
transmission genetics; it was found to provide Impact and Applications
equally valuable insight into the mechanisms of Genetic studies of Drosophila melanogaster
development at the level of DNA. have provided the world with a fundamental
Drosophila were discovered to be ideal organ- understanding of the mechanisms of inheri-
isms to use in the study of early development. tance. In addition to the inheritance modes
During its development in the egg, the Drosoph- shown by Mendels studies of pea plants, fruit
ila embryo orchestrates a cascade of events that fly genetics revealed that some genes are sex
results in the embryo having a polarity (a head linked in sexually reproducing animals. The re-
and a tail), with segments between each end de- search led to the understanding that while
fined to become a particular body part in the many genes are linked to a single chromosome,
adult. For example, the second segment of the the linkage is not necessarily static, and that
thorax will support one pair of wings and one chromosomes can exchange pieces during re-
of the three pairs of legs. By studying many combination. The ease with which mutant fruit
types of mutants that showed bizarre appear- flies could be generated led to the develop-
ances as adults (for example, two sets of wings ment of detailed linkage maps for all the chro-
or legs replacing the normal antennae on the mosomes and ultimately to the localization of
head), scientists were able to elucidate some of genes to specific regions of chromosomes.
the mechanisms that control development in With the advent of molecular techniques, it was
nearly all animals. discovered that Drosophila again provided a
Developmental instructions from the mother wealth of information in terms of mobile ge-
fruit fly are sequestered in the egg. When the netic elements and developmental studies.
egg is fertilized, these instructions begin to Although all of these breakthroughs were sci-
turn on genes within the fertilized eggs that entifically interesting in terms of the flies them-
begin to establish the directionality and seg- selves, many of the breakthroughs helped iden-
ment identity within the embryo. So many genes tify fundamental principles consistent among
are involved in this process that a defect in a sin- all animals. Most of what is known about hu-
Model Organism: Escherichia coli 527
man genetics and genetic diseases has come genesis; Natural Selection; Noncoding RNA
from these pioneering studies with Drosophila. Molecules; Population Genetics.
Because of the sheer numbers of offspring
from any mating of flies, their very short life cy- Further Reading
cle, and large numbers of traits that are easily Abstracts of Papers Presented at the 2001 Meeting on
observable, fruit flies have become an ideal sys- Neurobiology of Drosophila. Arranged by Hugo
tem to screen for potential chemical carcino- Bellen and Barbara Taylor. Cold Spring Har-
gens (cancer-causing agents) or mutagens bor, N.Y.: Cold Spring Harbor Laboratory
(agents that cause mutations in DNA) in hu- Press, 2001. Papers focus on Drosophila as a
mans. Flies are exposed to the chemical in model organism in neurobiology.
question and mated; then their offspring are Brookes, Martin. Fly: The Unsung Hero of Twen-
analyzed for any abnormal appearances or be- tieth-Century Science. San Francisco: Harper-
haviors, or for low numbers of offspring. Should Collins, 2001. A whimsical history of the
a test substance cause any variation in the ex- fruit fly, Drosophila melanogaster, as the star of
pected outcome of a cross, it is then subjected genetic research, from Thomas Hunt Mor-
to more rigorous research in other organisms. gan to DNA sequencing.
The versatile, easy-to-care-for, inexpensive
fruit fly is often a fixture in classrooms around Web Sites of Interest
the world. Indeed, many geneticists have traced Drosophila Virtual Librar y. http://www
their passion to their first classroom encoun- .ceolas.org/VL/fly. Links to databases, labs,
ters with fruit flies and the excitement of dis- and other Web resources of interest to re-
covering the inheritance patterns for them- searchers.
selves. Flies are also routinely used in the study FlyBase. http://flybase.bio.indiana.edu:82. A
of neural pathways, learning patterns, behav- joint venture of the Berkeley and European
ior, and population genetics. Because of the Drosophila Genome Projects. Includes data
ease of study and the volumes of information from the Drosophila genome projects and a
that have been compiled about its genetics, de- vast amount of other informationbibliog-
velopment, and behavior, Drosophila will con- raphies, directories, descriptions of chromo-
tinue to be an important model organism for somal aberrations, lists of Drosophila stocks,
biological study. The completion of the com- genome project data, images, and more.
plete genome sequence of Drosophila should
greatly increase the usefulness of this model
organism, allowing an even more detailed un-
derstanding of its genetics. Model Organism: Escherichia
Karen E. Kalumuck
See also: Aging; Bioinformatics; Biological
coli
Clocks; Chemical Mutagens; Chromosome Mu- Fields of study: Bacterial genetics;
tation; Chromosome Theory of Heredity; Devel- Techniques and methodologies
opmental Genetics; Genetics, Historical Devel- Significance: Through the study of the genetics of
opment of; Homeotic Genes; Human Genome Escherichia coli biologists have come to under-
Project; Inbreeding and Assortative Mating; In- stand the molecular-level regulation of gene expres-
complete Dominance; Lateral Gene Transfer; sion and how genes direct routine activities of liv-
Linkage Maps; Metafemales; Model Organism: ing cells. This understanding of the genetics of this
Arabidopsis thaliana; Model Organism: Caenor- bacterium has led to the extensive use of this organ-
habditis elegans; Model Organism: Chlamydo- ism in biotechnology. Such technology permits the
monas reinhardtii; Model Organism: Escherichia introduction of foreign genes into the organisms
coli; Model Organism: Mus musculus; Model Or- cells, which may result in new bacterial strains ca-
ganism: Neurospora crassa; Model Organism: Sac- pable of solving problems as diverse as environ-
charomyces cerevisiae; Model Organism: Xenopus mental pollution, food and energy shortages, and
laevis; Model Organisms; Mutation and Muta- the spread of diseases.
528 Model Organism: Escherichia coli
some using gene mapping (which determines polymerase from initiating operon transcrip-
the locations of genes along the chromosome) tion.
and recombinant DNA techniques such as In contrast to the lac operon, the trp operon
DNA sequencing (which determines the order is a repressible system, in which the production
of the nucleotides in DNA). Of the located of an enzyme stops with the addition of the end
genes, 260 of them are organized into seventy- product of the enzyme reaction. Transcription
five operons, with the remaining 740 genes of the operons five structural genes, which en-
scattered, perhaps randomly, around the rest code enzymes involved in tryptophan produc-
of the DNA molecule. tion, is repressed in the presence of trypto-
phan. A second regulatory mechanism, called
Regulation of Gene Expression attenuation, also controls the system.
The genetics of E. coli reveals that 26 percent Based on the genetics of E. coli, biologists
of its mapped genes are organized in tran- know that operon function may change if fused
scriptional units (DNA segments containing to a new operator. French molecular biologist
message-encoding start and stop signals) called Franois Jacobs research team showed this for
operons; these work to regulate gene expres- the structural genes of the lac operon. The
sion. Operons, coordinately regulated units, team used DNA fragments carrying parts of the
often contain genes with related functions. lac-pur region, but with an added deletion that
Each regulated unit has a set of adjoining struc- eliminated the lac operator and part of the Z
tural genes, a promoter for enzyme binding, gene. These modified DNA fragments were in-
and an operator for regulatory protein bind- serted into E. coli that were unable to produce
ing. If the genes encode enzymes involved in an the enzymes permease and acetylase. The func-
anabolic pathway (in which chemical reactions tional lac enzymes produced by the modified
form larger molecules from smaller ones), they particles were no longer activated by lactose.
are usually turned off in the presence of the Such enzymes were instead under control of
pathways end product. Alternatively, if the the deactivated purine operator. As a result, ex-
genes encode enzymes involved in a catabolic cessive purine caused repression of galactoside
pathway (in which chemical reactions break permease and acetylase. In E. coli, gene expres-
down large molecules into smaller ones), they sion can be regulated at different levels, but
are often expressed in the presence of the en- transcriptional regulation is the most common.
zymes substrates (molecules whose actions are
increased). DNA Replication, Transcription, and
The genetics of the lactose (lac) and the Translation
tryptophan (trp) operons were unraveled using Early in the study of E. coli, Matthew Mesel-
E. coli. This earned the bacterium a place in his- son and Franklin Stahl determined how DNA
tory for helping to explain the regulation of duplicates itself in the bacterium. They grew
gene expression. The lac operon consists of the organism, across several generations, in
three structural genesZ, Y, and Athat en- culture media containing nucleotides en-
code beta-galactosidase, beta-galactoside riched with nitrogen 15 (a heavier isotope of ni-
permease, and beta-galactoside transacetylase, trogen), which would be incorporated into all
respectively. Other operon components are newly synthesized strands of DNA. Then some
the promoter and the operator adjoining the Z of these cells with nitrogen 15 enriched DNA
gene. The regulator gene has its own promoter were transferred to media containing nucleo-
and adjoins the operon. The lac operon is an tides containing normal nitrogen 14, so that all
example of an inducible system because the newly synthesized strands of DNA would then
operons three structural genes are transcribed contain nitrogen 14 rather than nitrogen 15.
(put into message code) only in the presence of After allowing enough time for the cells to di-
lactose. In the absence of lactose, the lac vide once, they isolated their DNA and then
repressor (a protein product of the regulator used cesium chloride density-gradient centri-
gene) binds to the operator and prevents RNA fugation to characterize their results. Their
530 Model Organism: Escherichia coli
As part of the Human Genome Project (begun in in the former and the relative lack of such sequences
1990), several model organisms were selected for se- in the latter. This was borne out by the E. coli se-
quencing. Such direct DNA sequence information quence: The genome analysis indicates that there
could be correlated with the extensive data available are 4,405 genes, including 4,286 protein-coding se-
from classical and molecular genetics. Not only quences, about 50 percent more than originally pre-
would it provide a means for identifying similar dicted. Only about one-third of these represent well-
genes in the human genome; it would also provide a characterized proteins. There are also 7 ribosomal
means for comparative genomics, that is, to identify RNA (rRNA) operons and 86 transfer RNA (tRNA)
similar genes among both model organisms and se- genes.
quence data from related organisms. The latter is While E. coli is a normal inhabitant of the human
useful to explore the evolution of specific genes and gut, the average person associates the name E. coli
evolutionar y relatedness of organisms. Conse- with strain O157:H7, a human pathogen causing in-
quently, the sequencing of the Escherichia coli, the testinal hemorrhaging and resulting in about five
prokaryotic organism most studied genetically, bio- hundred deaths per year in the United States. Strain
chemically, and physiologically, was of high priority. O157:H7 has acquired two toxin genes from a re-
Due to efforts led by Frederick Blattner at the Uni- lated bacterium, Shigella dysenteriae, often found in
versity of Wisconsin, along with colleagues at four cattle. The complete sequenceof O157:H7 was com-
other institutions, the six-year project resulted in the pleted in January, 2001, and provides interesting
complete genomic sequence of E. coli K12 (strain comparisons. Its genome is 5,528,455 base pairs, with
MG1655), published on September 5, 1997, in the 5,416 genes of which 1,387 are not found in E. coli
journal Science; the final corrected sequence was up- MG1655. These new genes include those for viru-
dated in October, 2001. lence factors, alternative metabolic capacities, and
Although there are many different strains of E. new prophages. Moreover, O157:H7 lacks 528 genes
coli, strain MG1655 was chosen because it is a well- found in E. coli MG1655. These marked differences
established, stable laboratory strain. The sequencing lead some to believe that O157:H7 is actually a dif-
of a second laboratory strain, W3110, was completed ferent species, having evolutionarily diverged from
by a consortium of Japanese researchers. The E. coli standard E. coli about 4.5 million years ago. This ex-
MG1655 genome consists of 4,639,221 base pairs, a ample of comparative genomics illustrates its poten-
number slightly higher than estimated from earlier tial as a powerful tool for medical and other applica-
studies. Of these, 87.8 percent are found in protein- tions.
coding genes, 0.8 percent in stable RNA sequences, Sequencing of other strains of E. coli, particularly
0.7 percent in noncoding repeats, and approximately pathogenic strains, is ongoing under the aegis of the
11 percent in regulatory and other sequences. One E. coli Genome Project, based at the University of
difference between eukaryote and prokaryote ge- Wisconsin.
nomes is the large amount of noncoding sequences Ralph R. Meyer
findings, verified through autoradiography sev- tal template (guide) strands. The DNA dupli-
eral years later by John Cairns, showed that in cation process results in two double-stranded
E. coli, DNA duplicates itself semiconservatively. DNA molecules, each having one strand from
This means that in E. coli, the strands of the the parent molecule and one newly produced
DNA double helix separate and form a Y-shaped strand. This semiconservative mechanism en-
replication fork where DNA duplication be- sures the faithful copying of the genetic infor-
gins. Proteins stabilize the unwound helix and mation at each E. coli cell division.
assist in relaxing the coiling tension created During the message-encoding process (tran-
ahead of the duplication activity. A new, com- scription), the genic message (RNA transcript)
plementary strand of DNA, duplicated in E. coli is created step by step, using the DNA template.
at the rate of thirty thousand nucleotides per The template is read in one direction, while
minute, is produced on each of the two paren- RNA is produced in the opposite direction.
Model Organism: Escherichia coli 531
The process includes initiation, elongation, and to other chromosome locations. Insertion ele-
termination phases. The transcription initia- ments, the simplest transposable elements in E.
tion site is signaled by the promoter (a short coli, contain only genes for mobilizing the ele-
nucleotide sequence recognized by an RNA ments and inserting them into chromosomes
polymerase). During elongation, RNA polymer- at new locations.
ase migrates along the DNA molecule, melting In E. coli, as in all other organisms, many
and unwinding the double helix as it moves chemical and physical agents cause structural
and sequentially attaching ribonucleotides to changes in DNA. Consequently, mechanisms
one end of the growing RNA molecule. Base are needed for repairing such damaged DNA.
pairing to the template strand of the gene de- Such repair mechanisms exist in E. coli, al-
termines the identity of the ribonucleotide though they are complicated and require many
added to each position. By a complex signal, different proteins. The three main types of re-
transcription is terminated shortly after the pair mechanisms in E. coli are direct repair (the
ends of genes. As a result of the process, a gene- reversal of a structural change), excision repair
complementary, single-stranded RNA molecule (in which appropriate enzymes recognize and
(messenger RNA, or mRNA) is created. label a damaged nucleotide, excise it, fill in
Like the message-encoding process, the the gap, and seal the strand), and mismatch re-
message-decoding process (translation) con- pair (in which enzymes recognize the mis-
sists of initiation, elongation, and termination. match nucleotide and either label it or repair it
In E. coli, the small subunit of a ribosome (the directly). The parental strand is distinguished
cells interior structure for protein produc- from the newly created daughter strand by tag-
tion) attaches to the ribosome-binding site of ging the parental strand with methyl groups at-
an mRNA, resulting in an initiation complex. tached to adenines occurring within specific
In elongation, the large subunit of the ribo- sequences. Such modified adenines act as la-
some attaches to the initiation complex, creat- bels for the parent strand, enabling the repair
ing two different binding sites for transfer RNA enzymes to recognize which strand should be
(tRNA), the amino acid transporter. Ribo- repaired at a mismatch position.
somes use mRNA-coded information to take
amino acids brought by tRNA and assemble Biotechnology
them, on ribosomes, into protein. To test a genetic hypothesis, the genetic his-
tory of the organism involved must be well
Mutation and DNA Repair known so that the genetic background of the
In the genetics of E. coli, phenotypes result- parents used in the experimental crosses is
ing from changes in the DNA can occur be- known. The genetics of E. coli provides geneti-
cause of either mutation (a change in the nu- cists with such an experimental organism. As a
cleotide sequence of a gene) or recombination result, E. coli is used extensively in biotechnol-
(a process leading to new combinations of ogy. In this industry, a foreign gene inserted
genes on a chromosome). These new combina- into the bacterium may be replicated and
tions can occur following transfer of chromo- sometimes translated in the same manner as
somal genes from one bacterial cell to another the native bacterial DNA, producing a foreign
by transformation (in which a recipient cell ac- gene product. Escherichia coli can accept foreign
quires genes from free DNA in the medium), DNA derived from any organism because the
transduction (in which a virus carries DNA genetic code is nearly universal. As an example,
from donor to recipient cell), or conjugation genetic mapping of a free-living, nitrogen-fix-
(in which two bacterial cells make contact and ing bacterium showed that seventeen genes in-
exchange DNA). Transposon and insertion el- volved in nitrogen fixation are clustered on
ements, both found in E. coli, may also change one portion of the chromosome. Biologists
phenotypes. A transposon is a mobile DNA seg- transferred this gene cluster to a plasmida
ment containing genes for inserting DNA into circular, independently replicating DNA mole-
the chromosome and for moving the element culeand introduced the plasmid into E. coli
532 Model Organism: Escherichia coli
cells, which then produced the enzyme nitro- uted in a revolutionary way to the understand-
genase and fixed nitrogen. ing of significant scientific concepts and to the
A significant breakthrough occurred when a understanding of the genetics of organisms
synthetic gene coding for somatostatin, an more complex than bacteria, such as humans.
antigrowth hormone important in the treat- In addition, recombinant DNA technology
ment of different human growth disorders, was (techniques for constructing, studying, and us-
fused with the start of the lacZ gene contained ing DNA created in a test tube), which uses E.
within a cloning vector (a self-duplicating DNA coli extensively, is used in all areas of basic ge-
molecule containing inserted, foreign DNA). netics research to investigate genetic circum-
Cells of E. coli transformed with this recombi- stances. Many biotechnology companies owe
nant plasmid were able to transcribe the fused their existence to recombinant DNA technol-
gene, recognizing the lac promoter as its bind- ogyand to E. colias they seek to clone and
ing site. The mRNA was then translated by ribo- manipulate genes for the production of com-
somes that recognized the lac ribosome bind- mercial products, the improvement of plant
ing sequence. The resulting fused protein was and animal agriculture, the development of di-
cleaved with cyanogen bromide, which cuts agnostic tools for genetic diseases, and the de-
amino acid chains specifically at methionines, velopment of new or more effective pharma-
resulting in pure-form somatostatin. ceuticals.
Robert Haynes
Implications for Evolution See also: Antibodies; Archaea; Bacterial
The genetics of E. coli provides evidence for Genetics and Cell Structure; Bacterial Resis-
punctuated equilibrium caused by the appear- tance and Super Bacteria; Blotting: Southern,
ance of rare, beneficial mutations. This evi- Northern, and Western; Chromosome Theory
dence involved studies that measured changes of Heredity; Cloning Vectors; DNA Isolation;
in cell size over three thousand generations of DNA Repair; Emerging Diseases; Gene Fam-
bacteria in a constant environment. During the ilies; Gene Regulation: Lac Operon; Gene Reg-
studies, periods of stagnancy were interrupted ulation: Viruses; Genetic Code; Genetic En-
by periods of rapid change. The changes in cell gineering; Genetic Engineering: Historical
size may be the result of direct selection for a Development; Genetic Engineering: Industrial
rare, beneficial mutation that caused increased Applications; Genetic Engineering: Medical Ap-
cell size. This mutation swept through the pop- plications; Genetics, Historical Development
ulation, producing a change in cell size in one of; Human Genome Project; Human Growth
hundred generations or less. Hormone; Model Organisms; Noncoding RNA
Molecules; Plasmids; Proteomics; Restriction
Impact and Applications Enzymes; Shotgun Cloning; Synthetic Genes;
Geneticists use model organisms for their re- Transposable Elements.
search. Their favorite organisms, such as E. coli,
have qualities that make them well suited for Further Reading
genetic experimentationa rich genetic his- Birge, Edward R. Bacterial and Bacteriophage Ge-
tory, a short life cycle, production of large prog- netics. 4th ed. New York: Springer, 2000. A
eny from a mating, ease in handling, and ge- comprehensive yet concise introductory look
netic variation among the individuals in the at bacterial genetics.
population. Added to the much that was al- Blattner, Frederick R., et al. The Complete
ready known about E. coli was the completion of Genome Sequence of Escherichia coli K12.
the complete sequence of the chromosome of Science 277 (1997): 1453-1452. The paper an-
E. coli in 1995. The quantity of genetics involv- nouncing the completion of the E. coli ge-
ing E. coli is a testament to the bacteriums suit- nome sequence.
ability as an experimental organism for testing Brown, Terence A. Genetics: A Molecular Ap-
genetic hypotheses. The hypotheses tested us- proach. 3d ed. New York: Chapman & Hall,
ing this experimental organism have contrib- 1998. A general treatment of the genetics
Model Organism: Mus musculus 533
of bacteria, including E. coli. Bibliography, litter size. It shares many similarities with humans
index. and is useful for modeling complex phenomena
Miller, Jeffrey H. A Short Course in Bacterial Ge- such as cancer and development.
netics: A Laboratory Manual and Handbook for
Escherichia Coli and Related Bacteria. Cold Key terms
Spring Harbor, N.Y.: Cold Spring Harbor embryonic stem cells: cultured cells derived
Laboratory Press, 1999. Summarizes the from an early embryo
genes and proteins of E. coli. genomics: the study of the entire DNA content
Parker, James N., and Philip M. Parker, eds. The of an organism, called its genome
Official Patients Sourcebook on E. Coli. San inbreeding: the process of mating brothers
Diego: ICON Health, 2002. Discusses topics and sisters to create genetically identical off-
including the essentials, seeking guidance, spring
the treatment process, and learning more model organism: an organism well suited for
about E. coli using the Internet. Includes ap- genetic research because it has a well-known
pendices, glossaries, and an index. genetic history, a short life cycle, and genetic
Perna, Nicole T., et al. Genome Sequence of variation between individuals in the popula-
Enterohaemorrhagic Escherichia coli O157: tion
H7. Nature 409 (2001): 529-533. Announced phenotype: an observable trait
the genome sequence for the virulent O157: transgenics: the technique of modifying an
H7 strain of E. coli. organism by introducing new DNA into its
Riley, Monica, and Margrethe Hauge Serres. chromosomes
Interim Report on Genomics of Escherichia
coli. Annual Review of Microbiology 54 (2000): History of Mice in Genetic Research
341-411. Updates the genome sequence. The use of mice in genetic research had its
origin in the efforts of mouse fanciers, who
Web Sites of Interest raised mice as pets and developed numerous
E. coli Genome Project, University of Wiscon- strains with distinct coat colors. Researchers in
sin. http://www.genome.wisc.edu. The ge- the late 1800s who were trying to determine
nome research center that sequenced the the validity of Gregor Mendels laws of heredity
organisms complete K-12 genome now in animals found the existence of domesticated
maintains and updates that sequence as well mice with distinct coat colors to be an ideal
as those of other strains and other patho- choice for their experiments. Through the
genic Enterobacteriaceae. work of early mouse geneticists such as Lucien
National Institutes of Health, Center for Bio- Cunot and others, Mendels ideas were vali-
technology Information. http://www.ncbi dated and expanded.
.nih.nlm.gov/genbank/genbanksearch
.html. For information on E.coli, see acces- Development of Inbred Strains
sion number U00096. As genetic work on mice continued into the
1900s, a number of mouse facilities were cre-
ated, including the Bussey Institute at Harvard
University. One member of the institute, Clar-
Model Organism: Mus ence Little, carried out a set of experiments
musculus that would help establish the utility of mice in
scientific research. Little mated a pair of mice
Field of study: Techniques and and then mated the offspring with each other.
methodologies He continued this process for many genera-
Significance: Model organisms allow geneticists to tions. After a number of generations of in-
investigate how genes affect organismal and cellu- breeding, Littles mice lost all genetic variation
lar function. The mouse is an ideal organism for and became genetically identical. These mice,
genetic research because of its size, life span, and named DBA mice, became the first strain of in-
534 Model Organism: Mus musculus
bred mice and marked an important contribu- human cancers. These mice became some of
tion to mouse research. In an experiment using the first mouse models used to study a human
inbred DBA mice, any difference displayed by disease.
two mice could not be due to genetic variation
and had to be from the result of the experi- Unique Aspects of the Mouse Model
ment. Through inbreeding, genetic variation The ability of mice to acquire cancer illus-
was removed as a variable. Also, through care- trates why the mouse is a unique and valuable
ful crossing and selection of different inbred tool for research. Although mice are not as easy
strains, populations of mice that differed by to maintain as other model organisms, they are
only a few genes could be created. Geneticists vertebrates and thus share a number of physio-
could then examine the effects of these genes logical and developmental similarities with hu-
knowing that all other genes were the same. mans. They can be used to model processes,
The creation of inbred mice allowed geneti- such as those involved in cancer and skeletal
cists to study genes in a carefully controlled way. development, that do not exist in simpler or-
The first use of inbred mice was in the study ganisms. In this capacity, mice represent a bal-
of cancer. As inbred strains of mice were cre- ance between the need for an animal with de-
ated, it was noticed that certain strains had a velopmental complexity and the need for an
tendency to develop cancer at a very high fre- animal with a quick generation time that is eas-
quency. Some of these strains developed tu- ily bred and raised. Other organisms, such as
mors that were very similar to those found in chimpanzees, may more closely resemble hu-
One of the most amazing discoveries in genetics is that very different organisms can have very similar genomes. This figure from the
Human Genome Program, for example, shows the similaries between the genes of mice and those of human beings. Approximately 80
to 90 percent of the genes in humans have a counterpart in the mouse. (U.S. Department of Energy Human Genome Pro-
gram, http://www.ornl.gov/hgmis)
Model Organism: Mus musculus 535
mans, but their lengthy generation time and to custom design mice to display the genetic de-
small litter size make them difficult to use for fects they desire.
the many and repeated experiments needed In the era of genomics, transgenic mice have
for genetic research. become a powerful tool in the effort to under-
The use of the mouse model has advanced stand the function of human genes. Since the
considerably since the early 1900s. Initially, ge- complete sequences of the mouse and human
neticists relied on the random occurrence of genomes are known, it is possible to compare
natural mutations to generate mice with traits the genes of mice and humans directly. Ap-
that mirrored aspects of human biology and proximately 80 to 90 percent of the genes in hu-
disease. Careful crossbreeding and the use of mans have a counterpart in the mouse. Using
inbred strains allowed the trait to be isolated transgenics to target genes in the mouse that
and maintained. Although this process was are similar to humans can help geneticists un-
slow and tedious, a large number of inbred derstand their functions. However, care must
strains were identified. Later, it was discovered be used in drawing comparisons. There are a
that X rays and other chemicals could increase number of examples of mouse genes that carry
the rate of mutation, leading to an increase in out functions different from their human
the rate at which mice with interesting traits counterparts. Despite this concern, compari-
could be found. However, the discovery of a son of mouse and human genes has provided
mouse strain that modeled a particular human tremendous insight into the function of the hu-
disease was still a matter of chance. man genome.
It was the advent of molecular biology that
removed this element of chance and brought Economic and Ethical Considerations
the mouse to its full prominence as a model The demand for mice in research has re-
organism. Molecular biology provided a mech- sulted in a $100 million industry devoted to the
anistic understanding of gene function and maintenance and development of mouse mod-
offered tools that allowed for the direct manip- els. Companies specializing in mice have devel-
ulation of genes. oped thousands of inbred strains for use in re-
search. The economic impact of mice has led to
Transgenic Mice patents on transgenic mice and has caused con-
The technique of transgenics allows geneti- troversy over who has the right to own a particu-
cists to create mice that carry specific muta- lar mouse strain. Also, the extensive use of mice
tions in specific genes. Using recombinant in research (25 million mice in the year 2000)
DNA technology, a geneticist can construct a has raised concerns by some for the welfare of
piece of DNA containing a mutant form of a mice and questions about the ethics of using
chosen gene, then use the mutated gene to them in research.
modify the existing DNA of mouse embryonic
stem cells. These modified embryonic stem Research Using the Mouse Model
cells can be combined with a normal mouse The study of cancer was the first area of re-
embryo to form a transgenic embryo that can search to benefit from the use of mice. Early
be implanted into the uterus of a female mouse. mouse geneticists were able to learn about the
The transgenic mouse that is born from this genetic and environmental factors that influ-
process carries in every tissue a mixture of nor- enced the development of cancer. Todays can-
mal cells and cells with the specific DNA alter- cer research relies heavily on the mouse model
ation introduced by the researcher. Careful as a way of determining how genes affect the in-
crossing of the transgenic mouse with mice of teraction between cancer and the body. Under-
the same inbred strain can then be done to cre- standing the function of tumor-suppressor
ate a new line of mice that carry the DNA alter- genes such as p53 has come in part from the use
ation in all cells. These mice will then express a of transgenic mice. Mice have also been impor-
phenotype that results directly from the modi- tant in investigating the role of the immune sys-
fied gene. Transgenics has allowed geneticists tem and angiogenesis in tumor progression.
536 Model Organism: Neurospora crassa
Mouse work in cancer also made contribu- standing text that covers the fields of genet-
tions to immunology, which relies heavily on ics and molecular biology. The reference sec-
the mouse as a model of an intact immune sys- tion in the back contains detailed portraits
tem. Inbred strains of mice with defective im- of model organisms, including the mouse.
mune systems have been developed to help ge- Silver, Lee. Mouse Genetics: Concepts and Applica-
neticists understand the role of the immune tions. New York: Oxford University Press,
system in disease progression and transplant 1995. A comprehensive reference providing
rejection. Mice have also been instrumental in a thorough explanation of the history and
studying how genes in pathogenic microorgan- rationale for the use of mice in genetic re-
isms allow the microbes to cause disease. The search. Designed for readers who are new to
mouse model has been used to understand the field of mouse genetics as well as those
how diseases like cholera and anthrax are able with experience.
to infect and cause damage.
The study of many genetic diseases, such as Web Sites of Interest
sickle-cell disease and phenylketonuria (PKU), Mouse Atlas and Gene Expression Database.
has benefited from the existence of mouse http://www3.oup.co.uk/nar/database/
models that mimic the disease. The genetic summary/20. The Medical Research Coun-
components of such complex phenomena as cil and the University of Edinburgh sponsor
heart disease and obesity are also being eluci- the site free on the Web; the data are also
dated using the mouse model. available for a fee on CD-ROM. This ongo-
Developmental biology has relied heavily on ing project is intended to evolve into the pre-
the mouse to determine how gene expression mier source for three-dimensional images
leads to the formation of multicellular organ- on morphology, gene expression, and mu-
isms. Work that has shown the role homeo- tant phenotypes in mouse development.
genes play in determining mammalian body The initial digital embr yo images are
structure and how genes affect development of mounted, accessible through a controlled
organs has been done in mouse models. vocabulary linked to the images. Develop-
The mouse has also proven to be a valuable mental geneticists will be able to synthesize
model in investigating the effects of various information from many sources.
genes on brain development and function. Mouse Genome Informatics, Jackson Labora-
Mouse models have provided insights into the tory, Bar Harbor, Maine. http://www.infor
way the brain develops and functions, as well as matics.jax.org. A center for mutant mouse
genetic contributions to complex behaviors. research, providing access to genetic maps,
Genes have been identified that play roles in phenotypes, gene expression data, and se-
complex behaviors such as raising young and quence information. Includes the Mouse
predisposition toward addiction. Genome Database, the Gene Expression Da-
Douglas H. Brown tabase, and the Mouse Genome Sequence
See also: Altruism; Chromosome Theory of Project.
Heredity; Model Organism: Arabidopsis thali-
ana; Model Organism: Caenorhabditis elegans;
Model Organism: Chlamydomonas reinhardtii;
Model Organism: Drosophila melanogaster; Model Organism:
Model Organism: Escherichia coli; Model Organ-
ism: Neurospora crassa; Model Organism: Saccha-
Neurospora crassa
romyces cerevisiae; Model Organism: Xenopus Field of study: Techniques and
laevis; Model Organisms. methodologies
Significance: Neurospora crassa is a bread mold
Further Reading with a relatively small genome, allowing this or-
Hartwell, Leland, et al. Genetics: From Genes to ganism to be studied by causing mutations in its
Genomes. Boston: McGraw-Hill, 2003. An out- genes and observing the effects of these mutations.
Model Organism: Neurospora crassa 537
Such studies are important to the understanding mechanisms because the four products of mei-
of genetics and genetically related disease, particu- osis (later duplicated by mitosis to produce
larly because N. crassa is eukaryotic and more eight spores) are arranged in the organisms
similar to human DNA than it is to bacteria and saclike ascus in a way that exactly reflects the
viruses. orientation of the four chromatids of each
tetrad at the metaphase plate in the first mei-
Key terms otic division. The products of meiosis line up in
ascomycetes: organisms of the phylum order and therefore are more easily studied in
Ascomycota, a group of fungi known as the sac this organism.
fungi, which are characterized by a saclike
structure, the ascus One Gene, One Enzyme
auxotrophic strain: a mutant strain of an or- In 1941 George Beadle and Edward Tatum
ganism that cannot synthesize a substance published a paper establishing biochemical
required for growth and therefore must genetics as an experimental science. They in-
have the substance supplied in the growth troduced a procedure for isolating an impor-
medium tant class of lethal mutations in an organism,
cytogenetics: the study of normal and mu- namely, those for blocking the synthesis of es-
tated chromosomes and their behavior sential biological substances. These were ex-
diploid cell: a cell that contains two copies of pressed in the organism as new nutritional re-
each chromosome quirements.
haploid cell: a cell that contains one copy of By supplying a variety of compounds in the
each chromosome nutrient medium and seeing which allowed
minimal medium: an environment that con- various mutant strains to grow and which did
tains the simplest set of ingredients that the not, Beadle and Tatum saw that they could de-
microorganism can use to produce all the duce the sequence of biochemical reactions in
substances required for reproduction and cells that make necessary compounds, such as
growth amino acids. They concluded that the function
model organism: an organism well suited for of a gene is to direct the formation of a particu-
genetic research because it has a well-known lar enzyme which regulates a chemical event. A
genetic history, a short life cycle (allowing mutation can alter a gene so that it no longer
the production of several generations in a produces the normal enzyme, resulting in a
short space of time), and genetic variation physical symptom, such as the need for nutri-
between individuals in the population tional supplements. Beadle and Tatum pro-
posed that, in general, each gene directs the
The Beginning of Biochemical Genetics formation of one enzyme.
Neurospora crassa was first used in genetic ex- These mutation studies promoted under-
periments by Carl Lindegren in the 1930s. He standing of the biochemistry of gene expres-
was able to isolate several morphological mu- sion and promoted the use of fungi in genetic
tant strains and create the first linkage maps experiments. In 1958, Beadle and Tatum were
showing where genes are located on chromo- awarded the Nobel Prize in Physiology or Medi-
somes. This research determined some of the cine for their discovery that the characteristic
basic principles of crossing over during meio- function of the gene was to control the synthe-
sis. Crossing over is the exchange of genes be- sis of a particular enzyme.
tween homologous chromosome pairs by the
breaking and reunion of the chromosome. The Organism
Lindegren was able to show that crossing over The orange bread mold Neurospora crassa, a
occurs before the separation of the homolo- multicellular lower eukaryote, is the best char-
gous pair, between the second and fourth chro- acterized of the filamentous fungi. Filamen-
matids. Neurospora crassa was used as a model tous fungi are a group of fungi with a micro-
organism in the investigation of crossing-over scopic, stalklike structure called the mycelium.
538 Model Organism: Neurospora crassa
They grow on substances of plant or animal ori- known as repeat-induced point (RIP) muta-
gins and reproduce via spores. This group of tions, the creation of point mutations of a sin-
organisms has importance in agriculture, med- gle base pair in specific genes. RIP detects du-
icine, and the environment because they are plications of gene-sized segments and creates
so abundant and are able to proliferate very repeated point mutations. RIP specifically
quickly. It is therefore easy and cheap to repro- changes a GC (guanine-cytosine) pair to an AT
duce them rapidly. Moreover, the widespread (adenine-thymine) pair. Repeated sequences
availability of Neurospora crassa in nature makes are heavily mutated by RIP in the period be-
genetic population studies more feasible. Be- tween fertilization (the time when the sperm
cause it can be grown in large quantity, experi- comes into contact with the egg) and karyog-
ments are easier to conduct and their results amy (fusion of the haploid cells to form diploid
are more easily analyzed. cells). After the mutation, the altered sequence
Neurospora crassa is a filamentous ascomycete is methylated (a CH3, or methyl, group is at-
that has asci; an ascus is a saclike structure in- tached). The methyl group serves as a tag so
side of which four or eight ascospores develop the mutations can be easily identified. RIP mu-
during reproduction. In the N. crassa asci, one tations usually indicate a crossing over during
round of mitosis usually follows meiosis and meiosis. RIP mutations cause inactivations of
leaves eight nuclei (new daughter cells). These duplicate genes, whose functions are then more
nuclei eventually become eight ascospores easily detected.
(sexual spores produced by ascomycetes). Af-
ter the ascospores are formed within the ascus, Sequencing and Linkage
they are released and germinate to form a new Large-scale sequencing of the N. crassa ge-
haploid mycelium. nome has been initiated for several linkage
groups (genes that are located on the same
A Model Organism chromosomes). Early in the sequencing of the
Geneticists use a variety of organisms in their N. crassa genome, it became apparent that its
research. Because it is haploid (containing half genome contains many unique genes. These
the chromosomal material of the parent cell), genes and others have been sorted into linkage
genotypic changes in N. crassa (mutations in groups. There are many maps available for N.
genes) are directly obser ved through the crassa. The largest group is that at the White-
changes in the phenotype (physical character- head Institute Center for Genome Research
istics), because only one gene determines phys- under the Fungal Genome Initiative. Restric-
ical characteristics. The small size of the ge- tion fragment length polymorphism (RFLP)
nome is a result of a unique feature of N. crassa: maps show the restriction site for a particular
It has very little repeated DNA. The lack of re- restriction endonuclease. Linkage maps show
petitive DNA is also valuable to researchers the distribution and linkage of genes through-
when parts of the genome are amplified or se- out the N. crassa genome. These maps are par-
quenced. ticularly important when a researcher is inter-
Neurospora crassa has been extensively used ested in recombinant DNA research.
for genetic research, resulting in hundreds of Leah C. Nesbitt, James N. Robinson, and
published articles. They include research on Massimo D. Bezoari
gene expression and effects of external factors, See also: Chromosome Theory of Heredity;
metabolic studies, and genomal mapping ex- Complementation Testing; Extrachromosomal
periments. A large number of mutants have Inheritance; Genetics, Historical Development
been characterized, providing the foundation of; Model Organism: Arabidopsis thaliana; Model
for many genetic experiments. Organism: Caenorhabditis elegans; Model Organ-
ism: Chlamydomonas reinhardtii; Model Organ-
Repeat-Induced Point (RIP) Mutations ism: Drosophila melanogaster; Model Organism:
By using recombinant DNA methods, re- Escherichia coli; Model Organism: Mus musculus;
searchers can study N. crassa using a technique Model Organism: Saccharomyces cerevisiae; Model
Model Organism: Saccharomyces cerevisiae 539
Organism: Xenopus laevis; Model Organisms; ware, and sequencing databases; provides
One Gene-One Enzyme Hypothesis. access to one of the largest collections of
linkage maps for Neurospora under the Fun-
Further Reading gal Genome Initiative.
Beadle, G. W., and E. L. Tatum. Genetic Con-
trol of Biochemical Reactions in Neurospora.
Proceedings of the National Academy of Sciences
27 (1941): 499-506. This is the article that Model Organism:
made Neurospora famous. It lays down the Saccharomyces cerevisiae
foundations of the one gene, one enzyme
hypothesis. Field of study: Techniques and
Davis, Rowland H. Neurospora: Contributions of a methodologies
Model Organism. New York: Oxford Univer- Significance: Saccharomyces cerevisiae is a
sity Press, 2000. A full account of the organ- highly tractable yeast organism that was the first
isms history, biology, genome, mitosis, mei- eukaryote to have its DNA completely sequenced.
osis, metabolism, mutations, and more. Yeast genetic research has been at the forefront of
Horowitz, N. H. Fifty Years Ago: The Neuro- scientists efforts to identify the genes and processes
spora Revolution. Genetics 127 (1991): 631- required for cell growth and division and is now
636. This article is a brief history of Neuro- an important tool for nonyeast research to identify
spora and its contributions to genetics and proteins that physically interact with one another
biochemistry. The article outlines Beadles in the cell.
discovery of Neurospora as a model organism.
Kinsey, J. A., P. W. Garrett-Engele, E. B. Cam- Key terms
bareri, and E. U. Selker. The Neurospora ascus: the cellular structure that results from
Transposon Tad Is Sensitive to Repeat- meiosis in yeast, containing four recombi-
Induced Point Mutation (RIP). Genetics 138 nant spores that are fully capable of growing
(1994): 657-664. This paper describes the into haploid yeast cells
RIP mechanisms and the direct effects of budding: the asexual method of duplication
RIP on the transposon Tad. used by yeast to create a clone of the original
Thancker, Paul D. Understanding Fungi cell
Through Their Genomes. Bioscience 53, no. diploid cell: a cell that contains two copies of
1 (January, 2003): 10-15. Useful for students each chromosome
and researchers. haploid cell: a cell that contains one copy of
each chromosome
Web Sites of Interest mating type: one of two types of yeast cell, de-
Neugenesis. http://www.neugenesis.com. Site pending on a soluble factor that each cell se-
of a company that produces commercial cretes
quantities of monoclonal antibodies model organism: an organism well suited for
(MAbs), generates and screens for new gene genetic research because it has a well-known
sequences specifying commercially valuable genetic history, a short life cycle, and genetic
products, assembles combinatorial cellular variation between individuals in the popula-
arrays for screening of multicomponent tion
gene and protein variants, and produces cell
libraries expressing a wide range of recombi- The Organism
nant protein products. Includes a discussion Saccharomyces cerevisiae (S. cerevisiae, or
of the repeat-induced point mutation mech- bakers yeast) has been used for millennia to
anism. provide leavening to bread products. Yeast is a
Whitehead Institute for Biomedical Research. simple, one-celled eukaryote with six thousand
http://www-genome.wi.mit.edu. One of the genes on sixteen chromosomes. It was the first
major gateways to genomics research, soft- eukaryote to have its entire DNA sequenced.
540 Model Organism: Saccharomyces cerevisiae
Yeast produce offspring using two different and cellular division. Yeast use many of the
methods, a sexual life cycle and an asexual life same genes and proteins to govern the same
cycle. In the asexual life cycle, the yeast cell pro- processes that animal and plant cells use for
duces the next generation by a process called growth and division. Each single cell has to take
budding. All genetic components of the in nutrients, grow, and pass along information
mother cell are duplicated and a small bud to its progeny. In many ways, yeast can be con-
begins to grow from the mother cell. The bud sidered a simplified version of a plant or animal
continues to grow until it is nearly the size of cell, in that it lacks all the genes that provide
the mother cell. The DNA and other dupli- the determinants that are expressed as differ-
cated cellular components are then parti- ences between plants and animals. Another im-
tioned into the new bud. The cells undergo cy- portant reason for using yeast is that yeast is
tokinesis and are now separate entities able to amenable to investigation using both genetic
grow and continue reproducing indepen- and biochemical approaches. This allows for
dently of one another. correlation of findings from both approaches
To produce offspring that are not clones of and a better understanding of a specific pro-
the mother cell, yeast use a sexual life cycle. A cess or activity.
yeast cell exists stably as either a diploid or a Yeast is also ideal for use as a model system
haploid organism, but only the haploid organ- due to at least four well-established techniques
ism is able to mate and exchange genetic infor- and procedures. First, genetics in yeast takes
mation. Haploid yeast contain either the MATa advantage of well-established auxotrophic
or MATalpha gene. These genes produce solu- markers. These markers are usually mutations
ble factors that distinguish them as one of two in biosynthetic pathways that are used to syn-
mating types. An a cell (MATa) and an al- thesize required cellular components such as
pha cell (MATalpha) mate by sequentially fus- amino acids and nucleotides. By using these
ing their cell walls, their cytoplasms, and finally marker genes, researchers can follow genes
their nuclei. This diploid cell now contains two and their associated chromosomes from one
copies of each chromosome that can undergo generation to the next.
recombination during meiosis. When all envi- Second, yeast is readily transformed by plas-
ronmental signals are ideal, the diploid yeast mids that function as artificial chromosomes.
will undergo meiosis, allowing exchange and All that is needed is an auxotrophic marker to
recombination of genetic information brought follow the plasmid through succeeding genera-
to the diploid by both haploid cells. The result tions, a yeast origin of replication to allow repli-
of meiosis is an ascus that contains four recom- cation of the plasmid DNA, and a region into
binant spores that will grow into haploid yeast which the gene of interest can be inserted in
cells when environmental conditions are ideal. the plasmid DNA. This allows the researcher to
move genes easily from yeast strain to yeast
A Model Organism strain and quickly examine the effect of the
Researchers choose yeast as a model organ- gene in combination with many other genes.
ism to study specific areas of interest for many Third, yeast is easily mutated by chemicals
different reasons. Saccharomyces cerevisiae is non- and can be grown in a small space, which allows
pathogenic to humans, allowing manipulation the researcher quickly to identify mutations in
in a laboratory with little or no containment re- genes that result in a specific phenotype. For
quired. At a temperature of 30 degrees Celsius example, to define all the genes in the adenine
(86 degrees Fahrenheit), the yeast population biosynthetic pathway, a researcher would mu-
can double in ninety minutes, allowing many tate a yeast strain with one of many available
experiments to be completed in one day. mutagenic chemicals, resulting in changes
Among the primary reasons for selection of within the DNA. The mutated yeast strains
yeast as a model system is that they offer the would then be checked to see if the strain was
possibility of studying the genes and proteins able to grow on media lacking adenine. All
that are required for basic growth functions of the strains mutant for growth on adenine
Model Organism: Saccharomyces cerevisiae 541
would be collected and could identify a num- serves as a signal that both of the gene products
ber of genes involved in the adenine biosyn- interact in the cell. The yeast strain containing
thetic pathway. Further research could estab- the active reporter gene is then selected and
lish whether each of these mutations in the further examined to determine the unknown
yeast identified one gene or many genes. DNA that resides on the second plasmid by se-
Fourth, yeast is the model system of choice quence analysis.
when examining and identifying proteins that
interact with one another in the cell. This tech- Research and Implications
nique is called the two-hybrid system. The years of work on yeast as a model system
have provided many insights into how genes
Two-Hybrid System and their protein products interact to coordi-
The two-hybrid system takes advantage of nate the many cellular mechanisms that take
scientists understanding of transcription at place in all cells from simple yeast to compli-
the GAL1 gene in yeast. The promoter region cated humans. It is impossible to exhaustively
of GAL1 contains a binding site for the Gal4p list the different areas of research currently be-
transcription factor. When the cell is grown on ing examined or completely list the new under-
the sugar galactose, Gal4p binds to the promot- standings that have come to light through the
er of GAL1 and activates transcription of the use of the S. cerevisiae model system. Every ma-
GAL1 gene. Gal4p can be essentially divided jor area of cellular research has at one time or
into two functional regions: one region that another used yeast to ask some of the more dif-
binds to DNA and another region that activates ficult questions that could not be asked in
transcription. other systems. Work in yeast has aided identifi-
The two-hybrid system uses the GAL1-Gal4p cation of genes and elucidated the mechanism
transcription system to identify previously un- of many different areas of research, including
known proteins that interact with a protein of cell cycle regulation, mechanisms of signal
interest. The system consists of a reporter gene transduction, the process of secretion, replica-
under the control of the GAL1 promoter and tion of DNA, transcription of DNA, translation
two plasmids that produce fusions with the of messenger RNA into proteins, biosynthetic
Gal4p transcription factor. The first plasmid pathways of amino acids and other basic build-
contains a gene of interest fused to a DNA- ing blocks of cells, and regulation and progres-
binding domain. This plasmid expresses a pro- sion of cells through mitosis and meiosis. De-
tein that is able to bind to the DNA-binding site spite all these advances, there is still much to
in the GAL1 promoter of the reporter gene. learn from yeast and it will continue to provide
This plasmid is unable to activate transcription information for years to come.
of the reporter gene, since the Gal4p fragment John R. Geiser
does not contain the information to activate See also: Cloning Vectors; Extrachromo-
transcription. The second plasmid is provided somal Inheritance; Linkage Maps; Model Or-
from a collection of plasmids that consist of un- ganisms; Noncoding RNA Molecules; Plas-
known or random genes fused to the transcrip- mids.
tion activation domain of Gal4p. This plasmid
by itself is unable to bind to the DNA-binding Further Reading
site in the GAL1 promoter and thus is unable to Broach, J., J. Pringle, and E. Jones, eds. The Mo-
activate transcription of the reporter gene. If lecular and Cellular Biology of the Yeast Saccharo-
both plasmids contain genes whose protein myces. 3 vols. Cold Spring Harbor, N.Y.: Cold
products physically interact in the cell, the Spring Harbor Laboratory Press, 1991-1997.
complex is able to bind to the DNA-binding re- This comprehensive series is dedicated to re-
gion of the GAL1 promoter, and since the acti- viewing the current understanding in many
vation domain of Gal4p is also present in this areas of yeast research. Volume 1 covers ge-
complex, activation of the reporter gene will nome dynamics, protein synthesis, and
occur. The production of the reporter gene energetics; volume 2, gene expression; and
542 Model Organism: Xenopus laevis
volume 3, the cell cycle and cell biology. The southern Africa. Members of this species share
individual reviews contain many references a distinctive habitat and morphology. The or-
to primary literature. ganisms name alone provides insight into its
Fields, S., and O. Song. A Novel Genetic Sys- structure and habitats: The root xeno stems
tem to Detect Protein-Protein Interactions. from Greek for strange, while pus is from the
Nature 340 (1989): 245-246. A seminal article Greek for foot and laevis is Latin for slip-
that describes the first use of the two-hybrid pery. Xenopus laevis is entirely aquatic, a fea-
system. Contains illustrations and descrip- ture that makes it unique among the other
tion of how the two-hybrid system functions. members of the genus, feeding and breeding
under water. It is believed that they evolved
Web Site of Interest from terrestrial anurans, organisms that are
Saccharomyces Genome Database. http://www aquatic as tadpoles but are terrestrial as adults.
.yeastgenome.org. The central site for the Migration across land from pond to pond has
sequencing projects, with links to data, ta- been observed but is limited by distance and
bles, and much more. time of year (occurring during the rainy sea-
son) because out of water the frogs will dry out
and die within a day. In instances of extreme
drought, adult frogs will bury themselves in the
mud and wait until the next rainfall.
Model Organism: Xenopus Xenopus laevis is mottled greenish-brown on
laevis its dorsal surface and yellowish-white on its
ventral surface. In appearance, these frogs are
Field of study: Techniques and flattened dorsoventrally with dorsally oriented
methodologies eyes as adults. The members of the genus are
Significance: Xenopus laevis, the African clawed collectively known as platannas from the word
frog, has been used widely in the field of develop- plathander, meaning flat-handed. Three toes
mental biology. By following the development of of the hind limbs are clawed, and a line of spe-
this unique organism, scientists have identified cialized sensory organs (the lateral line or-
and now understand the role of many genes in frog gans) is found on both the dorsal and ventral
development, providing insight into vertebrate de- surfaces and encircles the eyes. The breeding
velopment. season for X. laevis depends on temperature
and rainfall. The tadpoles are herbivorous,
Key terms feeding on algae, whereas the adults are carniv-
embryology: the study of developing embryos orous, feeding on worms, crustaceans, and
fate map: a map created by following the adult other creatures living in the mud.
fate of embryonic cells
model organism: an organism well suited for A Model Organism
genetic research because it has a well-known A model organism is defined as one that
genetic history, a short life cycle, and genetic breeds quickly, is easily managed in the labora-
variation between individuals in the popula- tory, and has large numbers of offspring or
tion broods. Xenopus laevis meets these require-
transgenic animal: an animal that contains a ments nicely. An interesting feature of this or-
gene not normally expressed in its genome ganism is its responsiveness to human chori-
onic gonadotropin, a hormone secreted by the
The Organism placenta and present in the urine of pregnant
The African clawed frog, Xenopus laevis, is women. When exposed to the hormone, fe-
in the class Amphibia, order Anura, suborder male frogs will spawn (lay eggs). As a result of
Opisthocoela, family Pipidae, and genus Xenopus. this phenomenon, X. laevis was once used as an
This genus includes five other species that in- indicator in human pregnancy tests, whereby
habit silt-filled ponds throughout much of the female frogs were injected with human fe-
Model Organism: Xenopus laevis 543
male urine. At present, researchers take advan- create these kinds of maps. One technique in-
tage of this phenomenon to produce large volves destroying single cells during early devel-
numbers of offspring by injecting frogs with opment and following the development of the
the hormone. Another characteristic that embryo to see what tissue is altered. Other
makes X. laevis a good model organism is that methods include transplantation of individual
it is hardy and can survive in captivity for long cells or small groups of cells into a host organ-
periods of time with relatively low mortality ism and following the fate of the transplanted
rates. tissue.
A final requirement for an animal model to
be useful is that research on the animal should Genetic Manipulation in Xenopus
add to the understanding of biological princi- Much of what is known today about the in-
ples in other organisms. Xenopus laevis is widely teractions between cells in developing verte-
used in the field of developmental biology. brate embryos has come from X. laevis. The
For many decades, amphibian embryologists early work of embryologists Hans Spemann
used salamander embryos, such as Triturus, and Pieter Nieuwkoop has been supported
and embryos of the frog Rana species. As men- with molecular techniques, and many genes
tioned above, amphibian embryos have several have been identified that control nearly every
advantages over other organisms: Amphibian aspect of Xenopus development. A few exam-
embryos are large, can be obtained in large ples include the Xenopus Brachury gene (Xbra),
numbers, and can be maintained easily and in- which is involved in the establishment of the
expensively in the laboratory. However, one dorsal-ventral axis; Xenopus ventral (vent1),
disadvantage of traditional amphibian species which aids in the differentiation of ventral
is that they are seasonal breeders. As a result, mesoderm and epidermal structures; and
investigators cannot conduct experiments Xenopus nodal-related 1 (Xnr1), a gene that is re-
throughout the year on most amphibians. Xe- sponsible for the specification of the left-right
nopus laevis is a notable exception, because it axis.
can be induced to breed year-round. Xenopus embryos possess a number of advan-
As the fertilized X. laevis zygote develops, the tages that have allowed investigators to study
yolk-laden cytoplasm, known as the vegetal many aspects of developmental biology. One of
pole, is oriented downward by gravity. The rest the struggles that early researchers faced was
of the cytoplasm, termed the animal pole, ori- the lack of dependable techniques for creating
ents itself upward. The animal pole is the main transgenic embryos to study the functions and
portion of the cell, giving rise to the embryo role of individual genes. One can isolate and
proper. Cell division, or cleavage of cells, in the clone the genes of Xenopus and inject RNA into
animal pole increases the number of cells zygotes. RNA, however, is an unstable molecule
greatly. Movement and migration of these cells, and relatively short-lived. Therefore, the study
under the influences of interactions with of molecular events in the embryo after the
neighboring cells, give rise to a multilaminar period when the embryonic genes are turned
embryo that includes the ectoderm (which on remained problematic. Attempts to inject
gives rise to skin and nervous system), the cloned DNA to be expressed in the embryo
mesoderm (which gives rise to muscle), and were complicated by the fact that it does not in-
the endoderm (which gives rise to many of the tegrate into the frog genomic chromosomes
tubes of the organism, such as the intestines during cleavage. Exogenous DNA is then un-
and the respiratory tract). equally distributed in embryonic cells and,
By following embryos from the very earliest therefore, is always expressed in random pat-
stages, researchers have been able to create terns. In 1996, Kristen L. Kroll and Enrique
fate maps of fertilized eggs, which can be Amaya developed a technique to make stable
used to predict adult derivatives of specific re- transgenic Xenopus embryos. This technique
gions in a developing embryo. Early research- has the potential to boost the utility of Xenopus
ers introduced many different techniques to tremendously. One significant advantage of us-
544 Model Organism: Xenopus laevis
Gregor Mendel to elucidate how particular which is the mustard plant Arabidopsis thaliana,
traits are transmitted from generation to gen- whose small genome, rapid generation time,
eration. The patterns of inheritance described and prolific seed production make it useful for
by Mendel for the garden pea are applicable to studying plant inheritance patterns, flower
all diploid, sexually reproducing organisms, generation, genetic responses to stress and
making the pea a model organism for studying pathogen attack, and developmental pattern-
gene transmission. Many other organisms have ing, among other important plant activities.
subsequently been exploited to investigate all Model organisms are also critical for en-
aspects of genetic influence on cell function. hancing our understanding of vertebrate ge-
Prokaryotic cells, particularly the intestinal netics. The African clawed frog Xenopus laevis
bacterium Escherichia coli, have provided im- and zebrafish Danio rerio are used to study basic
portant insights into basic cellular activities, vertebrate developmental patterns and the or-
ranging from DNA synthesis to protein transla- ganization of specific cell types into tissues and
tion to secretion of extracellular material. As organs. The primary model organism for analy-
unicellular eukaryotic cells, the brewers yeast sis of mammalian gene function is the house
Saccharomyces cerevisiae and fission yeast Schizo- mouse, Mus musculus. The generation of thou-
saccharomyces pombe have provided models for sands of mouse mutants, the ability to perform
eukaryotic cell function, including how genes targeted knockouts of specific mouse genes,
regulate cell division, how proteins are tar- and the completion of DNA sequencing of the
geted to particular locations in cells, and how mouse genome have made the mouse a useful
specific genes are turned on and off under spe- model for examining the role of genes in virtu-
cific conditions. ally all aspects of mammalian biology. In addi-
Multicellular model species are used to re- tion, the regions of DNA encoding genes in
veal how genes influence the interactions be- mice and humans are approximately 85 per-
tween cells, as well as the organization and cent identical, making the mouse important
function of the whole organism. The fruit fly not only for studying basic human biology but
Drosophila melanogaster has been used since the also as a model for understanding genetic in-
early twentieth century to investigate the asso- fluences on human health and disease.
ciation of particular traits with specific chromo- Kenneth D. Belanger
somes and was the first organism in which sex- See also: Model Organism: Arabidopsis thali-
linked inheritance was described. Drosophila ana; Model Organism: Caenorhabditis elegans;
has also been used to study developmental and Model Organism: Chlamydomonas reinhardtii;
behavioral genetics, providing important in- Model Organism: Drosophila melanogaster;
sights into the role genes play in determining Model Organism: Escherichia coli; Model Organ-
the organizational pattern of developing em- ism: Mus musculus; Model Organism: Neuro-
bryos and in influencing how organisms be- spora crassa; Model Organism: Saccharomyces cer-
have. evisiae; Model Organism: Xenopus laevis.
More recently, genetic examination of the
roundworm Caenorhabditis elegans has provided Further Reading
further insights into the role of genes in gener- Brookes, M. Fly: The Unsung Hero of Twentieth
ating developmental patterns. Some of these Century Science. New York: Ecco Press, 2001.
insights resulted in the awarding of the 2002 A descriptive history and analysis of the use
Nobel Prize in Physiology or Medicine to Syd- of Drosophila melanogaster to study biological
ney Brenner, H. Robert Horvitz, and John E. principles, from inheritance and develop-
Sulston for their work on apoptosis, or pro- ment to aging and alcohol tolerance.
grammed cell death, in C. elegans and its appli- Malakoff, D. The Rise of the Mouse: Biomedi-
cability to investigations of apoptosis in other cines Model Mammal. Science 288 (2000):
organisms, including humans. 248-253. Describes the use of the mouse in
Genetic analysis of plants is also performed enhancing scientists understanding of hu-
using model organisms, the most important of man biology, including the role of genes in
Molecular Clock Hypothesis 547
disease and the development of new bio- per gene) that must be removed when it is
medical treatments. transcribed into messenger RNA (mRNA);
Moore, J. A. Science as a Way of Knowing: The introns are assumed to have no function and
Foundations of Modern Biology. Cambridge, therefore mutations in them are often con-
Mass.: Harvard University Press, 1993. A bi- sidered neutral
ologist describes the history of biological re- neutral mutation: a mutation in a gene
search from Aristotle to modern molecular which is considered to have no effect on the
analysis. Contains several outstanding chap- fitness of the organism
ters on the use of model organisms to under- phylogeny: often called an evolutionary tree,
stand fundamental genetic concepts. the branching patterns that show evolution-
Pennisi, E. Arabidopsis Comes of Age. Science ary relationships, with the taxa on the ends
290 (2000): 32-35. Insightfully reviews the of the branches
role of Arabidopsis thaliana in elucidating taxon (pl. taxa): a general term used by evo-
plant biology. lutionists to refer to a type of organism at any
taxonomic rank in a classification of organ-
Web Site of Interest isms
Genetics Society of America. http://www
.genetics-gsa.org. Click on Model Organ- History
isms for links to Web pages on more than In 1962 mile Zuckerkandl and Linus Pau-
two dozen model organisms. ling published evidence that the rate of amino
acid substitution in proteins is constant over
time. In 1965, after several protein sequences
(cytochrome c, hemoglobin, and fibrinopep-
Molecular Clock Hypothesis tides) seemed to show this pattern, they pro-
posed the molecular clock hypothesis (MCH).
Fields of study: Evolutionary biology; According to their hypothesis, mutations lead-
Molecular genetics ing to changes in the amino acid sequence of a
Significance: The molecular clock hypothesis protein should occur at a constant rate over
(MCH) predicts that amino acid changes in pro- time, rather than per generation, as previously
teins and nucleotide changes in DNA are approxi- assumed. In other words, if the sequence of cy-
mately constant over time. When first proposed, it tochrome c were determined 1,000,000 years
was immediately embraced by many evolutionists ago, 500,000 years ago, and in the present, the
as a way to determine the absolute age of evolution- rate of amino acid substitution would be the
ary lineages. After more protein sequences were an- same between the first two samples as it would
alyzed, however, many examples were inconsistent be between the second and third. To state this
with the MCH. The theory has generated a great more accurately, they considered the rate ap-
deal of controversy among evolutionists, and al- proximately constant, which means that one
though it is now generally accepted that many protein may display some variation, but if the
genes do not change at constant rates, methods are average rates of change for several were consid-
still being developed to determine the ages of lin- ered as a group, they would be constant.
eages based on amino acid and nucleotide substi-
tutions. Importance of the Molecular Clock
Hypothesis
Key terms The evolutionary importance of the MCH
codon: a three-letter nucleotide sequence in was almost immediately apparent. Paleontolo-
RNA or DNA that codes for a specific amino gists had long determined the ages of fossils us-
acid; a gene is composed of a long string of ing radioactive dating techniques, but deter-
codons mining the date of a fossil was not the same as
intron: an intervening sequence in a eukary- determining how long ago flowering plants di-
otic gene (generally there are several to many verged (evolved from) the other vascular
548 Molecular Clock Hypothesis
plants, for example. Using the MCH, research- The strength of the neutral theory was that,
ers could compare the amino acid sequences of unlike mutations that affect the amino acid se-
a protein in a flowering plant and another vas- quence, neutral mutations should occur at a
cular plant, and if the substitution rate (that is, constant rate over time. Therefore, Kimura
substitutions per unit of time) was known, they predicted that the MCH would be valid for neu-
could determine how long ago these two plants tral mutations. Most eukaryotic genomes are
diverged. The MCH held great promise for riddled with sequences, like introns or highly
solving many of the questions about when vari- repetitive DNA, that have no apparent function
ous groups of organisms diverged from their and can therefore be assumed to be prone to
common ancestors. To calibrate the clock neutral mutations. Even within the coding re-
that is, to determine the rate of amino acid gions (exons) of expressed genes, the third
substitutionsall that was needed were the se- position of many codons can be changed with-
quences of some taxa and a reliable age for fos- out affecting the amino acid for which it codes.
sils considered to represent the common an- A number of evolutionists expressed skepti-
cestor to the taxa. Once this clock had been cism concerning the neutral theory, arguing
calibrated, other taxa that might not be as well that there is probably no truly neutral muta-
represented in the fossil record could be stud- tion.
ied, and their time of divergence could be de- As DNA sequences poured in, much the
termined as well. same story emerged as for protein sequences.
As more data accumulated through the next Whether or not neutral mutations exist, nucle-
twenty years, it was discovered that amino acid otide substitutions that were assumed to be
substitutions in many proteins were not as neutral turned out to tick no better. In the
clocklike as hoped. Rates over time seemed to 1980s the controversy over the MCH reached
slow down and speed up, and there was no pre- its height, and most evolutionists were forced
dictable pattern to the changes. In fact, the to conclude that very few genes, or neutral se-
same proteins in different evolutionary lin- quences, behaved like a clock. Even those that
eages often ticked at a different rate. did behave like clocks did not tick at the same
rate in all lineages, and even worse, some genes
The Neutral Theory ticked more or less steadily in some lineages
During the time that more and more proteins and very erratically in others. Comparisons
were being sequenced, DNA sequencing grad- among the many amino acid and nucleotide se-
ually began to dominate. One of the theories quences revealed another surprise: Amino acid
about why the MCH did not seem to be working sequences tended, on average, to be more reli-
was that protein sequences were constrained by able than nucleotide sequences.
natural selection. The intensity of natural selec-
tion has always been assumed to vary over time, Beyond the Molecular Clock
and if this is true, then amino acid substitution Since the 1980s, the MCH has fallen into
rates should also increase and decrease as some disfavor among most evolutionists, but at-
kind of function of the pressure exerted by nat- tempts to use amino acid and nucleotide se-
ural selection. DNA sequences were quickly quences to estimate evolutionary ages are still
hailed as the solution to this problem. In 1968, being made. In a few cases, often in closely
Motoo Kimura proposed the neutral theory, in related taxa, the MCH works, but other ap-
which he proposed that any nucleotide substi- proaches are used more often. Many of these
tution in DNA that occurred in a noncoding re- approaches attempt to take into account the
gion, or that did not change the amino acid se- highly variable substitution rates among differ-
quence in the genes product, would be ent lineages and over time. Rather than using a
unaffected by natural selection. He suggested single protein or DNA sequence, as was at-
that because of this, neutral mutations (nucleo- tempted when the MCH was first developed,
tide substitutions) would be free to take place they use several in the same analysis. Data anal-
without being weeded out by selection. ysis relies on complex, and sometimes esoteric,
Molecular Genetics 549
and RNA, while thymine (T) is normally found the compact structure of chromosomes. These
only in DNA and uracil (U) only in RNA. In the can be seen with help of a microscope. The
double-helical DNA molecule, two strands are complex of DNA and protein is called chro-
helically intertwined in opposite directions. matin.
The nucleotide strands are held together in The term genome denotes the roster of
part by interactions specific to the bases, which genes and other DNA of an organism. Most eu-
pair perpendicular to the sugar-phosphate karyotes have more than one genome. The
strands. The structure can be envisioned as a principal genome is the genome of the nucleus
ladder. The A and T bases pair with each other, that controls most of the activities of cells. Two
and G and C bases pair with each other, form- organelles, the mitochondria (which produce
ing rungs; the sugar-phosphates, joined end energy by oxidizing chemicals) and the plastids
to end, form the sides of the ladder. The en- (such as chloroplasts, which convert light to
tire molecule twists and bends in on itself to chemical energy in photosynthesis) have their
form a compact whole. An RNA molecule is es- own genomes. The organelle genomes have
sentially half of this ladder, split down the only some of the genes needed for their func-
middle. RNA molecules generally adopt less tioning. The others are present in the nuclear
regular structures but may also require pairing genome. Nuclear genomes have many copies
between bases. of some genes. Some repeated sequences are
DNA and RNA, in various forms, serve as the organized tandemly, one after the other, while
molecules of heredity. RNA is the genetic mate- others are interspersed with unique sequences.
rial that some viruses package in viral particles. Some repeated sequences are genes present in
One or several molecules of RNA may make up many copies, while others are DNAs of un-
the viral information. The genetic material of known function.
most bacteria is a single circle of double-helical
DNA, the circle consisting of from slightly more Copying and Transmission of Genetic
than 500,000 to about 5 million nucleotide Nucleic Acids
pairs. In eukaryotes such as humans, the DNA James Watson and Francis Cricks double-
genetic material is organized into multiple lin- helical structure for DNA suggested to them
ear DNA molecules, each one the essence of a how a faithful copy of a DNA could be made.
morphologically recognizable and genetically The strands would pull apart. One by one, the
identifiable structure called a chromosome. new nucleotide units would then arrange
In each organism, the DNA is closely associ- themselves by pairing with the correct base on
ated with proteins. Proteins are made of one the exposed strands. When zipped together,
or more polypeptides. Polypeptides are linear the new units make a new strand of DNA. The
polymers, like nucleic acids, but the units linked process, called DNA replication, makes two
end to end are amino acids rather than nucleo- double-helical DNAs from one original one.
tides. More than twenty kinds of amino acids Each daughter double-helical DNA has one old
make up polypeptides. Proteins are generally and one new strand. This kind of replication,
smaller than DNA molecules and assume a vari- called semiconservative replication, was con-
ety of shapes. Proteins contribute to the biolog- firmed by an experiment by Matthew Meselson
ical characteristics of an organism in many and Franklin Stahl.
ways: They are major components of structures Enzymes cannot copy DNA of eukaryotic
both inside (membranes and fibers) and out- chromosomes completely to each end of the
side (hair and nails) the cell; as enzymes, they DNA strands. This is not a problem for bacte-
initiate the thousands of chemical reactions ria, whose circular genomes do not have ends.
that cells use to get energy and build new To keep the ends from getting shorter with
cells; and they regulate the activities of cells. each cycle of replication, eukaryotic chromo-
Histone proteins pack eukaryotic nuclear DNA somes have special structures called telomeres
into tight bundles called nucleosomes. Further at their ends that are targets of a special DNA
coiling and looping of nucleosomes results in synthesis enzyme.
Molecular Genetics 551
When a cell divides, each daughter cell must also respond to changes in their environment.
get one and only one complete copy of the The differences among cell types and among
mother cells DNA. In most bacterial chromo- cells in different environmental conditions are
somes, this DNA synthesis starts at only one caused by the synthesis of different proteins.
place, and that starting point is controlled so For the most part, regulation of which proteins
that the number of starts equals the number of are synthesized and which are not occurs by
cell fissions. In eukaryotes, DNA synthesis be- controlling the synthesis of the mRNAs for
gins at multiple sites, and each site, once it has these proteins. Genes can have their transcrip-
begun synthesis, does not begin another round tion switched on or switched off by the binding
until after cell division. When DNA has been of protein factors to a segment of the gene that
completely copied, the chromosomes line up determines whether transcription will start or
for distribution to the daughter cells. Protein not. An important part of this gene segment is
complexes called kinetochores bind to a spe- the promoter. It tells the transcription appara-
cial region of each chromosomes DNA called tus to start RNA synthesis only at a particular
the centromere. Kinetochores attach to point in the gene.
microtubules, fibers that provide the tracks Not all RNAs are ready to function the mo-
along which the chromosomes move during ment their synthesis is over. Many RNA tran-
their segregation into daughter cells. scripts have alternating exon and intron seg-
ments. The intron segments are taken out with
Gene Expression, Transcription, and splicing of the end of one exon to the begin-
Translation ning of the next. Other transcripts are cut at
DNA is often dubbed the blueprint of life. It several specific places so that several functional
is more accurate to describe DNA as the com- RNAs arise from one transcript. Eukaryotic
puter tape of lifes instructions because the mRNAs get poly-A tails (about two hundred nu-
DNA information is a linear, one-dimensional cleotide units in which every base is an A)
series of units rather than a two-dimensional di- added after transcription. A few RNAs are ed-
agram. In the flow of information from the ited after transcription, some extensively by
DNA tape to what is recognized as life, two steps adding or removing U nucleotides in the mid-
require the decoding of nucleotide sequence dle of the RNA, others by changing specific
information. The first step, the copying of the bases.
DNA information into RNA, is called transcrip- Translation occurs on particles called ribo-
tion, an analogy to medieval monks sitting in somes and converts the sequence of nucleotide
their cells copying, letter by letter, old Latin residues in mRNA into the sequence of amino
manuscripts. The letters and words in the new acid residues in a polypeptide. Since protein is
version are the same as in the old but are writ- created as a consequence of translation, the
ten with a different hand and thus have a process is also called protein synthesis. The
slightly different appearance. The second step, mRNA carries the code for the order of inser-
in which amino acids are polymerized in re- tion of amino acids in three nucleotide units
sponse to the RNA information, is called trans- called codons. Failure of the ribosome to read
lation. Here, the monks take the Latin words nucleotides three at a time leads to shifts in the
and find English, German, or French equiva- frame of reading the mRNA message. The
lents. The product is not in the nucleotide lan- frame of reading mRNA is set by starting trans-
guage but in the language of polypeptide se- lation only at a special codon.
quences. The RNAs that direct the order of Transfer RNA (tRNA) molecules actually do
amino acids are called messenger RNAs the translating. There is at least one tRNA for
(mRNAs) because they bring instructions from each of the twenty common amino acids. Anti-
the DNA to the ribosome, the site of transla- codon regions of the tRNAs each specifically
tion. pair with only a specific subset of mRNA
Multicellular organisms consist of a variety codons. For each amino acid there is at least
of cells, each with a particular function. Cells one enzyme that attaches the amino acid to the
552 Molecular Genetics
correct tRNA. These enzymes are thus at the of one or more nucleotides. Mutations may be
center of translation, recognizing both amino beneficial, neutral, or harmful. They are the
acid and nucleotide residues. targets of the natural selection that drives evo-
The ribosomes have sites for binding of lution. Since some mutations are harmful, sur-
mRNA, tRNA, and a variety of protein factors. vival of the species requires that they be kept to
Ribosomes also catalyze the joining of amino a low level.
acids to the growing polypeptide chain. The Systems that repair DNA are thus very im-
protein factors, usually loosely bound to ribo- portant for the accurate transmission of the
somes, assist in the proper initiation of poly- DNA information tape. Several kinds of sys-
peptide chains, in the binding of amino acid- tems have evolved to repair damaged DNA be-
bearing tRNA to the ribosome, and in moving fore it can be copied. In one, enzymes directly
the ribosome relative to the mRNA after each reverse the damage to DNA. In a second, the
additional step. Three steps in translation use damaged base is removed, and the nucleotide
biochemical energy: attaching the amino acid chain is split to allow its repair by a limited re-
to the tRNA, binding the amino acyl tRNA to synthesis. In a third, a protein complex recog-
the ribosome-mRNA complex, and moving the nizes the DNA damage, which results in inci-
ribosome relative to the mRNA. sions in the DNA backbone on both sides of the
damage. The segment containing the damage
Protein Processing and DNA Mutation is removed, and the gap is filled by a limited re-
The completed polypeptide chain is pro- synthesis. In still another, mismatched base
cessed in one or more ways before it assumes its pairs, such as those that result from errors in
role as a mature protein. The linear string of replication, are recognized, and an incision is
amino acid units folds into a complex, three- made some distance away from the mismatch.
dimensional structure, sometimes with the The entire stretch from the incision point to
help of other proteins. Signals in some pro- past the mismatch is then resynthesized. Fi-
teins amino acid sequences direct them to nally, the molecular machinery that exchanges
their proper destinations after they leave the ri- DNA segments, the recombination machinery,
bosomes. Some signals are removable, while may be mobilized to repair damage that cannot
others remain part of the protein. Some newly be handled by the other systems.
synthesized proteins are called polyproteins
because they are snipped at specific sites, giving Invasion and Amplification of Genes
several proteins from one translation product. Mutation is only one way that genomes
Finally, individual amino acid units may get change from generation to generation. An-
other groups attached to them or be modified other way is via the invasion of an organisms
in other ways. genome by other genomes or genome seg-
The DNA information can be corrupted by ments. Bacteria have evolved restriction modi-
reaction with certain chemicals, some of which fication systems to protect themselves from such
are naturally occurring while others are pres- invasions. The gene for restriction encodes an
ent in the environment. Ultraviolet and ioniz- enzyme that cleaves DNA whenever a particu-
ing radiation can also damage DNA. In addi- lar short sequence of nucleotides is present. It
tion, the apparatus that replicates DNA will does not recognize that sequence when it has
make a mistake at low frequency and insert the been modified with a methyl group on one of
wrong nucleotide. its bases. The gene for modification encodes
Collectively, these changes in DNA are the enzyme that adds the methyl group. Thus
called DNA damage. When DNA damage goes the bacteriums own DNA is protected. How-
unrepaired before the next round of copying ever, DNA that enters the cell from outside,
of the DNA, mutations (inherited changes in such as by phage infection or by direct DNA up-
nucleotide sequence) result. Mutations may be take, is not so protected and will be targeted for
substitutions, in which one base replaces an- degradation by the restriction enzyme. Despite
other. They may also be insertions or deletions restriction, transfer of genes from one species
Molecular Genetics 553
to another (horizontal, or lateral, gene trans- chains. In most cells in the body, the genes for
fer) has occurred. light chains are in two separated segments, and
As far as is known, restriction modification those for heavy chains are in three. During the
systems are unique to bacteria. Gene transfer maturation of cells that make antibodies, the
from bacteria to plants occurs naturally in dis- genes are rearranged, bringing these segments
eases caused by bacteria of the Agrobacterium ge- together. The joining of segments is not pre-
nus. As part of the infection process, these bac- cise. The imprecision contributes to the diver-
teria transfer a part of their DNA containing sity of possible antibody molecules.
genes, only active in plants, into the plant ge- Cells of bakers or brewers yeast (Saccharo-
nome. Studies with fungi and higher plants myces cerevisiae) have genes specifying their sex,
suggest that eukaryotes cope with gene inva- or mating type, in three locations. The infor-
sion by inactivating the genes (gene silencing) mation at one location, the expression locus, is
or their transcripts (cosuppression). the one that determines the mating type of the
Another way that genomes change is by du- cell. A copy of this information is in one of the
plications of gene-sized DNA segments. When other two sites, while the third has the informa-
the environment is such that the extra copy is tion specifying the opposite mating type. Yeast
advantageous, the cell with the duplication sur- cells switch mating types by replacing the infor-
vives better than one without the duplication. mation at the expression locus with informa-
Thus genes can be amplified under selective tion from a storage locus. Mating-type switching
pressure. In some tissues, such as salivary and antibody gene maturation are only two ex-
glands of dipteran insects and parts of higher amples of programmed gene rearrangements
plant embryos, there is replication of large seg- known to occur in a variety of organisms.
ments of chromosomes without cell division.
Monster chromosomes result. Genetic Recombination
Genomes also change because of movable Recombination occurs when DNA informa-
genetic elements. Inversions of genome seg- tion from one chromosome becomes attached
ments occur in bacteria and eukaryotes. Other to the DNA of another. When participating
segments can move from one location in the chromosomes are equivalent, the recombina-
genome to another. Some of these movements tion is called homologous. Homologous re-
appear to be rare, random events. Others serve combination in bacteria mainly serves a repair
particular functions and are programmed to function for extreme DNA damage. In many
occur under certain conditions. One kind of eukaryotes, recombination is essential for the
mobile element, the retrotransposon, moves segregation of chromosomes into gamete cells
into new locations via an RNA intermediate. during meiosis. Nevertheless, aspects of the
The element encodes an enzyme that makes a process are common between bacteria and eu-
DNA copy of the elements RNA transcript. karyotes. Starting recombination requires a
That copy inserts itself into other genome loca- break in at least one strand of the double-helical
tions. The process is similar to that used by ret- DNA. In the well-studied yeast cells, a double-
roviruses to establish infection in cells. Other strand break is required. Free DNA ends gener-
mobile elements, called transposons or ated by breaks invade the double-helical DNA
transposable elements, encode a transposase of the homologous chromosome. Further inva-
enzyme that inserts the element sequence, or a sion and DNA synthesis result in a structure in
copy of it, into a new location. When that new which the chromosomes are linked to one an-
location is in or near a gene, normal function- other. This structure, called a half-chiasma, is
ing of that gene is disturbed. recognized and resolved by an enzyme system.
The production of genes for antibodies (an Resolution can result in exchange so that one
important part of a humans immune defense end of one chromosome is linked to the other
system) is a biological function that requires end of the other chromosome and vice versa.
gene rearrangements. Antibody molecules con- Resolution can also result in restoration of the
sist of two polypeptides called light and heavy original linkage. In the latter case, the DNA
554 Molecular Genetics
around the exchange point may be that of the and recombinant growth hormone are rou-
other DNA. This is known as gene conversion. tinely given to those whose conditions demand
them. Through molecular genetics, doctors
Impact and Applications have diagnostic kits that can, with greater ra-
Molecular genetics is at the heart of biotech- pidity, greater specificity, and lower cost, deter-
nology, or genetic engineering. Its fundamen- mine whether a pathogen is present. Finally,
tal investigation of biological processes has pro- molecular genetics has been used to identify
vided tools for biotechnologists. Molecular genes responsible for many inherited diseases
cloning and gene manipulation in the test tube of humankind. Someday medicine may correct
rely heavily on restriction enzymes, other nu- some of these diseases by providing a good
cleic-acid-modifying enzymes, and extrachro- copy of the gene, a strategy called gene therapy.
mosomal DNA, all discovered during molecu- Ulrich Melcher
lar genetic investigation. The development of See also: Ancient DNA; Antisense RNA;
nucleic acid hybridization, which allows the Biochemical Mutations; Central Dogma of Mo-
identification of specific molecular clones in a lecular Biology; Chemical Mutagens; Chloro-
pool of others, required an understanding of plast Genes; Chromatin Packaging; DNA Isola-
DNA structure and dynamics. The widely used tion; DNA Repair; DNA Str ucture and
polymerase chain reaction (PCR), which can Function; Gene Families; Genetic Code; Ge-
amplify minute quantities of DNA, would not netic Code, Cracking of; Genome Size;
have been possible without discoveries in DNA Genomics; Molecular Clock Hypothesis; Muta-
replication. Genetic mapping, a prelude to the tion and Mutagenesis; Noncoding RNA Mole-
isolation of many genes, was sped along by mo- cules; Oncogenes; One Gene-One Enzyme Hy-
lecular markers detectable with restriction en- pothesis; Protein Structure; Protein Synthesis;
zymes or the PCR. Transposable elements and Proteomics; Pseudogenes; Repetitive DNA; Re-
the transferred DNA of Agrobacterium, because striction Enzymes; Reverse Transcriptase; RNA
they often inactivate genes when they insert in Isolation; RNA Structure and Function; RNA
them, were used to isolate the genes they inacti- Transcription and mRNA Processing; RNA
vate. The inserted elements served as tags or World; Signal Transduction; Steroid Hor-
handles by which the modified genes were mones; Telomeres; Transposable Elements;
pulled out of a collection of genes. Tumor-Suppressor Genes.
The knowledge of the molecular workings of
genes gained by curious scientists has allowed Further Reading
other scientists to intervene in many disease sit- Brown, Terence A. Genetics: A Molecular Ap-
uations, provide effective therapies, and im- proach. 3d ed. New York: Chapman & Hall,
prove biological production. Late twentieth 1998. Solid text with bibliography, index.
century scientists rapidly developed an under- Carroll, Sean B., Jennifer K. Grenier, and Scott
standing of the infection process of the acquired D. Weatherbee. From DNA to Diversity: Molecu-
immunodeficiency syndrome (AIDS) virus. The lar Genetics and the Evolution of Animal Design.
understanding, built on the skeleton of existing Malden, Mass.: Blackwell, 2001. Discusses
knowledge, has helped combat this debilitating morphology and its genetic basis, and evolu-
disease. Molecular genetics has also led to the tionary biologys synthesis with genetics and
safe and less expensive production of proteins embryology. Illustrations (some color), fig-
of industrial, agricultural, and pharmacological ures, tables, glossary, bibliography.
importance. The transfer of DNA from Agrobac- Clark, David P., and Lonnie D. Russell. Mo-
terium to plants has been exploited in the cre- lecular Biology Made Simple and Fun. 2d ed.
ation of transgenic plants. These plants offer a Vienna, Ill.: Cache River Press, 2000. A de-
new form of pest protection that provides an al- tailed and entertaining account of molecu-
ternative to objectionable pesticidal sprays and lar genetics. Bibliography, index.
protects against pathogens for which no other Hancock, John T. Molecular Genetics. Boston:
protection is available. Recombinant insulin Butterworth-Heinemann, 1999. Covers the
Monohybrid Inheritance 555
Mendel experimented with seven contrast- fect, by doing this, the investigator is working
ing traits in peas: stem height (tall vs. dwarf), with the equivalent of a monohybrid cross. In
seed form (smooth vs. wrinkled), seed color selecting an example, it is best to choose a trait
(yellow vs. green), pod form (inflated vs. con- that does not produce a major health or clini-
stricted), pod color (green vs. yellow), flower cal effect; otherwise, the clear-cut segregation
color (red vs. white), and flower position (axial ratios expected under monohybrid inheri-
vs. terminal). Within each of the seven sets, tance might not be seen in the matings.
there was no overlap between the traits and Consider the trait of albinism, a phenotype
thus no problem in classifying a plant as one or caused by a recessive gene. Albinism is the ab-
the other. For example, although there was sence of pigment in the hair, skin, and eyes.
some variation in height among the tall plants Similar albino genes have been found in many
and some variation among the dwarf plants, animals, including mice, buffalo, bats, frogs,
there was no overlap between the tall and dwarf and rattlesnakes. Since the albino gene is reces-
plants. sive, the gene may be designated with the sym-
Mendels first experiments crossed parents bol c and the gene for normal pigmentation as
that differed in only one trait. Matings of this C. Thus a mating between a homozygous nor-
type are known as monohybrid crosses, and the mal person (CC) and a homozygous albino
rules of inheritance derived from such matings person (cc) would be expected to produce chil-
yield examples of monohybrid inheritance. dren who are heterozygous (Cc) but pheno-
These first experiments provided the evidence typically normal, since the normal gene is dom-
for the principle of segregation and the princi- inant to the albino gene. Only normal genes, C,
ple of dominance. The principle of segregation would be passed on by the normally pigmented
refers to the separation of members of a gene parent, and only albino genes, c, would be
pair from each other during the formation of passed on by the albino parent. If there was a
gametes (the reproductive cells: sperm in mating between two heterozygous people (Cc
males and eggs in females). It was Mendel who and Cc), the law of segregation would predict
first used the terms dominant and reces- that each parent would produce two kinds of
sive. It is of interest to examine his words and gametes: C and c. The resulting progeny would
to realize how appropriate his definitions are be expected to appear at a ratio of 1CC: 2Cc: 1cc.
today: Those characters which are transmitted Since C is dominant to c, 3 4 of the progeny
entire, or almost unchanged by hybridization, would be expected to have normal pigment,
and therefore in themselves constitute the and 1 4 would be expected to be albino. There
characters of the hybrid, are termed the domi- are three genotypes (CC, Cc, and cc) and two
nant and those which become latent in the pro- phenotypes (normal pigmentation and albino).
cess recessive. The terms dominant and reces- By following the law of segregation and taking
sive are used to describe the characteristics of a account of the dominant gene, it is possible to
phenotype, and they may depend on the level determine the types of matings that might oc-
at which a phenotype is described. A gene that cur and to predict the types of children that
acts as a recessive for a particular external trait would be expected (see the table Phenotype
may turn out not to be so when its effect is mea- Predictions: Albino Children).
sured at the biochemical or molecular level. Because of dominance, it is not always possi-
ble to tell what type of mating has occurred. For
An Example of Monohybrid Inheritance example, in matings 1, 2, and 4 in the table, the
The best way of describing monohybrid in- parents are both normal in each case. Yet in
heritance is by working through an example. mating 4, 1 4 of the offspring are expected to be
Although any two people obviously differ in albino. A complication arises when it is realized
many genetic characteristics, it is possible, as that in mating 4 the couple might not produce
Mendel did with his pea plants, to follow one any offspring that are cc; in that case, all off-
trait governed by a single gene pair that is sepa- spring would be normal. Often, because of the
rate and independent of all other traits. In ef- small number of offspring in humans and
Monohybrid Inheritance 557
autosomes or body
Phenotype Predictions: Albino Children
chromosomes. The dif-
Parents Phenotypes Offspring Expected
ference in chromosomes
between the two sexes oc-
1. AA AA Normal Normal All AA (Normal) curs in the remaining two
2. AA Aa Normal Normal AA, Aa (All Normal) chromosomes. The two
chromosomes are known
3. AA aa Normal Albino All Aa (Normal) as the sex chromosomes.
4. Aa Aa Normal Normal AA, Aa, aa ( Normal, Albino) Males have an unlike pair
of sex chromosomes, one
5. Aa aa Normal Albino Aa, aa ( Normal, Albino)
designated the X chro-
6. aa aa Albino Albino All aa (Albino) mosome and the other,
smaller one designated
the Y chromosome. Fe-
males, on the other hand,
other animals, the ratios of offspring expected have a pair of like sex chromosomes, and these
under monohybrid inheritance might not be are similar to the X chromosome of the male.
realized. Looking at the different matings and Although the Y chromosome does not contain
the progeny that are expected, it is easy to see many genes, it is responsible for male develop-
how genetics can help to explain not only why ment. A person without a Y chromosome would
children resemble their parents but also why undergo female development. Since genes are
children do not resemble their parents. located on chromosomes, the pattern of trans-
mission of the genes demonstrates some strik-
Modification of Basic Mendelian ing differences from that of genes located on
Inheritance any of the autosomes. For practical purposes,
After Mendels work was rediscovered early sex linked usually refers to genes found on
in the twentieth century, it soon became appar- the X chromosome since the Y chromosome
ent that there were variations in monohybrid contains few genes. Although X-linked traits do
inheritance that apparently were not known to not follow the simple pattern of transmission
Mendel. Mendel studied seven pairs of con- of simple monohybrid inheritance as first de-
trasting traits, and in each case, one gene was scribed by Mendel, they still conform to his law
dominant and one gene was recessive. For each of segregation. Examination of a specific exam-
trait, there were only two variants of the gene. It ple is useful to understand the principle.
is now known that other possibilities exist. For The red-green color-blind gene is X-linked
example, other types of monohybrid inheri- and recessive, since females must have the gene
tance include codominance (in which both on both X chromosomes in order to exhibit the
genes are expressed in the heterozygote) and trait. For males, the terms recessive and dom-
sex linkage (an association of a trait with a gene inant really do not apply since the male has
on the X chromosome). Nevertheless, the law only one X chromosome (the Y chromosome
of segregation operates in these cases as well, does not contain any corresponding genes)
making it possible to understand inheritance and will express the trait whether the gene is re-
of the traits. cessive or dominant. An important implication
Within a cell, genes are found on chromo- of this is that X-linked traits appear more often
somes in the nucleus. Humans have forty-six in males than in females. In general, the more
chromosomes. Each person receives half of the severe the X-linked recessive trait is from a
chromosomes from each parent, and it is con- health point of view, the greater the proportion
venient to think of the chromosomes in pairs. of affected males to affected females.
Examination of the chromosomes in males and If the color-blind gene is designated cb and
females reveals an interesting difference. Both the normal gene Cb, the types of mating and
sexes have twenty-two pairs of what are termed offspring expected may be set up as they were
558 Monohybrid Inheritance
for the autosomal recessive albino gene. In the port or story in the media involving an example
present situation, the X and Y chromosomes of monohybrid inheritance. Furthermore, ge-
will also be included, remembering that the Cb netic conditions or disorders regularly appear
and cb genes will be found only on the X chro- as the theme of a movie or play. An understand-
mosome and that any genotype with a Y chro- ing of the principles of genetics and monohy-
mosome will result in a male. (See the table brid inheritance provides a greater appreciation
Phenotype Predictions: Color Blindness.) of what is taking place in the world, whether it is
Carrier females are heterozygous females in the application of DNA fingerprinting in the
who have normal vision but are expected to courtroom, the introduction of disease-resistant
pass the gene to half their sons, who would be genes in plants and animals, the use of genetics
color blind. Presumably, the carrier female in paternity cases, or the description of new in-
would have inherited the gene from her father, herited diseases.
who would have been color blind. Thus, in Perhaps it is in the area of genetic diseases
some families the trait has a peculiar pattern of that knowledge of monohybrid inheritance of-
transmission in which the trait appears in a fers the most significant personal applications.
womans father, but not her, and then may ap- Single-gene disorders usually fall into one of
pear again in her sons. the four common modes of inheritance: auto-
somal dominant, autosomal recessive, sex-
Impact and Applications linked dominant, and sex-linked recessive. Ex-
The number of single genes known in hu- amination of individual phenotypes and family
mans has grown dramatically since Victor Mc- histories allows geneticists to determine which
Kusick published the first Mendelian Inheritance mode of inheritance is likely to be present for a
in Man catalog in 1966. In the first catalog, specific disorder. Once the mode of inheri-
there were 1,487 entries representing loci iden- tance has been identified, it becomes possible
tified by Mendelizing phenotypes or by cellular to determine the likelihood or the risk of oc-
and molecular genetic methods. In the 1994 currence of the disorder in the children. Since
catalog, the number of entries had grown to the laws governing the transmission of Mendel-
6,459. Scarcely a day goes by without a news re- ian traits are so well known, it is possible to pre-
against the type A red blood cells, which will at- its cells that will be recognized as foreign and
tach to them, causing them to agglutinate, or destroyed by the recipients antibodies. The
form clumps. By this principle, a person with genes that build these cell-surface antigens,
type O blood can donate it to people with any called human leukocyte antigen (HLA), occur
blood type, because their blood cells have nei- in two main forms. HLA-A has nearly twenty
ther an A nor a B antigen. Thus, people with different alleles, and HLA-B has more than
type O blood are often referred to as universal thirty. Since any individual can only have two of
donors because no antibodies will be formed each type, there are an enormous number of
against type O blood red blood cells. Likewise, possible combinations in the population. Find-
people with type AB blood are often referred to ing donors and recipients with the same or a
as universal recipients because they have both very close combination of HLA alleles is a very
types of antigens and therefore will not pro- difficult task for those arranging successful or-
duce antibodies against any of the blood types. gan transplantation.
Medical personnel must carefully check the Geneticists are coming to suspect that multi-
blood type of both the recipient and the do- ple alleles, once thought to be the exception to
nated blood to avoid agglutination and subse- the rule, may exist for the majority of human
quent death. genes. If this is so, the study of multiple alleles
Blood types have been used to establish pa- for many disease-producing genes should shed
ternity because a childs blood type can be used more light on why the severity of so many ge-
to determine what the parents blood types netic diseases varies so widely from person to
could and could not be. Since a child receives person.
one allele from each parent, certain men can Grace D. Matzen, updated by Bryan Ness
be eliminated as a childs potential father if See also: Complementation Testing; Cystic
the alleles they possess could not produce the Fibrosis; Organ Transplants and HLA Genes;
combination found in the child. However, this Population Genetics.
proves only that a particular person could be
the father, as could millions of others who pos- Further Reading
sess that blood type; it does not prove that a par- Klug, William S. Essentials of Genetics. 3d ed. Up-
ticular man is the father. Modern methods of per Saddle River, N.J.: Prentice Hall, 1999.
analyzing the DNA in many of the individuals Supplies a solid explanation of multiple al-
genes now make the establishment of paternity leles. Bibliography, index.
a more exact science.
netic diversity in the gene pool provides the radiation) therefore also cause cancer.
variation that allows adaptation to new con- Mutation also has an important, beneficial
ditions role in natural populations of all organisms.
germinal mutation: a mutation in gamete- The ability of a species to adapt to changes in its
forming (germinal) tissue, which can be environment, combat new diseases, or respond
passed from a parent to its offspring to new competitors is dependent on genetic di-
mutagen: a chemical or physical agent that versity in the populations gene pool. Without
causes an increased rate of mutation sufficient resources of variability, a species
mutagenesis: the process of a heritable change faced by a serious new stress can become ex-
occurring in a gene, either spontaneously or tinct. The reduced population sizes in rare and
in response to a mutagen endangered species will result in reduced ge-
mutation rate: the probability of a heritable netic diversity and a loss of the capacity to re-
change occurring in the genetic material spond to selection pressures. Zoo breeding
over a given time period, such as a cell divi- programs often take data on genetic diversity
sion cycle or a generation into account when planning the captive breed-
phenotype: the observable effects of a gene; ing of endangered species. The creation of new
phenotypes include physical appearance, agricultural crops or of animal breeds with eco-
biochemical activity, cell function, or any nomically desirable traits also depends on mu-
other measurable factor tations that alter development in a useful way.
somatic mutation: a mutation that occurs in a Therefore, mutation can have both damaging
body cell and produces a group of mutant and beneficial effects.
cells but is not transmitted to the next gener-
ation The Role of Mutations in Cell Activity and
wild type: the normal genetic makeup of an Development
organism, as it occurs in nature (the wild); a The genetic information in a cell is encoded
mutation alters the phenotype of a wild-type in the sequence of subunits, the nucleotides,
trait to produce a mutant phenotype that make up the DNA molecule. A mutation is
a change in the cells genetic makeup, and it
Definitions can range from changing just a single nucleo-
A mutation is any change in the genetic ma- tide in the DNA molecule to altering long
terial that can be inherited by the next genera- pieces of DNA. To appreciate how such changes
tion of cells or progeny. A mutation can occur can affect an organism, it is important to un-
at any time in the life of any cell in the body. If derstand how information is encoded in DNA
a mutation occurs in the reproductive tissue, and how it is translated to produce a specific
the change can be passed to an offspring in the protein. There are four different nucleotides
egg or sperm. That new mutation may then af- in the DNA molecule: adenine (A), guanine
fect the development of the offspring and be (G), thymine (T), and cytosine (C). The DNA
passed on to later generations. However, if the molecule is composed of two strands linked to-
mutation occurs in cells of the skin, muscle, gether by a sequence of base pairs (bp). An ade-
blood, or other body (somatic) tissue, the new nine on one strand pairs with a thymine on the
mutation will only be passed on to other body other (A-T), and a guanine on one strand pairs
cells when that cell divides. This can produce a with a cytosine on the other (G-C). When a
mosaic patch of cells carrying the new genetic gene is activated, one of the two strands is
change. Most of these are undetectable and used as a model, or template, for the synthesis
have no effect on the carrier. An important ex- of a single-stranded molecule called messenger
ception is a somatic mutation that causes the RNA (mRNA). The completed mRNA mole-
affected cell to lose control of the cell cycle cule is then transported out of the nucleus, and
and divide uncontrollably, resulting in cancer. it binds with ribosomes (small structures in the
Many environmental chemicals and agents that cytoplasm of the cell), where a protein is made
cause mutations (such as X rays and ultraviolet using the mRNAs nucleotide sequence as its
Mutation and Mutagenesis 563
coded message. The nucleotides are read on the severity of their effects. Some are undetect-
the ribosome in triplets, with three adjacent able in the carrier, some cause small defects
nucleotides (called a codon) corresponding to or even beneficial changes in the function of
one of the twenty amino acids found in protein. a protein, while others can produce major
Thus the sequence of nucleotides eventually changes in several different developmental
determines the order of amino acids that are processes at the same time.
linked together to form a specific protein. The Gene mutations are sometimes called point
amino acid sequence in turn determines how mutations because their genetic effects are lim-
the protein will work, either as a structural part ited to a single point, or gene, on a chromo-
of a cell or as an enzyme that will catalyze a some that can carry up to several thousand dif-
specific biochemical reaction. A gene is often ferent genes. The simplest kind of point
1,000 bp or longer, so there are many points at mutation is a base substitution, in which one
which a genetic change can occur. If a mutation base pair is replaced by another (for example,
occurs in an important part of the gene, even the replacement of an A-T base pair at one
the change of a single amino acid can cause a point in the DNA molecule by a C-G base pair).
major change in protein function. Sickle-cell This can change a codon triplet so that a differ-
disease is a good example of this. In sickle-cell ent amino acid is placed in the protein at that
disease a base-pair substitution in the DNA point. This often changes the function of the
causes the sixth codon in the mRNA to change protein, at least in minor ways. However, some
from GAG to GUG. When this modified mRNA base substitutions are silent. Since several dif-
is used to create a protein, the amino acid ferent triplets can code for the same amino
valine is substituted for the normal glutamic acid, not all base changes will result in an
acid in the sixth position in a string of 146 amino acid substitution.
amino acids. This small change causes the pro- Another common kind of gene mutation
tein to form crystals and thus deform cells called a frame shift can have a much larger ef-
when the amount of available oxygen is low. fect on protein structure. A frame-shift muta-
Since this protein is one of the parts of the oxy- tion occurs when a nucleotide is added to, or
gen-carrying hemoglobin molecule in red lost from, the DNA strand when it is duplicated
blood cells, this single DNA nucleotide change during cell division. Since translation of the
has potentially severe consequences for an af- mRNA is done by the ribosomes adding one
fected individual. amino acid to the growing protein for every
three adjacent nucleotides, adding or deleting
Types of Mutation one nucleotide will effectively shift that read-
Because they can be so diverse, one way to ing frame so that all following triplets are differ-
organize mutations is to describe the kind of ent. By analogy, one can consider the following
molecular or structural change that has oc- sentence of three-letter words: THE BIG DOG
curred. There are three broad classes of muta- CAN RUN FAR. If a base (for example, a letter
tion. Genomic mutations are changes in the X, in this analogy) is added at the end of the sec-
number of chromosomes in a cell. Inheriting ond triplet, the sentence will still read three
an extra chromosome, as in Down syndrome, is letters at a time during translation and the
an example of a genomic mutation. Chromo- meaning will be completely altered. THE BIX
some mutations are changes in the structure GDO GCA NRU NFA R. In a cell, a nonfunc-
of a chromosome and can include the loss, tional protein is produced unless the frame
gain, or altered order of a series of genes. shift is near the terminal end of the gene.
Gene mutations are genetic changes limited Environmental agents such as ultraviolet
to an individual gene or the adjacent regions (UV) radiation can affect DNA and base pair-
that control its activity during development. ing. Certain UV wavelengths, for example,
Thus, the amount of genetic information af- cause some DNA nucleotides to pair abnor-
fected by a mutation can vary from a single mally. Gene mutations have also been traced to
gene to hundreds of them. Genes also vary in the movement of transposable DNA elements.
564 Mutation and Mutagenesis
Transposable elements were first discovered by chromosomes provide an extra copy of each of
Barbara McClintock while studying chromo- their genes, the amount of each protein they
some breakage and kernel traits in maize. Now code for is unusually high, and this, too, can
they are known from many organisms, includ- create biochemical abnormalities for the or-
ing humans. Transposable elements are small ganism. In humans, an interesting exception is
DNA segments that can become inserted into a changes in chromosome number that involve
chromosome and later excised and change the sex-determining chromosomes, especially
their position. If one becomes inserted in the the X chromosome (the Y is relatively silent in
middle of a gene, it effectively separates the development). Since normal males have one X
gene into two widely spaced fragments. In the and females have two, the cells in females inac-
fruit fly (Drosophila melanogaster), in which tivate one of the X chromosomes to balance
spontaneous mutations have been studied in gene dosage. This dosage compensation mech-
detail at the DNA level, as many as half of the anism can, therefore, also come into operation
spontaneous mutations in certain genes have when one of the X chromosomes is lost or an
been traced to transposable elements. extra one is inherited because of an error in
There are four major kinds of chromosome cell division. The resulting conditions, such as
mutations. A chromosome deletion or defi- Turner syndrome and Klinefelter syndrome,
ciency is produced when two breaks occur in are much less severe than the developmental
the chromosome but are repaired by leaving problems associated with other changes in
out the middle section. For example, if the chromosome number.
sections of a chromosome are labeled with the
letters ABCDEFGHIJKLMN and chromosome Mutation Rate
breaks occur at F-G and at K-L, the broken A mutation is any heritable change in the ge-
chromosome can be erroneously repaired by netic material, but there are several different
enzymes that link the ABCDEF fragment to the ways one can look at genetic change. For exam-
LMN fragment. The genes in the unattached ple, errors can occur when the DNA molecule
middle segment, GHIJK, will be lost from the is being duplicated during cell division. In sim-
chromosome. Losing these gene copies can af- ple organisms such as bacteria, about one thou-
fect many different developmental processes sand nucleotides are added to the duplicating
and even cause the death of the organism. DNA molecule each second. The speed is not
Chromosome breaks and other processes can as great in plants and animals, but errors still
also cause some genes to be duplicated in the occur when mispairing between A and T or be-
chromosome (for example, ABCDEFGHDEFG tween C and G nucleotides occurs. DNA breaks
HIJKLMN). A third kind of chromosome muta- are also common. These kinds of genetic
tion, an inversion, changes the order of the change can be classified as genetic damage.
genes when the segment between two chromo- Some mutations are spontaneous, caused by
somal breaks is reattached backward (for ex- changes that occur in the process of normal
ample, ABCDJIHGFEKLMN). Finally, chromo- cell biochemistry. Other damage that can be
some segments can be moved from one kind of traced to environmental factors changes bases,
chromosome to another in a structural change causes mispairing, or breaks DNA strands. For-
called a translocation. Some examples of heri- tunately, almost all of this initial genetic dam-
table Down syndrome are caused by this type of age is repaired by enzymes that recognize and
chromosome mutation. correct errors in nucleotide pairing or DNA
Genomic mutations are a large factor in the strand breaks. It is the unrepaired genetic dam-
genetic damage that occurs in humans. Whole age that appears as new mutations. One of the
chromosomes can be lost or gained by errors first geneticists to design experiments to mea-
during cell division. In animals, almost all ex- sure mutation rate was Hermann Mller, who
amples of chromosome loss are so develop- received the Nobel Prize for his work on muta-
mentally severe that the individual cannot sur- genesis, including the discovery that X rays
vive to birth. On the other hand, since extra cause mutations.
Mutation and Mutagenesis 565
are mammals, they are a close model system to mutation carrier dies, a geneticist can piece to-
humans. Thus, results from mutation studies in gether a picture of the timing and role of im-
mice have helped identify agents that are likely portant gene functions.
to be mutagenic in humans. Another useful insight comes from muta-
tions with effects that vary. For example, many
The Use of Mutations to Study mutations have phenotypic effects that depend
Development on the conditions, such as temperature, in
Mutations offer geneticists a powerful tool which the individual develops. An interesting
to analyze development. By understanding the example of such temperature sensitivity is the
way development is changed by a mutation, fur color of Siamese cats. The biochemical
one can determine the role the normal gene pathway for pigmentation is active in cool tem-
plays. Although most people tend to think of peratures but is inactivated at warmer body
mutations as causing some easily visible change temperature. For this reason, a Siamese cat will
in the appearance of a plant or animal (such as only be pigmented in the cooler parts such as
wrinkled pea seeds or white mouse fur), most the tips of the ears and tail. Gene interactions
mutations are actually lethal when present in like this allow geneticists to study the condi-
two copies (homozygous). These lethal muta- tions under which the protein coded by a mu-
tions affect some critical aspect of cell structure tant gene works.
or other fundamental aspect of development It would be a mistake, however, to think that
or function. Genes turn on and off at specific all mutations have large phenotypic effects.
times during development, and by studying the Many complex traits are produced by many
abnormalities that begin to show when a lethal genes working together and are affected by
The coats of Siamese cats are darker at their extremities as the result of a mutation that is affected by body temperature. (AP/Wide
World Photos)
Mutation and Mutagenesis 567
was shown to be entirely compatible with Dar- type (or, equivalently, one that is incapable of
winian evolution. With this recognition, the reproduction).
role of mutation in evolution was relegated to The simplest models of selection include the
the source of variation in traits upon which nat- assumption that a genotypes fitness does not
ural selection can act. change with time or context and demonstrate
The potential for natural selection of an or- three basic types of selection, defined by how
ganism is measured by its fitness. In practice, selection acts on a distribution of varying forms
the fitness of an individual is some measure of of a trait (where extreme forms are rare and av-
the representation of its own offspring in the erage forms are common). These three types
next generation, often relative to other individ- are directional selection (in which one extreme
uals. If a trait has evolved as a result of natural se- is favored), disruptive selection (in which both
lection, it is said to be an adaptation. The term extremes are favored), and stabilizing selection
adaptation can also refer to the process of nat- (in which average forms are favored). The first
ural selection driving the evolution of such a two types (with the first probably being the
trait. There are several evolutionary forces in ad- most common) can lead to substantial genetic
dition to selection (for example, genetic drift, change and thus evolution, though in the pro-
migration, and mutation) that can influence the cess genetic variation is depleted. The third
evolution of a trait, though the process is called type maintains variation but does not result in
adaptation as long as selection is involved. much genetic change. These results create a
problem: Natural populations generally have
Population Genetics and Natural substantial genetic variation, but most selection
Selection is expected to deplete it. The problem has led
Population geneticists explore the actual population geneticists to explore the role of
and theoretical changes in the genetic compo- other forces working in place of, or in conjunc-
sition of natural or hypothetical populations. tion with, natural selection and to study more
Not surprisingly, a large part of the theoretical complex models of selection. Examples include
and empirical work in the field has concen- models that allow a genotype to be more or less
trated on the action of natural selection on fit if it is more common (frequency-dependent
genetic variation in a population. Ronald A. selection) or that allow many genes to interact
Fisher and J. B. S. Haldane were the primary ar- in determining a genotypes fitness (multilocus
chitects of selection theory beginning in the selection). Despite the role of other forces, se-
1930s, and Theodosius Dobzhansky was a pio- lection is considered an important and per-
neer in the detection of natural selection act- haps complex mechanism of genetic change.
ing on genetic variants in populations of Dro-
sophila melanogaster (fruit flies). Detecting and Measuring Fitness
The most basic mathematical model of genes Although a great amount of theoretical work
in a population led to the Hardy-Weinberg law, on the effects of selection has been done, it
which predicts that there would be no change is also important to relate theoretical results
in the genetic composition of a population in to actual populations. Accordingly, there has
the absence of any evolutionary forces such as been a substantial amount of research on natu-
natural selection. However, models that include ral and laboratory populations to measure the
selection show that it can have specific influ- presence and strength of natural selection. In
ences on a populations genetic variation. In practice, selection must be fairly strong for it to
such models, the fitness of an organisms geno- be distinguished from the small random effects
type is represented by a fitness coefficient (or that are inherent in natural processes.
the related selection coefficient), in which the Ideally, a researcher would measure the total
genotype with the highest fitness is assigned a selection on organisms over their entire life cy-
value of 1, and the remaining genotypes are as- cles, but in some cases this may be too difficult
signed values relative to the highest fitness. A or time-consuming. Also, a researcher may be
fitness coefficient of 0 represents a lethal geno- interested in discovering what specific parts of
570 Natural Selection
the life cycle selection influences. For these the role of bird predation in the selection pro-
reasons, many workers choose to measure com- cess. Nevertheless, selection of some sort is still
ponents of fitness by breaking down the life cy- considered the best explanation for the changes
cle into phases and looking for fitness differ- observed in peppered moth populations, even
ences among individuals at some or all of them. though the selective factor responsible is not
These components can differ with different known.
species but often include fertility selection (dif- Later, a second method of fitness measure-
ferences in the number of gametes produced), ment was applied to the peppered moth using a
fecundity selection (differences in the number mark-recapture experiment. In such an experi-
of offspring produced), viability selection (dif- ment, known quantities of marked genotypes
ferences in the ability to survive to reproduc- are released into nature and collected again
tive age), and mating success (differences in some time later. The change in the proportion
the ability to successfully reproduce). It is often of genotypes in the recaptured sample provides
found in such studies that total lifetime fitness a way to estimate their relative fitnesses. In
is caused primarily by fitness in one of these practice, this method has a number of difficul-
components, but not all. In fact, it may be that ties associated with making accurate and com-
genotypes can have a disadvantage in one com- plete collections of organisms in nature, but
ponent but still be selected with a higher over- the fitness measure of melanic moths by this
all fitness because of greater advantages in method was in general agreement with that of
other components. the first method. A third method of measuring
There are several empirical methods for de- fitness is to measure deviations from the geno-
tection and measurement of fitness. One rela- type proportions expected if a population is
tively simple way is to observe changes in gene in Hardy-Weinberg equilibrium. This method
or genotype frequencies in a population and fit can be very unreliable if deviations are the re-
the data on the rate of change to a model of sult of something other than selection.
gene-frequency change under selection to
yield an estimate of the fitness of the gene or ge- Units of Selection
notype. The estimate is more accurate if the Darwin envisioned evolution by selection on
rate of mutation of the genes in question is individual organisms, but he also considered
taken into account. In the famous example of the possibility that there could be forms of se-
industrial melanism, it was observed that me- lection that would not favor the survival of the
lanic (dark-colored) individuals of the pep- individual. He noted that in many sexual spe-
pered moth Biston betularia became more com- cies, one sex often has traits that are seemingly
mon in Great Britain in the late nineteenth disadvantageous but may provide some advan-
century, corresponding to the increase in pol- tage in attracting or competing for mates. For
lution that came with the Industrial Revolu- instance, peacocks have a large, elaborately
tion. It was suggested that the melanic moths decorated tail that is energetically costly to
were favored over the lighter moths because grow and maintain and might be a burden
they were camouflaged on tree trunks where when fleeing from predators. However, it
soot had killed the lichen and were therefore seems to be necessary to attract and secure
less conspicuous to bird predators. Although it a mate. Darwin, and later Fisher, described
is now known that the genetics of melanism are how such a trait could evolve by sexual selec-
more complex, early experiments suggested tion if the female evolves a preference for it,
that there was a single locus with a dominant even if natural selection would tend to elimi-
melanic allele and a recessive light allele; the nate it.
data from one hundred years of moth samples Other researchers have suggested that in
were used to infer that light moths have two- some cases selection may act on biological units
thirds the survival ability of melanic moths. other than the individual. Richard Dawkinss
Later studies also showed that peppered moths The Selfish Gene (1976) popularized the idea
do not rest on tree trunks, calling into question that selection may be acting directly on genes
Natural Selection 571
and only indirectly on the organisms that carry traits, they could gradually improve the lin-
them. This distinction is perhaps only a philo- eage. Darwin used numerous examples of arti-
sophical one, but there are specific cases in ficial selection to illustrate biological change
which genes are favored over the organism, and argued that natural selection, while not
such as the segregation distorter allele in Dro- necessarily as strong or directed, would influ-
sophila that is overrepresented in offspring of ence change in much the same way. It is impor-
heterozygotes but lethal in homozygous condi- tant to make a clear distinction between the
tions. two processes: Breeders have clear, long-term
The theory of kin selection was developed to goals in mind in their breeding programs, but
explain the evolution of altruistic behavior there are no such goals in nature. There is only
such as self-sacrifice. In some bird species, for the immediate advantage of the trait to the con-
example, an individual will issue a warning call tinuation of the lineage. The application of se-
against predators and subsequently be targeted lection theory to more recent breeding pro-
by the predator. Such behavior, while bad for grams has benefited human populations in the
the individual, can be favored if those benefit- form of new and better food supplies.
ing from it are close relatives. While the individ- Stephen T. Kilpatrick
ual may perish, relatives that carry the genes See also: Altruism; Ancient DNA; Artificial
for the behavior survive and altruism can evolve. Selection; Classical Transmission Genetics;
Kin selection is a specific type of group selec- Evolutionary Biology; Genetic Code; Genetic
tion in which selection favors attributes of a Code, Cracking of; Genetics, Historical Devel-
group rather than an individual. It is not clear opment of; Hardy-Weinberg Law; Human Ge-
whether group selection is common in evolu- netics; Lamarckianism; Mendelian Genetics;
tion or limited to altruistic behavior. Molecular Clock Hypothesis; Mutation and
Mutagenesis; Population Genetics; Punctuated
Impact and Applications Equilibrium; Repetitive DNA; RNA World;
The development of theories of selection Sociobiology; Speciation; Transposable Ele-
and the experimental investigation of selection ments.
have always been intertwined with the field of
evolutionary biology and have led to a better Further Reading
understanding of the history of biological Dawkins, Richard. Extended Phenotype: The Long
change in nature. More recently, there have Reach of the Gene. Rev. 2d ed. Afterword by
been medical applications of this knowledge, Daniel Dennett. New York: Oxford Univer-
particularly in epidemiology. The specific sity Press, 1999. Argues that the selfish (indi-
mode of action of a disease organism or other vidual) gene extends to making artifacts,
parasite is shaped by the selection pressures of such as birds nests, and to manipulative,
the host it infects. Selection theory can aid in persuasive behavior for survival. Bibliogra-
the understanding of cycles of diseases and the phy, index.
response of parasite populations to antibiotic _______. The Selfish Gene. New York: Oxford
or vaccination programs used to combat them. University Press, 1989. Argues that the world
Although the idea of natural selection as a of the selfish gene revolves around competi-
mechanism of biological change was suggested tion and exploitation and yet acts of appar-
in the nineteenth century, artificial selection in ent altruism do exist in nature. A popular
the form of domestication of plants and ani- account of sociobiological theories that revi-
mals has been practiced by humans for many talized Darwins natural selection theory.
thousands of years. Early plant and animal Dover, Gabriel A. Dear Mr. Darwin: Letters on the
breeders recognized that there was variation in Evolution of Life and Human Nature. Berkeley:
many traits, with some variations being more University of California Press, 2000. A fic-
desirable than others. Without a formal under- tional tale of correspondence with Charles
standing of genetics, they found that by choos- Darwin. Illustrated.
ing and breeding individuals with the desired Fisher, Ronald Aylmer. The Genetical Theory of
572 Neural Tube Defects
Natural Selection: A Complete Variorum Edition. Michod, Richard E. Darwinian Dynamics: Evolu-
Edited with a foreword and notes by J. H. tionary Transitions in Fitness and Individuality.
Bennett. New York: Oxford University Press, Princeton, N.J.: Princeton University Press,
1999. Facsimile of the 1930 edition. Illus- 1999. Argues that cooperation instead of
trated. competition and violence accounts for spe-
Gould, Stephen Jay. The Structure of Evolutionary cies survival and fitness, and that evolution
Theory. Cambridge, Mass.: Harvard Univer- occurs through genetic change instead of
sity Press, 2002. Gould considers this book the more common theory of endurance. Il-
on natural selection his major work, a col- lustrations, bibliography, index.
lection of twenty-five years of study explor- Ryan, Frank. Darwins Blind Spot: Evolution Be-
ing the history and future of evolutionary yond Natural Selection. Boston: Houghton
theory. Includes a chapter on punctuated Mifflin, 2002. Argues for a symbiotic instead
equilibrium. Illustrations, bibliography, and of the most widely accepted competitive and
index. survival-based theory of evolution. Bibliog-
Keller, Laurent, ed. Levels of Selection in Evolu- raphy, index.
tion. Princeton, N.J.: Princeton University Shermer, Michael. In Darwins Shadow: The Life
Press, 1999. Addresses the question of what and Science of Alfred Russel Wallace: A Biograph-
keeps competition between various levels of ical Study on the Psychology of History. New
natural selection from destroying the com- York: Oxford University Press, 2002. The un-
mon interests to be gained from coopera- sung contemporary of Darwin deserves
tion between members of a species. Illus- equal credit for developing early evolution-
trated. ary theory. Illustrated.
Levy, Charles K. Evolutionary Wars: A Three-Bil- Williams, George C. Adaptation and Natural Se-
lion-Year Arms Race: The Battle of Species on lection: A Critique of Some Current Evolutionary
Land, at Sea, and in the Air. Illustrations by Thought. 1966. Reprint. Princeton, N.J.:
Trudy Nicholson. New York: W. H. Freeman, Princeton University Press, 1996. A good in-
1999. Discusses the often violent nature of troduction to adaptation and units of selec-
natural selection and adaptation, including tion. New preface. Bibliography, index.
the survival skills and mechanisms of drag-
onflies, frogs, viruses, poison-filled jellyfish, Web Site of Interest
and beetles, and the tongues of woodpeck- Writings of Charles Dar win. http://pages
ers and anteaters. Ninety-four illustrations, .britishlibrary.net/charles.darwin. Resource
index. for Darwins writings, a bibliography, and
Lynch, John M., ed. Darwins Theory of Natural biographical material. Includes online ver-
Selection: British Responses, 1859-1871. 4 vols. sion of Darwins On the Origin of Species by
Bristol, England: Thoemmes Press, 2002. A Means of Natural Selection (1859).
collection of rare, primary sources by scien-
tists, theologians, and others on Darwins
theory, including the 1867 critical review by
Fleeming Jenkin that Darwin thought best
summarized his work on natural selection.
Bibliography, index.
Neural Tube Defects
Magurran, Anne E., and Robert M. May, eds. Field of study: Diseases and syndromes
Evolution of Biological Diversity: From Popula- Significance: Neural tube defects are a category of
tion Differentiation to Speciation. New York: Ox- birth defects that usually result from the failure of
ford University Press, 1999. Discusses species the neural tube to close properly during gestational
variation as theorized by proponents of nat- development. Many neural tube defects can be pre-
ural selection, ecological, and behavioral vented through folic acid supplementation and
models. Looks at fossil records for empirical avoidance of other risk factors. However, because
data. Illustrations, bibliography, index. the neural tube closes during the first gestational
Neural Tube Defects 573
Skin
Deficient vertebral arches Sac containing Normal cord Cord displaced into sac,
and dura, associated with CSF position associated with serious
minor nerve defects, esp. nervous deficit, esp.
bladder dysfunction in legs, bladder
Spina bifida is among the most common neural tube disorders. (Hans & Cassidy, Inc.)
574 Neural Tube Defects
beginning at its midportion and ending at the protrusion of neural tissue occurs through an
anterior and posterior neuropores around the opening along the midline of the skull. The
twenty-fifth and twenty-seventh gestational prognosis and outcome of infants born with
days, respectively. encephalocele depends upon the size of the le-
sion and the extent to which neural tissues are
Classification of Neural Tube Defects involved.
Disruption in the formation and closure of
the posterior neuropores is associated with Prevalence-at-Birth Rates and Causes
spina bifida. Spina bifida occulta is generally Prevalence-at-birth rates of neural tube de-
unaccompanied by protrusion of the spinal fects show substantial geographic and tempo-
cord or its coverings through the open, un- ral variation. Historically, some of the highest
fused arches of the vertebrae. On the other prevalence-at-birth rates have been docu-
hand, much more severe conditions, catego- mented in the British Isles and range from as
rized as spina bifida cystica, result in the hernia- high as 4.5 in 1,000 births in Belfast, Ireland, to
tion of neural tissues and the formation of cys- as low as 1.5 in 1,000 births in London, En-
tic swelling. One form of spina bifida cystica, gland. In the United States, the highest rates of
meningomyelocele, is marked by the protru- neural tube defects have historically occurred
sion of both the meninges and the spinal cord in northeastern states. Rates of neural tube de-
through the unfused vertebral arch. In the fects are declining in most areas of the world,
most severe cases, portions of the spinal cord although regional outbreaks, marked by higher
and nerve roots are encased in the walls of the birth prevalence rates, have been reported and
sac, damaging and hindering normal neuro- are generally unexplained. Typically, rates in the
logical functioning and development. In such contemporary United States average around 1
instances, the severity of the neurological dys- to 2 in 1,000 births, and the risk of having an in-
function depends on the location of the lesion fant with a neural tube defect increases by
along the vertebral column, as nerves below about 2 percent if a couple has previously had a
the defect are adversely affected. Meningocele, child with such a defect.
a more moderate manifestation of spina bifida Among the most important risk factors are
cystica, is encountered four to five times less those relating to the diet and health status of
frequently than meningomyelocele. Unlike the prospective mothers. Also, there are indica-
latter condition, the cystic sacs of meningoceles tions that excessive elevation of a womans body
are made up solely of meninges and spinal temperature during early pregnancy, through
fluid. This factor, coupled with the lack of in- hot baths or recreational hot tubs, may increase
volvement of the spinal cord, generally affords her chances of having an infant with a neural
a more favorable prognosis, although some sen- tube defect. A number of studies have sug-
sory and motor deficits may persist after surgery. gested that women who give birth to infants
Anencephalus, which results from the dis- with neural tube defects have lower health sta-
ruption of the anterior neuropore, is the most tus and poorer diets than other women. Inade-
devastating and severe of all the neural tube de- quate levels of folate appear to place women
fects. Infants born with this birth defect are at greater risk of having an infant with a neu-
lacking significant areas of their brain and ral tube defect. Doctors now recommend that
skull. The region normally occupied by the ce- women planning a pregnancy supplement their
rebral hemispheres consists of a formless mass diets with folate, although any woman plan-
of highly vascular connective tissue, while most ning to become pregnant should first consult
of the bones of the skull are simply absent. her doctor before taking any supplement. Tests
Many anencephalic infants are stillborn; most for alpha-fetaprotein in the mothers blood
die soon after birth. during the prenatal period can help detect the
Encephalocele, like anencephalus, is be- presence of a neural tube defect in the develop-
lieved to result from defective closure of the an- ing fetus.
terior neuropore. In these conditions, a saclike Mary K. Sandford
Noncoding RNA Molecules 575
See also: Amniocentesis and Chorionic Vil- nificance and functions began to be understood.
lus Sampling; Congenital Defects; Develop- The functions of the many ncRNAs so far discov-
mental Genetics; Prenatal Diagnosis. ered include roles in DNA replication, post-
transcriptional control of gene expression, process-
Further Reading ing of other RNAs, and mRNA stability.
Bock, Gregory, and Joan Marsh, eds. Neural
Tube Defects. New York: Wiley, 1994. Discusses Key terms
prenatal screening, before- and after-birth cDNA library: a collection of clones pro-
treatment, and the genetic and environmen- duced from all the RNA molecules in the
tal causes of congenital malformations. Illus- cells of a particular organism, often from a
trations, bibliography, index. single tissue
Evans, Mark I., ed. Metabolic and Genetic clone: a culture of bacteria, usually Escheri-
Screening. Philadelphia: W. B. Saunders, chia coli, whose cells contain a recombinant
2001. Covers principles of screening, neural plasmid
tube defects, prenatal genetic screening in codon: a three-letter nucleotide sequence in
the Ashkenazi Jewish population, cystic fi- RNA or DNA that codes for a specific amino
brosis, and identifying and managing hered- acid; a gene is composed of a long string of
itary risk of breast and ovarian cancer. codons
Massaro, Edward J., and John M. Rogers, eds. intron: an intervening sequence in a eukary-
Folate and Human Development. Totowa, N.J.: otic gene (generally there are several to
Humana Press, 2002. Focuses on how folate many per gene) which must be removed
could help prevent human developmental when it is transcribed into messenger RNA
disorders, including neural tube defects. Il- (mRNA); introns are assumed to have no
lustrations, bibliography, index. function and therefore mutations in them
are often considered neutral
Web Sites of Interest spliceosome: a complex assemblage of pro-
Medline Plus. http://www.nlm.nih.gov/ teins and RNA in the nucleus of cells that
medlineplus/neuraltubedefects.html. Med- cuts out introns and splices the exons of a
line, sponsored by the National Institutes of maturing mRNA
Health, is one of the first stops for any medi-
cal question; this page provides descriptions Definition
and links to clinical trials and other resources Noncoding RNAs (ncRNAs) include any
for neural tube defects. RNA that is not messenger RNA (mRNA), ribo-
Spina Bifida Association of America. http:// somal RNA (rRNA), or transfer RNA (tRNA).
www.sbaa.org. Offers information, fact The discovery of the first ncRNAs in the 1960s
sheets, testimonials, a clinic directory, copi- occurred because they were expressed in such
ous links to other resources, and more. high numbers. At the time, RNA was consid-
ered to function only as a means to express a
gene, all three of the main types of RNA being
intimately involved in this process. Many of the
Noncoding RNA Molecules ncRNAs discovered over the next twenty years
were also discovered fortuitously, before any
Field of study: Molecular genetics speculation about their possible functions was
Significance: Although less familiar than mRNA, even considered. Once transcription and pro-
tRNA, and rRNA, noncoding RNA molecules cessing of mRNAs was elucidated, many of the
(ncRNAs) play many rolesincluding some that ncRNAs were considered leftover fragments
have not yet been elucidatedin normal cellular representing the introns that had been cut out
functions. The existence of ncRNAs has been of pre-mRNAs. At the same time it was discov-
known since the 1960s, but it was not until the ered that some of the ncRNAs were involved in
last decade of the twentieth century that their sig- the process of intron removal and exon splic-
576 Noncoding RNA Molecules
ing. Systematic searches for ncRNAs did not be- terrupt the coding sequence of the gene, when
gin until the later 1990s and, once under- an RNA is first transcribed it cannot be trans-
taken, revealed a veritable universe of ncRNAs, lated without being processed. Processing in-
ranging from very short sequences of less than volves removal of the introns and the splicing
100 nucleotides to some around 100,000 nucle- of the remaining fragments, the exons, which
otides, and possibly more. For a system consid- contain the coding sequence of the gene. The
ered so well understood, the entry of so many cellular machine that does this job is the
new players has added a whole new layer of spliceosome. It is a complex assemblage of pro-
complexity to the study of genetics. teins and small RNAs. The proteins and RNAs
are grouped together into several particles
Types of ncRNA and Their Occurrence called small nuclear ribonucleoproteins
Researchers have now identified ncRNAs in (snRNPs, pronounced snurps by geneticists).
essentially all organisms, from bacteria to hu- The RNA component of snRNPs are small nu-
mans. In bacteria they tend to be smaller and in clear RNAs (snRNAs), the best known being
most cases are called small RNA (sRNA). Al- U1 snRNA. Several different snRNAs are now
though the most common name for noncoding known, and they are components of the several
RNAs in other organisms is ncRNA, they also snRNPs that come together to make a func-
have gone by the name small non-messenger tional spliceosome.
RNA (snmRNA). After these general names, Subsequent discoveries revealed that
there is a collection of names for ncRNAs that snRNPs, and thus snRNAs, were involved in
have particular characteristics or functions, other types of RNA processing. Some are in-
and the list of names will probably grow as new volved in polyadenylation, the addition of ade-
ncRNAs are discovered. Some newly discov- nine nucleotides to the 3 end of mRNAs to
ered ncRNAs cannot be assigned a function. make what is called a poly-A tail. Histone pro-
tein mRNAs are known to lack poly-A tails, but
ncRNAs Involved in RNA Processing in Xenopus (the African clawed frog), snRNPs
Because almost all eukaryotic genes contain are still involved in properly finishing the 3
intervening sequences, called introns, that in- end. A final role for some is maturation of
rRNA transcripts, whose spacer RNA se-
quences must be removed. All of these func-
tions verge on being enzyme-like.
Types of ncRNA A complex related to snRNPs was first found
in bacteria and has now been found in all
Type of ncRNA Abbreviation
groups of organisms. It contains proteins and
guide RNA gRN RNA and is called ribonuclease P (RNase P); it
is involved in the processing of tRNA and some
heterogeneous nuclear RNA hnRNA
rRNAs. Experiments have shown that the RNA
micro-RNA miRNA component can catalyze the required reac-
small cytoplasmic RNA scRN tions, even without the protein component,
making it the first clear-cut ribozyme, an RNA
small interfering RNA siRNA
with catalytic properties. Several types of
small non-messenger RNA snmRNA ncRNA are now known to act as ribozymes, and
small nuclear RNA snRNA this ability prompted the evolutionary commu-
nity to propose that early life was RNA-based
small nucleolar RNA snoRNA
rather than protein and DNA-based.
small temporal RNA stRNA
transfer messenger RNA tmRNA ncRNAs Involved in RNA Modification
RNA modification by small nucleolar RNAs
Bryan Ness (snoRNAs) has been best studied in Saccharo-
myces cerevisiae (yeast). Mature rRNAs must
Noncoding RNA Molecules 577
have some of their ribose sugars methylated, A final ncRNA, originally believed to be
and although their exact role in the process found only in the nematode Caenorhabditis ele-
has not yet been completely defined, snoRNAs gans, is small temporal RNA (stRNA). The
are involved. They bind to rRNAs in small re- stRNAs block translation of specific mRNAs af-
gions where they have complementary base ter translation has begun, but apparently they
sequences and somehow direct methylation. do not tag the mRNA for degradation. They are
Other snoRNAs are involved in pseudouridyla- now believed to represent a subset of miRNA
tion (that is, conversion of some of the uracil with slightly different properties. Their size is
nucleotides in rRNA to pseudouracil, a modi- typically between twenty-one and twenty-five
fied nucleotide) of rRNA. The enzyme that ac- nucleotides, and screening of a variety of other
tually performs the pseudouridylation is not organisms suggests that they may be more wide-
known. Many eukaryotes have snoRNAs, and spread than first assumed.
recently snoRNA homologs (a homolog is a
molecule that is similar to another) have been Other Specialized ncRNAs
found in Archaea, but not yet in Bacteria. A variety of other ncRNAs carry out more
Not as well known are guide RNAs (gRNAs), specialized functions, some just beginning to
discovered in some protists. They also modify be understood. Gene silencing is a very impor-
rRNA, by guiding the insertion or deletion of tant component of normal development. As
uracil nucleotides. The details of the process cells become differentiated and specialized,
are not well understood, but the mechanism in- they must express certain genes, and the re-
volves complementary base pairing between maining genes must be silenced. One form of
the rRNA and a gRNA, much like that seen with silencing is called imprinting, whereby certain
snoRNAs. It is possible that, as more studies are alleles from an allele pair are silenced, often
undertaken, gRNAs will be found in other those received from only one sex. A large
types of organisms. ncRNA (a little longer than 100,000 nucleo-
tides) called Air is responsible for silencing the
ncRNAs Affecting mRNA Stability and paternal alleles in a small autosomal gene clus-
Translation ter. How it does this is still being studied.
Another type of ncRNA that has been known In human females, one of the X chromo-
for some time is small interfering RNA somes (females have two) must be inactivated
(siRNA). A type of antisense RNA, siRNAs have so the genes on it will not be expressed. This in-
base sequences complementary to the coding, activation, called Lyonization after the discov-
or sense, region of an mRNA. By binding to erer of the phenomenon, Mary Lyon, occurs
an mRNA, a siRNA is able to block translation, during development on a random basis in each
and there is evidence that it also tags the mRNA cell, so that the X chromosome subjected to de-
for degradation. This type of genetic control is activation is randomly determined. An ncRNA
often called post-transcriptional gene silenc- called Xist plays a central part in this process. It
ing, or RNAi (RNA interference). Another is a large RNA of 16,500 nucleotides and is tran-
ncRNA, micro-RNA (miRNA), also seems to scribed from genes on both X chromosomes. It
target specific mRNAs for degradation. Both of is inherently unstable but somehow becomes
these types represent very small RNA mole- stable and binds all over one of the two X chro-
cules of generally fewer than thirty nucleotides. mosomes. The X chromosome that gets coated
Apparently targeting specific mRNAs for with Xist is then inactivated, and the only gene
degradation in bacteria are sRNAs, the mecha- it transcribes thereafter is the Xist gene. Tran-
nism being somewhat uncertain. Another func- scription of Xist ceases on the active X chromo-
tion of sRNAs in bacteria is activation of certain some.
mRNAs by preventing formation of an inhibi- A type of ncRNA called transfer messenger
tory structure in the mRNA. Another ncRNA, RNA (tmRNA) is involved in resuming transla-
simply called OxyS RNA, represses translation tion at ribosomes that have stalled. When a
by interfering with ribosome binding. stalled ribosome is encountered, a tmRNA first
578 Noncoding RNA Molecules
acts as a tRNA charged with the amino acid gions, many geneticists have become ever more
alanine. The stalled polypeptide is transferred cautious in calling any DNA sequence junk
to the alanine on the tmRNA. Then translation DNA.
continues, but now the tmRNA acts as the Because the field of RNomics is in its infancy
mRNA, instead of the mRNA the ribosome was and the functions of many of the ncRNAs are
initially translating. A termination codon is just barely understood, it may be premature to
soon reached and the amino acids that were predict specific medical applications, but cer-
added based on the tmRNA code act as a tag for tainly the potential is there. The population of
enzymes in the cytoplasm to break it down. ncRNAs in a cell, in some sense, resembles a
This allows those ribosomes that would nor- complex set of switches that turn genes on and
mally remain tied up with an mRNA they can- offbefore they are transcribed, while they are
not complete translating to be recycled for being transcribed, or even once translation has
translating another mRNA. begun. Once these switches are better under-
stood, researchers may be able to exploit the
The Future of ncRNA Research system with artificially produced RNAs. Geneti-
Most of the ncRNAs described above were cists will probably also discover that a number
unknown until the 1980s, and some of them of diseases that appeared to have unexplained
were only discovered in the 1990s. What ap- genetic behavior will find the solutions in
peared to be a relatively simple picture of ge- ncRNA.
netic control in cells has now gained many, pre- Bryan Ness
viously hidden, layers involving all manner of See also: cDNA Libraries; Central Dogma
RNAs, ranging from a mere 20 nucleotides to of Molecular Biology; DNA Structure and
100,000 nucleotides or so in length. Some are Function; RNA Structure and Function; RNA
suggesting that this glimpse is just the tip of Transcription and mRNA Processing.
the iceberg and that continued research will
reap increasingly complex interactions among Further Reading
RNAs and between RNAs and proteins. Ge- Bass, Brenda L. The Short Answer. Nature 411
nomics, the study of the DNA sequence of ge- (2001): 428-429. A look at RNA interference
nomes, has been a hot field for some time, but (RNAi) and the role of ncRNAs.
now it looks as if RNomics is beginning to Gottesman, Susan. Stealth Regulation: Biolog-
steal the show. ical Circuits with Small RNA Switches. Genes
Some strides have already been made in and Development 16 (2002): 2829-2842. A rela-
RNomics with surveys of cDNA libraries for tively comprehensive overview of what is
ncRNA sequences, especially some of the known about ncRNA. Contains some help-
smaller ones that were long thought merely to ful figures showing some of the mechanisms
be leftover scraps from other processes. For ex- of action.
ample, one study in 2001, which included a sur- Grosshans, Helge, and Frank J. Slack. Micro-
vey of a mouse-brain cDNA library, revealed RNAs: Small Is Plentiful. The Journal of Cell
201 potential novel, small ncRNAs. In a 2003 Biology 156, no. 1 (2002): 17-21. Overviews
survey of a cDNA library from Drosophila me- stRNA and miRNA and their functions.
lanogaster (fruit fly), sixty-six potential novel Hentze, Matthias W., Elisa Izaurralde, and
ncRNAs were discovered. Judging by the large Bertrand Sraphin. A New Era for the RNA
numbers of candidate ncRNAs showing up in World. EMBO Reports 1, no. 5 (2000): 394-
what are essentially first-time surveys, many 398. A report on the RNA 2000 Conference,
more may remain to be found. There could po- hosted by the RNA Society. Focuses on cer-
tentially be thousands of ncRNA genes. What is tain ncRNAs, such as those in spliceosomes
surprising is that many of these ncRNA genes and in the brain.
are being found in spacer regions and introns, Lewin, Benjamin. Genes VII. New York: Oxford
places that were once considered useless junk. University Press, 2001. An upper-division
With so much now being found in these re- college textbook that is better than many
Nondisjunction and Aneuploidy 579
other textbooks. Various chapters include is contributed to a new individual by each par-
discussion of ncRNAs. ent in sexual reproduction through the egg
Storz, Gisela. An Expanding Universe of Non- and sperm, which are both haploid. Thus, a fer-
coding RNAs. Science 296 (2002): 1260- tilized egg will contain two sets of chromo-
1263. A fairly complete overview of the vari- somes and will be diploid.
ous kinds of ncRNA, along with as much as is A karyotype is a drawing or picture that dis-
known about many of them. plays the number and physical appearance of
the chromosomes from a single cell. A normal
human karyotype contains twenty-two pairs of
autosomes (chromosomes that are not sex
chromosomes) and one pair of sex chromo-
Nondisjunction and somes. Females normally possess two X chro-
Aneuploidy mosomes in their cells, one inherited from
each parent. Males have a single X chromo-
Fields of study: Cellular biology; Diseases some, inherited from the mother, and a Y chro-
and syndromes mosome, inherited from the father.
Significance: Nondisjunction is the faulty disjoin- The many cells of a multicellular organism
ing of replicated chromosomes during mitosis or are created as the fertilized egg undergoes a se-
meiosis, which causes an alteration in the normal ries of cell divisions. In each cell division cycle,
number of chromosomes (aneuploidy). Nondis- the chromosomes are replicated, and, subse-
junction is a major cause of Down syndrome and quently, one copy of each chromosome is dis-
various sex chromosome anomalies. Understand- tributed to two daughter cells through a pro-
ing the mechanisms associated with cell division cess called mitosis. When gametes (eggs or
may provide new insight into the occurrence of sperm) are produced in a mature organism, a
these aneuploid conditions. different type of nuclear division occurs called
meiosis. Gametes contain one set of chromo-
Key terms somes instead of two. When two gametes join
meiosis: a series of two nuclear divisions that (when a sperm cell fertilizes an egg cell), the
occur in gamete formation in sexually repro- diploid chromosome number for the species is
ducing organisms restored, and, potentially, a new individual will
mitosis: nuclear division of chromosomes, form with repeated cell divisions.
usually accompanied by cytoplasmic divi- When replicated chromosomes are distrib-
sion; two daughter cells are formed with uted to daughter cells during mitosis or meio-
identical genetic material sis, each pair of chromosomes is said to disjoin
from one another (disjunction). Occasionally,
Background this process fails. When faulty disjoining (non-
Each cell in multicellular organisms con- disjunction) of replicated chromosomes oc-
tains all the hereditary information for that in- curs, a daughter cell may result with one or
dividual, in the form of DNA. In eukaryotes, more chromosomes than normal or one or
DNA is packaged in rodlike structures called more fewer than normal. This alteration in the
chromosomes, and any given species has a normal number of chromosomes is called
characteristic chromosome number. There are aneuploidy. One chromosome more than nor-
typically two of each kind of chromosome, mal is referred to as a trisomy. For example,
which is referred to as being diploid. In hu- Down syndrome is caused by trisomy 21 in hu-
mans (Homo sapiens), there are forty-six chro- mans. One chromosome fewer than normal is
mosomes; in corn (Zea mays), there are twenty called monosomy. Turner syndrome in hu-
chromosomes. A haploid cell has half the num- mans is an example of monosomy. Turners in-
ber of chromosomes as a diploid cell of the dividuals are women who have only one X chro-
same species, which constitutes one of each mosome in their cells, whereas human females
kind of chromosome. One set of chromosomes normally have two X chromosomes. When
580 Nondisjunction and Aneuploidy
1 2 3 4 5
6 7 8 9 10 11 12
13 14 15 16 17 18
19 20 21 22 X Y
A karyotype is a picture that displays the number and physical appearance of the chromosomes from a single cell. This karyotype
shows the trisomy at chomosome 21 that results in Down syndrome. (U.S. Department of Energy Human Genome Program,
http://www.ornl.gov/hgmis)
nondisjunction occurs in the dividing cells of a may induce nondisjunction include physical
mature organism or a developing organism, a factors such as heat, cold, maternal age, and
portion of the cells of the organism may be ionizing radiation, in addition to a wide variety
aneuploid. If nondisjunction occurs in meiosis of chemical agents.
during gamete formation, then a gamete will In humans, it is well established that in-
not have the correct haploid chromosome creased maternal age is a cause of nondisjunc-
number. If that gamete joins with another, the tion associated with the occurrence of Down
resulting embryo will be aneuploid. Examples syndrome. For mothers who are twenty years of
of human aneuploid conditions occurring in age, the incidence of newborns with Down syn-
live births include Down syndrome (trisomy drome is 0.4 in 1,000 newborns. For mothers
21), Edwards syndrome (trisomy 18), Patau over forty-five years of age, the incidence of
syndrome (trisomy 13), metafemale (more newborns with Down syndrome is 17 in 1,000
than two X chromosomes), Klinefelter syn- newborns. While it is clear that increased ma-
drome (XXY), and Turner syndrome (XO). ternal age is linked to nondisjunction, it is not
Most aneuploid embryos do not survive to known what specific physiological, cellular, or
birth. molecular mechanisms or processes are associ-
ated with this increased nondisjunction. While
Causes of Nondisjunction nondisjunction in maternal meiosis may be the
There are both environmental and genetic major source of trisomy 21 in humans, paternal
factors associated with nondisjunction in nondisjunction in sperm formation does occur
plants and animals. Environmental factors that and may result in aneuploidy.
Nondisjunction and Aneuploidy 581
In a study conducted by Karl Sperling and search into the mechanics of cell division and
colleagues published in the British Medical Jour- the various factors that influence that process
nal (July 16, 1994), low-dose radiation in the will increase the understanding of the conse-
form of radioactive fallout from the Chernobyl quences of nondisjunction and possibly pro-
nuclear accident (April, 1986) was linked to a vide the means to prevent its occurrence.
significant increase in trisomy 21 in West Berlin Jennifer Spies Davis
in January, 1987: twelve births of trisomy 21 See also: Chromosome Theory of Heredity;
compared to the expected two or three births. Down Syndrome; Hereditary Diseases; Kline-
This study suggests that, at least under certain felter Syndrome; Metafemales; Polyploidy;
circumstances, ionizing radiation may affect Turner Syndrome; XYY Syndrome.
the occurrence of nondisjunction. Researchers
have shown that ethanol (the alcohol in alco- Further Reading
holic beverages) causes nondisjunction in Bender, Bruce G., and Robert J. Harmon.
mouse-egg formation, suggesting a similar pos- Psychosocial Adaptation of Thirty Nine Stu-
sibility in humans. Other researchers have dents with Sex Chromosome Abnormal-
found that human cells in tissue culture (cells ities. Pediatrics 96 (August, 1995). Evaluates
growing on nutrient media) had an increased the risks for problems with cognitive skills,
occurrence of nondisjunction if the media learning abilities, and psychosocial adapta-
was deficient in folic acid. This implies that fo- tion in adolescents.
lic acid may be necessary for normal chromo- Berch, Daniel B., and Bruce G. Bender, eds. Sex
some segregation or distribution during cell Chromosome Abnormalities and Human Behav-
division. ior. Boulder, Colo.: Westview Press, 1990. Ex-
Scientists know from genetics research that plores the cognitive, emotional, and psycho-
mutations (changes in specific genes) in the social skills of those with sex chromosome
fruit fly result in the occurrence of nondis- abnormalities.
junction. This genetic component of nondis- Cunningham, Cliff. Understanding Down Syn-
junction is further supported by the observa- drome: An Introduction for Parents. 1988. Re-
tion that an occasional family gives birth to print. Cambridge, Mass.: Brookline Books,
more than one child with an aneuploid condi- 1999. Expanded and updated to reflect
tion. In these instances, it is likely that genetic changes in the education and care of chil-
factors are contributing to repeated nondis- dren and adults with Down syndrome. Also
junction. provides in-depth advice and information
for parents, including issues of professional
Impact and Applications guidance, treatment, and prenatal testing.
There are several reasons scientists are de- Massimini, Kathy, ed. Genetic Disorders Source-
voting research efforts to understanding the book: Basic Consumer Information About Heredi-
consequences of nondisjunction and aneu- tary Diseases and Disorders. 2d ed. Detroit,
ploidy. First, at least 15 to 20 percent of all Mich.: Omnigraphics, 2001. Discusses the
recognized human pregnancies end in sponta- ethics of gene testing, the causes of and
neous abortions. Of these aborted fetuses, be- treatments for genetic disorders, and in-
tween 50 and 60 percent are aneuploid. Sec- cludes a section on chromosomal disorders.
ond, of live births, 1 in 700 is an individual with Glossary, resource directory, charts, tables,
Down syndrome. Mental retardation is a major and index.
symptom in individuals with Down syndrome. Orr-Weaver, Terry L., and Robert A. Weinberg.
Thus, nondisjunction is one cause of mental re- A Checkpoint on the Road to Cancer. Na-
tardation. Finally, aneuploidy is common in ture (March 19, 1998). Examines the possi-
cancerous cells. Scientists do not know whether ble role of aneuploidy in tumor progression.
nondisjunction is part of the multistep process Pai, G. Shashidhar, Raymond C. Lewandowski,
of tumor formation or whether aneuploidy is a Digamber S. Borgaonkar. Handbook of Chro-
consequence of tumor growth. Continued re- mosomal Syndromes. New York: John Wiley &
582 Nondisjunction and Aneuploidy
Sons, 2002. Covers two hundred chromo- the history of the syndrome, and associated
somal aneuploidy syndromes, including in- disorders.
formation on diagnosis, behavior, and life Vig, Baldev K., ed. Chromosome Segregation and
expectancy. Illustrated. Aneuploidy. New York: Springer-Verlag, 1993.
Patterson, D. The Causes of Down Syndrome. A comprehensive collection of research into
Scientific American 257 (August, 1987). Dis- the beginning stages of aneuploidy, the mal-
cusses nondisjunction, the ongoing research segregation of chromosomes, and environ-
into what genes occur on chromosome 21 mental mutagenesis. Illustrations, bibliogra-
and how they contribute to Down syndrome, phy, index.
Oncogenes was responsible for the cancer-causing proper-
Fields of study: Molecular genetics; Viral ties of these viruses. The first oncogene discov-
genetics ered was the src gene of the Rous sarcoma virus.
Significance: Oncogenes are a group of genes origi- Subsequently, at least thirty different oncogenes
nally identified in RNA tumor viruses and later were discovered in avian and mammalian RNA
identified in many types of human tumors. The tumor viruses. Each of these oncogenes has a
discovery of oncogenes has revolutionized the un- cellular counterpart that is the presumed ori-
derstanding of cancer genetics and contributed to gin of the viral gene; with the exception of the
the development of a model of cancer as a multi- Rous sarcoma virus, the incorporation of the
stage genetic disorder. The identification of these host-cell gene into the virus, involving a process
abnormally functioning genes in many types of called transduction, results in the loss of viral
human cancer has also provided new molecular genes, generating a defective virus.
targets for therapeutic intervention. In addition to the oncogenes originally iden-
tified in viruses, more than fifty oncogenes have
Key terms been identified in malignant tumors as part of
proto-oncogenes: cellular genes that carry chromosomal rearrangements or the amplifica-
out specific steps in the process of cellular tion or mutations of specific genes. The first ge-
proliferation; as a consequence of mutation netic rearrangement linked to a specific type of
or deregulation, these genes may be con- human malignancy involved the Philadelphia
verted into cancer-causing genes chromosome in patients with chronic myelog-
retrovirus: a virus that converts its RNA ge- enous leukemia (CML). This chromosome rep-
nome into a DNA copy that integrates into resents a shortened version of chromosome 22,
the host chromosome which results from an exchange of genetic mate-
rial between chromosomes 9 and 22 (called a re-
The Discovery of Oncogenes ciprocal translocation). Subsequent molecular
The discovery of oncogenes has been closely analyses showed that the oncogene abl, origi-
linked to the study of the role of a group of nally identified in a mammalian RNA tumor
RNA tumor viruses, retroviruses (Retroviridae), virus, was translocated to chromosome 22 in
in the etiology of many animal cancers. In the CML patients. Additional human malignancies
early part of the twentieth century, Peyton involving translocated oncogenes previously
Rous identified a virus (called Rous sarcoma vi- identified in RNA tumor viruses have been iden-
rus after its discoverer) capable of inducing tu- tified, notably the oncogene myc in patients with
mors called sarcomas in chickens. Many other Burkitts lymphoma, a disease primarily found
RNA tumor viruses capable of causing tumor in parts of Africa.
formation in animals or experimental systems Additional genetic rearrangements repre-
were later discovered, which led to a search for sent amplification of existing oncogenes (seg-
specific viral genes responsible for the cancer- ments of genetic material duplicated many
causing properties of these viruses. times in genetically unstable tumor cells). These
The identification of these cancer-causing gene amplifications may be associated with the
genes (oncogenes) awaited developments in presence of multiple copies of genetic segments
the area of recombinant DNA technology and along a chromosome, designated as homoge-
molecular genetics, which ultimately facili- neously staining regions (HSRs), or may appear
tated the molecular analysis of this group of in the form of minichromosomes containing
genes. These analyses revealed that viral onco- the amplified genes, termed double-minutes
genes were actually cellular genes that were in- (DMs). For example, late-stage neuroblastomas
corporated into the genetic material of the often contain numerous double-minute chro-
RNA tumor virus during the process of infec- mosomes containing amplified copies of the
tion. The acquisition of these host-cell genes N-myc gene.
584 Oncogenes
Oncogenic Viruses
been identified, including single base changes tion, these dysfunctional gene products rep-
(point mutations), gene truncations, gene am- resent potential targets for therapeutic appli-
plifications, and gene rearrangements result- cations. Research studies have been directed
ing from exchanges between different chromo- toward the design of inhibitors of specific onco-
somes called translocations. genes such as ras and erb-b in order to block
One of the most dramatic discoveries in- the effects of oncogenes in malignant cells.
volved a comparative analysis of the structures Additional molecular targets include overex-
of the normal and oncogene forms of the ras pressed oncogenes that stimulate cellular pro-
proto-oncogene isolated from human bladder liferation or blood vessel formation (angiogen-
carcinomas. Surprisingly, a single-base change esis), processes critical to tumor establishment.
was sufficient to convert a normal cellular gene The advantages of these approaches include
to a cancer-causing gene. The observed muta- better targeting of cancer cells, as well as a
tions were localized to regulatory regions of potential decrease in side effects as compared
the ras gene product, resulting in its perma- to conventional chemotherapy. Structural ab-
nent activation. Molecular analyses of many normalities in oncogene products may be used
other oncogenes have shown that the observed in the development of monoclonal antibod-
mutations fall into several categories: nucleo- ies directed against these dysfunctional pro-
tide base changes that result in gene products teins. Toxins may also be linked to the antibod-
whose functions are not subject to normal in- ies to generate immunotoxins whose cell-killing
hibitory processes, overproduction of gene activities directly target malignant cells. Malig-
products caused by gene amplification or trans- nant melanoma (skin cancer) has been the
location, and loss of regulatory components focus of many of these targeted approaches di-
caused by gene translocation or truncation. rected against specific abnormal gene prod-
The generalized consequence of these muta- ucts. Successful clinical applications will most
tions is to convert normal cellular gene prod- likely combine approaches involving cyto-
ucts important in cell division to dominant, toxic drugs and inhibitors targeting multiple
unregulated gene products that cause the inap- sites of oncogene dysfunction in the cancer
propriate stimulation of cell division. cell.
Interestingly, most tumors analyzed show the Sarah Crawford Martinelli
involvement of multiple oncogenes and tumor- See also: Aging; Blotting: Southern, North-
suppressor genes (another class of otherwise ern, and Western; Breast Cancer; Burkitts
normal genes that are modified in some man- Lymphoma; Cancer; Cell Culture: Animal
ner). Studies of tumor development in human Cells; Cell Cycle, The; Gene Therapy; Genetics,
colorectal carcinomas in which it is possible to Historical Development of; Human Genetics;
identify discrete stages of tumor development Hybridomas and Monoclonal Antibodies; Re-
have indicated a progressive increase in the petitive DNA; RNA Transcription and mRNA
number and types of cellular oncogenes at suc- Processing; Tumor-Suppressor Genes.
cessive stages of tumor development. From
these studies, a model of oncogenesis has Further Reading
emerged in the form of a multistage disorder Angier, Natalie. Natural Obsessions: Striving to
characterized by the successive accumulation Unlock the Deepest Secrets of the Cancer Cell.
of mutations in specific cellular oncogenes and Boston: Mariner Books/Houghton Mifflin,
tumor-suppressor genes, which results in the 1999. Explores mutant-gene research and
inability to regulate cellular proliferation. laboratory work to find the essence of the
human cancer cell.
Impact and Applications Cooper, Geoffrey M. Oncogenes. 2d ed. Boston:
The identification of oncogenes has pro- Jones and Bartlett, 1995. Provides a frame-
vided enormous amounts of information on work for studying oncogenes and tumor-
the cellular mechanisms responsible for the suppressor genes and discusses advances in
loss of growth control in cancer cells. In addi- the field, including knowledge of signal trans-
586 One Gene-One Enzyme Hypothesis
duction pathways, which lead to cell prolifer- dational to understanding the molecular basis of
ation. gene action. Today, with a more detailed under-
Ehrlich, Melanie, ed. DNA Alterations in Cancer: standing of how genes work, geneticists consider
Genetic and Epigenetic Changes. Natick, Mass.: the original hypothesis an oversimplification and
Eaton, 2000. Provides an introduction to have reformulated it as the one gene-one polypep-
cancer genes, tumor-suppressor genes, in- tide hypothesis. Even in its new form, however,
herited mutations, and more. Illustrations, there are exceptions.
bibliography, index.
Hartwell, Leland, et al. Cell Cycle Control and Key terms
Cancer. Science 266 (1994). Provides a clear messenger RNA (mRNA) processing: chemi-
description of the role of oncogenes in cell- cal modifications that alter messenger RNAs,
cycle dysregulation. often resulting in more than one gene prod-
La Thangue, Nicholas B., and Lasantha R. uct formed from the same gene
Bandara, eds. Targets for Cancer Chemotherapy: metabolic pathway: a series of enzyme-cata-
Transcription Factors and Other Nuclear Pro- lyzed reactions leading to the complete
teins. Totowa, N.J.: Humana Press, 2002. Dis- breakdown or synthesis of a particular bio-
cusses research on protein targets for cancer logical molecule
drugs. Illustrations, bibliography, index. polypeptide: a complex molecule encoded by
Mulvihill, John J. Catalog of Human Cancer the genetic code and composed of amino ac-
Genes: McKusicks Mendelian Inheritance in ids; one or more of which compose a protein
Man for Clinical and Research Oncologists. Fore- post-translational modification: chemical
word by Victor A. McKusick. Baltimore: alterations to proteins that alter their prop-
Johns Hopkins University Press, 1999. Dis- erties as enzymes
cusses the hereditary traits and genes that
lead to susceptibility or resistance to cancer. Genetics Meets Biochemistry
Includes seven hundred entries grouped ac- In the early part of the twentieth century, ge-
cording to body organ. netics was becoming an established discipline,
Varmus, Harold. The Molecular Genetics of but the relationship between genes and how
Cellular Oncogenes. Annual Review of Genet- they are expressed as phenotypes was not yet un-
ics 18 (1994). Nobel laureate Varmus details derstood. Biochemistry was also in its infancy,
the structure and function of oncogenes. particularly the study of the enzyme-catalyzed
chemical reactions of metabolic pathways. In
Web Sites of Interest 1902, a British medical doctor named Archibald
American Cancer Society. http://www.cancer Garrod brought genetics and biochemistry to-
.org. Site has searchable information on on- gether in the discovery that a human disease
cogenes and tumor suppressor genes. called alkaptonuria, which causes individuals
American Society of Clinical Oncology. http:// with the disease to accumulate a black pigment
www.asco.org. Searchable site on oncogenes in their urinewas inherited as a recessive
and molecular oncology. trait. Equally important, however, was Garrods
observation that alkaptonurics were unable to
metabolize alkapton, the molecule responsible
for the black pigmentation, an intermediate in
One Gene-One Enzyme the degradation of amino acids. Garrods con-
Hypothesis clusion was that people with alkaptonuria lack
the enzyme that normally degrades alkapton.
Field of study: History of Genetics; Because it thus appeared that a defective gene
Molecular genetics led to an enzyme deficiency, Garrod predicted
Significance: The formulation of the one gene-one that genes form enzymes. This statement was
enzyme hypothesis in 1941, which simply states the precursor of what came to be known as the
that each gene gives rise to one enzyme, was foun- one gene-one enzyme hypothesis.
One Gene-One Enzyme Hypothesis 587
polypeptide, each of which is the product of a zymatic properties, often essentially making
different gene. For example, the enzyme ATP them into different enzymes. Once insulin is
synthase is composed of at least seven different no longer present, the cell can undo the modi-
polypeptides, all encoded by separate genes. fications, returning the enzymes back to their
Thus, the one-to-one ratio of genes to enzymes original forms.
implied by the hypothesis is clearly incorrect. Stephen Cessna
This fact was recognized early and led to the See also: Complementation Testing; Ge-
theorys reformulation as the one gene-one netics, Historical Development of; Model Or-
polypeptide hypothesis. However, even this ganism: Neurospora crassa; Signal Transduction.
newer version of the hypothesis has since been
shown to be inaccurate. Further Reading
Second, several important genes do not en- Beadle, G. W., and E. L. Tatum. Genetic Con-
code enzymes. For example, some genes en- trol of Biochemical Reactions in Neurospora.
code transfer RNAs (tRNAs), which are re- Proceedings of the National Academy of Sciences
quired for translating mRNAs. Thus, clearly 27 (1941): 499-506. The original research ar-
even the one gene-one polypeptide hypothesis ticle that postulated the one gene-one en-
is insufficient, since tRNAs are not polypep- zyme hypothesis.
tides. Davis, Rowland H. Neurospora: Contributions of a
Finally, further deviation from the original Model Organism. New York: Oxford Univer-
one gene-one enzyme hypothesis is required sity Press, 2000. A full account of the organ-
when one considers that several modifications isms history, biology, genome, mitosis, mei-
to RNAs and polypeptides occur after gene osis, metabolism, mutations, and more.
transcription, and can do so in more than one Science 291 (February, 2001). A special issue on
way. Thus, a single gene can give rise to more the human genome. Articles estimate the
than one mRNA, and potentially to numerous number of genes in the human genome and
different polypeptides with varying properties. guess at the corresponding number of active
Post-transcriptional variation in gene expres- gene products.
sion occurs first during RNA processing, when Weaver, Robert F. Molecular Biology. 2d ed. New
the polypeptide-encoding regions of mRNA York: McGraw-Hill, 2002. Gives a modern
are spliced together. It is important to note that overview of gene expression, including dif-
the exact splicing pattern can vary depending ferential mRNA processing, and explains
on the exact needs of the cell. One example of the original work of Beadle and Tatum in de-
a gene that undergoes differential mRNA pro- tail.
cessing leading to two dramatically different
phenotypes is the fruit fly gene sex-lethal (sxl).
A long version of sxl mRNA is generated in de-
veloping male flies and a shorter one in female Organ Transplants and HLA
flies. Because the sxl protein regulates sexual
development, mutant female flies that mistak-
Genes
enly splice sxl mRNA display male sexual char- Field of study: Immunogenetics
acteristics. Significance: Organ transplantation has saved
Like differential mRNA processing, post- the lives of countless people. Although the success
translational protein modification varies by cel- rate for organ transplantation continues to im-
lular context, allowing a single gene to gener- prove, many barriers remain, including an inade-
ate more than one kind of enzyme. However, quate supply of donor organs and the phenomenon
unlike mRNA processing, protein modifica- of transplant rejection. Transplant rejection is
tion is often reversible. For example, liver cells caused by an immune response by the recipient to
responding to insulin will chemically modify molecules on the transplanted organs that are
some of their enzymes by way of a process called coded for by the human leukocyte antigen (HLA)
signal transduction, thereby changing their en- gene complex.
Organ Transplants and HLA Genes 589
A two-week-old piglet in April, 2002, one of three that were the first to be cloned from both human and pig cells. Normal pigs have been
sources of human replacement parts (such as heart valves) from some time. The hope is that organs from pigs with human genes
will be more easily accepted by the human body after transplantion. (AP/Wide World Photos)
important histocompatibility antigens, called to make an immune response to the virus. The
the major histocompatibility complex (MHC). existence of multiple MHC alleles in a popula-
tion, therefore, ensures that some individuals
MHC Polymorphism, HLA Genes, and will have MHC alleles allowing them to mount
Tissue Typing an immune response against a particular patho-
Each MHC locus is highly polymorphic, gen. If an entire population lacked these al-
meaning that many different alleles exist leles, their inability to respond to certain patho-
within a population (members of a species gens could threaten the very existence of the
sharing a habitat). The explanation for the species. The disadvantage of MHC polymorph-
polymorphism of histocompatibility antigens is ism, however, is the immune response to the
related to the actual function of these mole- donors histocompatibility antigens that causes
cules within the body. Clearly, histocompati- organ rejection.
bility molecules did not evolve to induce the re- The human leukocyte antigen (HLA) gene
jection of transplants, despite the fact that this complex is located on chromosome 6 in hu-
characteristic led to their discovery and name. mans. Six important histocompatibility anti-
Histocompatibility molecules function by gens are coded for by the HLA complex: the A,
regulating immunity against foreign antigens. B, C, DR, DP, and DQ alleles. Differences in
Each allele codes for a protein that allows the HLA antigens between the donor and recipi-
immune response to recognize a different set ent are determined by tissue typing. For many
of antigens. Many pathogens, including the vi- years, tissue typing was performed using anti-
ruses associated with influenza and acquired bodies specific to different HLA alleles. Anti-
immunodeficiency syndrome (AIDS), undergo bodies are proteins secreted by the cells of the
genetic mutations that lead to changes in their immune system that are used in the laboratory
antigens, making it more difficult for the body to identify specific antigens. As scientists began
Organ Transplants and HLA Genes 591
to clone the genes for the most common HLA sponse to pathogens, their susceptibility to a va-
alleles in the 1980s and 1990s, however, it ap- riety of diseases will be increased. Thus trans-
peared that direct genetic analysis would even- plant recipients must take special precautions
tually replace or at least supplement these pro- to avoid exposure to potential pathogens, espe-
cedures. cially when receiving high doses of the drugs.
Fewer differences in these antigens between James A. Wise
donor organ and recipient mean a better prog- See also: Animal Cloning; Bacterial Genet-
nosis for transplant survival. Therefore, closely ics and Cell Structure; Bioethics; Biological
related individuals who share many of their Weapons; Cancer; Cloning; Cloning: Ethical Is-
histocompatibility alleles are usually preferred sues; Diabetes; Gene Therapy: Ethical and Eco-
as donors. When a family member is not avail- nomic Issues; Genetic Engineering: Historical
able, the process of finding a donor is problem- Development; Genetics, Historical Develop-
atic. Worldwide computer databases are used ment of; Heart Disease; Huntingtons Disease;
to match potential donors with recipients, who Hybridomas and Monoclonal Antibodies;
are placed on a waiting list based on the severity Immunogenetics; In Vitro Fertilization and Em-
of their disease. bryo Transfer; Model Organism: Mus musculus;
Model Organism: Xenopus laevis; Multiple Al-
Immunosuppressive Antirejection Drugs leles; Paternity Tests; Polymerase Chain Reac-
Perhaps the most important medical break- tion; Prion Diseases: Kuru and Creutzfeldt-
through responsible for the increased success of Jakob Syndrome; Race; Sickle-Cell Disease;
organ transplantation occurred in the last two Stem Cells; Synthetic Antibodies; Totipotency;
decades of the twentieth century. This break- Transgenic Organisms; Xenotransplants.
through involved the discovery and successful
use of antirejection drugs, most of which act by Further Reading
suppressing the immune response to the trans- Browning, Michael, and Andrew McMichael,
planted tissue. Immunosuppressive drugs are eds. HLA and MHC: Genes, Molecules, and
usually given in high doses for the first few weeks Function. New York: Academic Press, 1999.
after transplantation or during a rejection cri- A review of molecular genetics of MHC,
sis, but the dosage of these drugs is usually re- the structure and function of MHC-encoded
duced thereafter to avoid their toxic effects. molecules, and how they factor in health and
Cyclosporine is by far the most effective of disease. Illustrations, bibliography, index.
these drugs and has largely been responsible Janeway, Charles A., Paul Travers, et al. Immuno-
for the increased efficacy of liver, pancreas, biology: The Immune System in Health and Dis-
lung, and heart transplantation procedures. In ease. 5th rev. ed. Philadelphia: Taylor & Fran-
spite of its successes, cyclosporine has limita- cis, 2001. Provides an excellent review of the
tions in that it can cause kidney damage when HLA complex.
given in high doses. Azathioprine, associated Lechler, Robert I., et al. The Molecular Basis
with bone marrow toxicity, was largely sup- of Alloreactivity. Immunology Today 11
planted by the introduction of the less toxic cy- (March, 1990). Discusses the molecular ba-
closporine. However, azathioprine has been sis of transplantation rejection.
used as part of a combined cyclosporine- Sasaki, Mutsuo, et al., eds. New Directions for Cel-
azathioprine regimen. This practice allows the lular and Organ Transplantation. New York:
reduction of both the cyclosporine and azathio- Elsevier Science, 2000. A collection of con-
prine dosages, reducing the toxicity of both ference papers on organ transplantation
drugs. The search for more effective and less and organ donation. Illustrations, bibliogra-
toxic antirejection drugs continues. Individ- phy, index.
uals receiving immunosuppressive therapy have Scientific American 269 (September, 1993). A
other concerns in addition to the toxicity of the special issue devoted to Life, Death, and
drugs themselves. As these individuals will have the Immune System, providing an excellent
an impaired ability to mount an immune re- overview of the immune system.
Parthenogenesis produce by parthenogenesis; late in the sum-
Field of study: Genetic engineering and mer, however, as the food source is decreasing,
biotechnology sexually reproducing females appear. The same
Significance: Parthenogenesis is the development pattern has been observed in rotifers, in which a
of unfertilized eggs, which produces individuals decrease in the quality of the food supply leads
that are genetically alike and allows rapid expan- to the appearance of females that produce hap-
sion of a population of well-adapted individuals loid eggs by normal meiosis that require fertil-
into a rich environment. This clonal reproduction ization for development. The strategy appears
strategy is used by a number of species for rapid re- to involve the clonal production of large num-
production under very favorable conditions, and bers of genetically identical individuals that are
it appears to offer a selective advantage to individ- well suited to the environment when the condi-
uals living in disturbed habitats. tions are favorable and the production of a vari-
ety of different types, by the recombination that
Key terms occurs during normal meiosis and the mixing of
adaptive advantage: increased fertility in off- alleles from two individuals in sexual reproduc-
spring as a result of passing on favorable ge- tion, when the conditions are less favorable. In
netic information social insects, such as bees, wasps, and ants, par-
diploid: having two sets of homologous chro- thenogenesis is a major factor in sex determina-
mosomes tion, although it may not be the only factor. In
fertilization: the fusion of two cells (egg and these insects, eggs that develop by parthenogen-
sperm) in sexual reproduction esis remain haploid and develop into males,
haploid: having one set of chromosomes while fertilized eggs develop into diploid, sexu-
meiosis: nuclear division that reduces the ally reproducing females.
chromosome number from diploid to hap- In algae and some forms of plants, partheno-
loid in the production of the sperm and the genesis also allows rapid reproduction when
egg conditions are favorable. In citrus, seed devel-
zygote: the product of fertilization in sexually opment by parthenogenesis maintains the fa-
reproducing organisms vorable characteristics of each plant. For this
reason, most commercial citrus plants are
The Nature of Parthenogenesis propagated by asexual means, such as grafting.
Parthenogenesis is derived from two Greek Parthenogenesis has also been induced in or-
words that mean virgin (parthenos) and ori- ganisms that do not show the process in natural
gin (genesis) and describes a form of reproduc- populations. In sea urchins, for example, devel-
tion in which females lay diploid eggs (contain- opment can be induced by mechanical stimula-
ing two sets of chromosomes) that develop into tion of the egg or by changes in the chemistry
new individuals without fertilizationthere is of the medium. Even some vertebrate eggs
no fusion of a sperm nucleus with the egg nu- have shown signs of early development when
cleus to produce the new diploid individual. artificially stimulated, but haploid vertebrate
This is a form of clonal reproduction because all cells lack all of the information required for
of the individuals are genetically identical to the normal development, so such zygotes cease
mother and to each other. The mechanisms of development very early.
parthenogenesis do not show any single pattern
and have evolved independently in different Parthenogenesis in Vertebrates
groups of organisms. In some organisms, such Parthenogenesis has been observed in verte-
as rotifers and aphids, parthenogenesis alter- brates such as fish, frogs, and lizards. In these
nates with normal sexual reproduction. When parthenogenetic populations, all the individu-
there is a rich food source, such as new rose als are females, so reproduction of the clone is
bushes emerging in the early spring, aphids re- restricted to parthenogenesis. Parthenoge-
Parthenogenesis 593
netic fish often occur in populations along with cally identical. Since the parthenogenetic form
sexually reproducing individuals. The parthe- may, at least in vertebrates, be a hybrid, it is het-
nogenetic forms produce diploid eggs that de- erozygous at most of its genetic loci. This pro-
velop without fertilization; in rare cases, how- vides greater variation that may provide the ani-
ever, fertilization of a parthenogenetic egg mal with a greater range of responses to the
gives rise to a triploid individual that has three environment. Maintaining this heterozygous ge-
sets of chromosomes rather than the normal notype may give the animals an advantage in en-
two sets (two from the diploid egg and one vironments where the parental species are not
from the sperm). In some groups, penetration able to reproduce successfully and may be a ma-
of a sperm is necessary to activate development jor reason for the persistence of this form of re-
of the zygote, but the sperm nucleus is not in- production. Many vertebrate parthenogenetic
corporated into the zygote. populations are found in disturbed habitats, so
Evidence indicates that in each of these ver- their unique genetic composition may allow for
tebrate situations, the parthenogenetic pop- adaptation to these unusual conditions.
ulations have resulted from a hybridization
between two different species. The partheno- Mechanisms of Development
genetic forms always occur in regions where The mechanisms of diploid egg develop-
the two parental species overlap in their distri- ment are as diverse as the organisms in which
bution, often an area that is not the most favor- this form of reproduction is found. In normal
able habitat for either species. The hybrid ori- meiosis, the like chromosomes of each pair sep-
gin has been confirmed by the demonstration arate at the first division and the copies of each
that the animals have two different forms of an chromosome separate at the second division
enzyme that have been derived from the two (producing four haploid cells). During the
different species in the region. Genetic identity meiotic process in the egg, three small cells
has also been confirmed using skin graft stud- (the polar bodies), each with one set of chro-
ies. In unrelated organisms, skin grafts are mosomes, are produced, and one set of chro-
quickly rejected because of genetic incompati- mosomes remains as the egg nucleus. In par-
bilities; clonal animals, on the other hand, thenogenetic organisms, some modification of
readily accept grafts from related donors. Par- this process occurs that results in an egg nu-
thenogenetic fish from the same clone accept cleus with two sets of chromosomesthe dip-
grafts that confirm their genetic identity, but loid state. In some forms, the first meiotic divi-
rejection of grafts by other parthenogenetic sion does not occur, so two chromosome sets
forms from different populations shows that remain in the egg following the second divi-
they are different clones and must have a differ- sion. In other forms, one of the polar bodies
ent origin. This makes it possible to better un- fuses back into the cell so that there are two sets
derstand the structure of the populations and of chromosomes in the final egg. In another
helps in the study of the origins of partheno- variation, there is a replication of chromo-
genesis within those populations. Comparisons somes after the first division, but no second di-
using nuclear and mitochondrial DNA also al- vision takes place in the egg, so the chromo-
low the determination of species origin and the some number is again diploid. In all of these
maternal species of the parthenogenetic form mechanisms, the genetic content of the egg is
since the mitochondria are almost exclusively derived from the mothers genetic content,
transmitted through the vertebrate egg. Within and there is no contribution to the genetic con-
the hybrid, a mechanism has originated that tent from male material.
allows the egg to develop without fertilization, The situation may be even more complex,
although, as already noted, penetration by a however, because some hybrid individuals may
sperm may be required to activate develop- retain the chromosomal identity of one species
ment in some of the species. by a selective loss of the chromosomes of the
The advantage of parthenogenesis appears to other species during meiosis. The eggs may
be the production of individuals that are geneti- carry the chromosomes of one species but the
594 Patents on Life-Forms
mitochondria of the other species. The hap- ented under federal law. The case involved
loid eggs must be fertilized, so these individu- Ananda M. Chakrabarty, a scientist who, while
als are not parthenogenetic, but their presence working for General Electric in 1972, had cre-
in the population shows how complex repro- ated a new form of bacteria, Pseudomona
ductive strategies can be and how important originosa, which could break down crude oil,
it is to study the entire population in order to and, therefore, could be used to clean up oil
understand its dynamics fully: A single popula- spills. Chakrabarty filed for a patent, but an ex-
tion may contain individuals of the two sexual aminer for the Patent Office rejected the appli-
species, true parthenogenetic individuals, and cation on the ground that living things are not
triploid individuals resulting from fertilization patentable subject matter under existing pat-
of a diploid egg. ent law. Commissioner of Patents and Trade-
D. B. Benner marks Sidney A. Diamond supported this view.
See also: Totipotency. Federal patent law provided that a patent could
be issued only to a person who invented or dis-
Further Reading covered any new and useful manufacture or
Beatty, Richard Alan. Parthenogenesis and Poly- composition of matter. The U.S. Court of
ploidy in Mammalian Development. Cambridge, Customs and Patent Appeals reversed that deci-
England: Cambridge University Press, 1957. sion in 1979, concluding that the fact that mi-
An early but still useful study. croorganisms are alive has no legal significance.
Kaufman, Matthew H. Early Mammalian Devel- It held that a live, human-made bacterium is a
opment: Parthenogenetic Studies. New York: patentable item since the microorganism was
Cambridge University Press, 1983. By a well- manufactured by crossbreeding four existing
known expert in mouse studies. strains of bacteria and had never existed in na-
ture.
Writing for the majority, Chief Justice War-
ren Burger upheld the patent appeals court
Patents on Life-Forms judgment, making a distinction between the
new bacterium and laws of nature, physical
Field of study: Bioethics; Human genetics phenomena and abstract ideas, which are not
and social issues patentable. In the Court majoritys view,
Significance: In 1980, the U.S. Supreme Court Chakrabarty had invented a form of life that
upheld the right to patent a live, genetically altered did not exist in the natural world, so it could
organism. The decision was opposed by many sci- not be considered part of nature. Instead, it was
entists and theologians who believed that such or- a product of human ingenuity and research
ganisms would pose a threat to the future of hu- that deserved patent protection. Items not
manity. Although legally settled, the debate has patentable include new minerals that are dis-
continued, opponents arguing that patenting life- covered in the earth or a new species of plant
forms and DNA sequences imposes too great a cost found in a distant forest. These things occur
and greatly inconveniences genetic research. naturally and are not created by humans. Bur-
ger also stressed that physicist Albert Einstein
Key term could not have patented his formula E = mc 2,
patent: a grant made by the government that since it is a law of nature, nor could Sir Isaac
gives the creator or inventor the sole right to Newton have received a patent for the law of
make, use, or sell that invention for a specific gravity. Discoveries such as these are part of the
period of time, usually seventeen years in the natural world and cannot be owned by a single
United States individual.
Chakrabarty, on the other hand, had not
Patent on Life-Form Upheld found an unknown, natural species, nor had he
On June 16, 1980, the U.S. Supreme Court discovered a law of nature. His new bacterium
voted 5 to 4 that living organisms could be pat- had a distinctive name and was developed in
Patents on Life-Forms 595
the laboratory for a specific purpose. None of or accept them. Such a determination was not
the characteristics of the new organism could the responsibility of the Court, however. Ques-
be found in nature. His discovery, Burger re- tions of the morality of genetic research and
emphasized, was patentable because he had manipulation were better left to Congress
created it. and the political process. How to proceed in
these matters could only be resolved after the
Opposition to the Ruling kind of investigation, examination, and study
The Court majority refused to consider that legislative bodies can provide and courts
arguments made in friend-of-the-court briefs cannot.
filed by opponents of genetic engineering. The Justice William J. Brennan, Jr., presented a
briefs were presented by groups representing brief dissenting opinion. He noted that Con-
scientists, including several Nobel Prize win- gress had twice, in 1930 and 1970, permitted
ners, and religious organizations. One brief new types of plants to be patented. However,
suggested that genetic research posed a dan- those laws made no mention of bacteria. Thus,
gerous and serious threat to the future of hu- Brennan argued, Congress had indicated that
manity and should, therefore, be prohibited. only plants could receive patents and that the
Possible dangers included the spread of pol- legislators had thus clearly indicated that other
lution and disease by newly created bacteria, life-forms were excluded from the patent pro-
none of which would have any natural enemies. cess. The Court majority rejected this view, ar-
Other threats involved the possible loss of ge- guing that Congress had not specifically ex-
netic diversity, if, for instance, only the best cluded other life-forms.
form of laboratory-created plant seeds were
grown. Research into human genetics could Developments Since 1980
lead to newly designed gene material that could Since the patenting of the petroleum-eating
be used to build a master race, thereby deval- bacteria, a variety of other genetically modified
uing other human lives. Justice Burger con- (GM) organisms have been patented, includ-
cluded, however, that humans could be trusted ing pest-resistant crop plants and numerous
not to create such horrible things. Quoting types of knockout mice used by many re-
William Shakespeares Hamlet, the chief justice searchers. The controversy around such pat-
asserted that it is sometimes better to bear ents initially calmed, but more recent develop-
those ills we have than to fly to others that we ments have rekindled the flames. Since the
know not of. People can try to guess what ge- advent of the Human Genome Project, the se-
netic manipulation could lead to, but it would quencing of genomes has accelerated expo-
also be a good idea to expect good things from nentially. Because many sequences might con-
science rather than a gruesome parade of tain valuable genes or markers, companies and
horribles. Besides, he then said, it did not mat- nonprofit organizations began patenting the
ter whether a patent was granted in this case; in sequences.
either case, scientific research would continue After much debate, the patenting of DNA se-
into the nature of genes. quences has been allowed, and although the
The Peoples Business Commission, a non- guidelines are still being fine-tuned, the gen-
profit educational foundation, had argued that eral rule is that any distinctive DNA sequence
granting General Electric and Chakrabarty a can be patented. Those opposed to the patent-
patent would give corporations the right to ing of DNA sequences say that it will impede re-
own the processes of life in the centuries to search and even the development of useful
come through genetic manipulation. Chief medical applications. Ethicists argue that no
Justice Burger wrote that the Court was with- one should have a right to patent DNA se-
out competence to entertain these arguments. quences, which represent the very basis of life.
They did not have enough information avail- Some scientists have pushed for more restric-
able to determine whether to ignore such fears tive rules, such as that a sequence cannot be
as fantasies generated by fear of the unknown patented unless there is clear evidence that the
596 Paternity Tests
sequence codes for a useful product or would Hastings Center Law Report, November/
likely lead to a specific application. December, 1997. Discusses the religious, le-
At present it is too early to predict the final gal, moral, and scientific concerns about
outcome of the push for patenting DNA se- patenting human genetic material, DNA and
quences. There is still debate and there is a patents, and the biotechnology industry.
large backlog of sequences for which patents Vogel, Fredrich, and Reinhard Grunwald, eds.
are still pending. A survey of medical testing Patenting of Human Genes and Living Organ-
laboratories in 2003 found that a number of isms. New York: Springer, 1994. Provides an
labs either no longer used certain tests or did overview of patent acquisition and legal con-
not plan to develop them when licensing fees cerns. Illustrated.
were required for permission to use a relevant
DNA sequence. Overwhelmingly, the labs sur-
veyed saw patenting of DNA sequences as hav-
ing a negative effect on the development of af-
fordable clinical genetic tests. Paternity Tests
Leslie V. Tischauser, updated by Bryan Ness
See also: Genetic Engineering: Historical Field of study: Human genetics and social
Development; Genetic Engineering: Industrial issues
Applications; Genetic Engineering: Social and Significance: Establishing paternity can be impor-
Ethical Issues; Human Genetics; Human Ge- tant for establishing legal responsibility for child
nome Project; Hybridization and Introgres- support, health insurance, veterans and social se-
sion; Model Organism: Mus musculus; Trans- curity benefits, and legal access to medical records.
genic Organisms. It may also affect a childs future as it relates to in-
herited diseases.
Further Reading
Chapman, Audrey R., ed. Perspectives on Genetic Key terms
Patenting: Religion, Science, and Industry in Di- forensic genetics: the use of genetic tests and
alogue. Washington, D.C.: American Associa- principles to resolve legal questions
tion for the Advancement of Science, 1999. human leukocyte antigens (HLA): antigens
Discusses questions such as, Should prod- produced by a cluster of genes that play a
ucts of nature be patentable? Are genes or critical role in the outcome of transplants;
gene fragments discoveries or inventions? because they are made up of a large number
Should patenting of genes, cell lines, or ge- of genes, they are used in individual identifi-
netically modified organisms be equated cation and the matching of parents and off-
with ownership of them? Is the DNA in genes spring
just a complex molecule or is it sacred? Does paternity exclusion: the indication, through
patenting human DNA and tissue demean genetic testing, that a particular man is not
human life and human dignity? the biological father of a particular child
Diamond, Commissioner of Patents and Trademarks
v. Chakrabarty (1980), 447 U.S. 303. The offi- Genetic Principles of Paternity Testing
cial citation of the Supreme Court decision. The basic genetic principles utilized in pa-
Doll, John. Talking Gene Patents. Scientific ternity testing have remained the same from
American, August, 2001. A brief interview the first applications of ABO blood groups to
with the director of biotechnology for the applications of DNA fingerprinting. Available
U.S. Patent and Trademark Office on what tests may positively exclude a man from being a
makes a gene eligible for a chemical com- childs biological father. Evidence supporting
pound patent and the number of genes pat- paternity, however, cannot be considered con-
ented. clusive. Ultimately, a court must decide whether
Hanson, Mark J. Religious Voices in Biotech- a man is determined to be the legal father
nology: The Case of Gene Patenting. based on all lines of evidence.
Paternity Tests 597
The genetic principles can be illustrated with Mating 7 satisfies the condition of a father be-
a very simple example that uses ABO blood ing B and the mother A, but mating 7 cannot
types. The four blood groups (A, B, AB, and O) produce a child being A. The putative father
are controlled by three pairs of genes. In the ex- cannot be the father, and he is excluded.
ample, however, only three of the blood groups
will be used to demonstrate the range of mat- DNA Fingerprinting
ings with the possible children for each of them After the initial use of ABO blood groups in
(see the table headed Blood Types, Genes, paternity testing, it became apparent that there
and Possible Offspring). were many cases in which the ABO phenotypes
did not permit exclusion. Other blood group
Example 1: A man is not excluded.
systems have also been used, including the MN
Mother: A
and Rh groups. As more blood groups are uti-
Child: A
Putative Father: AB
lized, the probability of exclusion (or nonex-
clusion) increases. Paternity tests have not been
It can be seen that the mothers in matings 1 restricted to blood groups alone; tissue types
and 4 satisfy the condition of the mother being and serum enzymes have also been used.
A and possibly having a child being A. Mating 4 The most powerful tool developed has been
satisfies the condition of a father being AB, the DNA testing. DNA fingerprinting was devel-
mother A, and a possible child being A. Results oped in England by Sir Alec Jeffreys. DNA is ex-
indicate that the putative father could be the fa- tracted from white blood cells and broken
ther. He is not excluded. down into fragments by bacterial enzymes (re-
striction endonucleases). The fragments are
Example 2: A man is excluded.
separated by size, and specific fragments are
Mother: A
identified. Each individual has a different DNA
Child: A
Putative Father: B
profile, but the profiles of parents and children
have similarities in greater proportion than
Again, it is seen that the mothers in matings 1, those between unrelated people. Also, frequen-
4, and 7 satisfy the condition of the mother be- cies of different fragments tend to vary among
ing A and possibly having a child being A. ethnic groups. It is possible not only to exclude
Examples of Pedigrees
Family A
I
1 2
II
1 2 3 4 5
III
1 2 3 4 5 6
IV
1 2 3 4
Family B Family C
I
3 4 5 6
II
6 7 8 9 10 11 12 13 14 15
III
7 8 9 10 11 12 13 14 15 16
IV
5 6 7 8 9 10 11 12 13 14 15
Typical pedigree charts for three families: Roman numerals indicate generations. Squares denote male individuals; circles, female in-
dividuals; white or blank individuals are normal phenotype; black denotes affected phenotype. The charts read like a family tree,
with mother and father at the top and vertical lines denoting offspring; individuals connected only by horizontal lines are mates
that have entered the genetic line from outside (in-laws in the case of humans). Family A provides an example of a sex-linked reces-
sive trait. Families B and C (joined at 12 and 13) give examples of autosomal traits and how they can resemble sex-linked recessive
traits sometimesand hence the reason for using large families when constructing pedigrees. (Bryan Ness)
The pattern of autosomal dominant inheri- rence risk to the unborn sibling of an affected
tance is perhaps the easiest type of Mendelian individual is one in four. The majority of X-
inheritance to recognize in a pedigree. A trait linked traits are recessive. The hallmark of X-
that appears in successive generations, and is linked recessive inheritance is that males are
found only among offspring where at least one much more likely to be affected than females,
of the parents is affected, is normally due to a because males are hemizygous, that is, they pos-
dominant allele. sess only one X chromosome, while females
If neither parent has the characteristic phe- have two X chromosomes. Therefore, a reces-
notype displayed by the child, the trait is reces- sive trait on the X chromosome will be ex-
sive. For recessive traits, on average, the recur- pressed in all males who possess that X chro-
Pedigree Analysis 601
mosome, while females with one affected X penetrance, some individuals who possess the
chromosome will be asymptomatic carriers un- dominant allele may not express the disease
less their other X chromosome also carries the phenotype at all. Some traits have a high recur-
recessive trait. The trait or disease is typically rent mutation rate. An example is achondro-
passed from an affected grandfather through plasia (a type of dwarfism), in which 85 percent
his carrier daughters to half of his grandsons. of cases are due to new mutations, where both
X-linked dominant traits are rare but distinc- parents have a normal phenotype. Traits due to
tive. All daughters of an affected male and a multifactorial inheritance have variable ex-
normal female are affected, while all sons of an pression as a result of interactions of the genes
affected male and a normal female are normal. involved with the environment. Early-acting le-
For matings between affected females and nor- thal alleles can lead to embryonic death and a
mal males, the risk of having an affected child is resulting dearth of expected affected individu-
one in two, regardless of the sex of the child. als. Pleiotropy is the situation in which a single
Males are usually more severely affected than gene controls several functions and therefore
females. The trait may be lethal in males. In the has several effects; it can result in different
general population, females are more likely to symptoms in different affected individuals.
be affected than males, even if the disease is not Finally, one trait can have a different basis of in-
lethal in males. heritance in different families. For example,
mutations in any one of more than four hun-
Usefulness dred different genes can result in hereditary
Pedigrees are important both for helping deafness.
families identify the risk of transmitting an in-
herited disease and as starting points for Modern Applications
searching for the genes responsible for inher- Genetic counseling is one of the key areas in
ited diseases. Mendelian ratios do not apply in which pedigrees are employed. A genetic coun-
individual human families because of the small seling session usually begins with the counselor
size. Pooling of families is possible; in the taking a family history and sketching a pedi-
United States, the Mormons and the Amish gree with paper and pencil, followed by use of a
have kept good records that have aided genetic computer program to create an accurate pedi-
studies. gree. The Human Genome Project has acceler-
However, even using large, carefully con- ated the number of genetic disorders that can
structed records, pedigrees can be difficult to be detected by heterozygote and prenatal
construct and interpret for several reasons. screening. A large part of the genetic coun-
Tracing family relationships can be compli- selors job is to determine for whom specific ge-
cated by adoption, children born out of wed- netic tests are appropriate.
lock, blended families, and assisted reproduc- Although genetic tests for many disorders
tive technologies that result in children who are now available, the genes involved in many
may not be genetically related to their parents. other disorders have yet to be identified. There-
Additionally, people are sometimes hesitant to fore most human gene mapping utilizes molec-
supply information because they are embar- ular DNA markers, which reflect variation at
rassed by genetic conditions that affect behav- noncoding regions of the DNA near the af-
ior or mental stability. fected gene, rather than biochemical, morpho-
Many traits do not follow clear-cut Mendel- logical, or behavioral traits. A DNA marker is a
ian ratios. Extensions and exceptions to Men- piece of DNA of known size, representing a spe-
dels laws that can confound efforts to develop cific locus, that comes in identifiable variations.
a useful pedigree are numerous. In diseases These allelic variations segregate according to
with variable expressivity, some of the symp- Mendels laws, which means it is possible to fol-
toms of the disease are always expressed but low their transmission as one would any genes
may range from very mild to severe. In auto- transmission. If a particular allelic variant of
somal dominant diseases with incomplete the DNA marker is found in individuals with a
602 Penetrance
particular phenotype, the DNA marker can be several case studies and numerous problems.
used to develop a pedigree. The DNA from all Wolff, G., T. F. Wienker, and H. Sander. On the
available family members is examined and the Genetics of Mandibular Prognathism: Anal-
pedigree is constructed using the presence of ysis of Large European Noble Families.
the DNA marker rather than phenotypic cate- Journal of Medical Genetics 30, no. 2 (1993):
gories. This method is particularly useful for 112-116. Good, not overly technical, exam-
late-onset diseases such as Huntingtons dis- ple of the use of human pedigrees to deter-
ease, whose victims may not know they carry mine mode of inheritance.
the deleterious allele until they are in their
forties or fifties, well past reproductive years.
Although using DNA markers is a powerful
method, crossover in the chromosome between Penetrance
the marker and the gene can cause an individ-
ual to be normal but still have the marker that Field of study: Population genetics
suggests presence of the mutant allele. Thus, Significance: Penetrance is a measure of how fre-
for all genetic tests there is a small percentage quently a specific genotype results in the same, pre-
of false positive and false negative results, which dictable phenotype. Such variable expression of the
must be factored into the advice given during same genotype is the result of different genetic back-
genetics counseling. grounds and the effects of variations in the envi-
Lisa M. Sardinia ronment. Geneticists desire 100 percent penetrance
See also: Artificial Selection; Classical for desirable genes that offer disease resistance but
Transmission Genetics; Complete Dominance; reduced penetrance and low expressivity for others
Eugenics; Genetic Counseling; Homosexual- that may contribute to human diseases.
ity; Incomplete Dominance; Multiple Alleles.
Key terms
Further Reading expressivity: the degree to which a pheno-
Bennett, Robin L. The Practical Guide to the Ge- type is expressed, or the extent of expression
netic Family History. New York: Wiley-Liss, of a phenotype
1999. Designed for primary care physicians, phenotype: the physical appearance or bio-
this practical book provides the foundation chemical and physiological characteristics
in human genetics necessary to recognize of an individual, which is determined by
inherited disorders and familial disease sus- both heredity and environment
ceptibility. Shows how to create a family ped-
igree. Gene Expression and Environment
Bennett, Robin L., et al. Recommendations Gene expression results in a chemical prod-
for Standardized Human Pedigree Nomen- uct (protein) with a specific function. The geno-
clature. American Journal of Human Genetics type (genetic makeup, or gene) and environ-
56, no. 3 (1995): 745-752. A report from the mental conditions determine the phenotype of
Pedigree Standardization Task Force that an individual.
addresses current usage, consistency among
symbols, computer compatibility, and the Penetrance and Expressivity
adaptability of symbols to reflect the rapid Gene expression is dependent upon envi-
technical advances in human genetics. ronmental factors and may be modified, en-
Cummings, Michael R. Pedigree Analysis in hanced, silenced, and/or timed by the regula-
Human Genetics. In Human Heredity, edited tory mechanisms of the cell in response to
by Cummings. Pacific Grove, Calif.: Brooks/ internal and external forces. A range of pheno-
Cole, 2003. Textbook designed for an in- types can result from a genotype in response to
troductory human genetics course for non- different environments; the phenomenon is
science majors. This chapter contains many called norms of reaction or phenotypic plas-
useful diagrams and pictures, ending with ticity. Norms of reaction represent the expres-
Penetrance 603
sion of phenotypic variability in individuals of a only 30 percent of those carrying the mutant al-
single genotype. lele exhibit the mutant phenotype, the pene-
The question of which is more important in trance is 30 percent. Sometimes an individual
the formation of an organism, nature (geno- with a certain genotype fails to express the ex-
type) or nurture (environment), has been de- pected phenotype, and then the allele is said to
bated for centuries. The answer is that it de- be nonpenetrant in the individual. If the phe-
pends. The genotype defines phenotypic notype is expressed to any degree, the geno-
potential. The environment works on the plas- type is penetrant.
ticity of expression to produce different phe- Given a particular phenotypic trait and a ge-
notypes from similar genotypes. notype, penetrance can be expressed as the
Penetrance is the proportion of individuals probability of the phenotype given the geno-
with a specific genotype who display a defined type. For example, penetrance can be the prob-
phenotype. Some individuals may not express a ability of round seeds, a phenotype, given the
gene if modifiers, epistatic genes, or suppres- genotype G; it can also be the probability of
sors are also present in the genome. Penetrance wrinkled seeds, another phenotype, given the
is the likelihood, or probability, that a condi- genotype G. One could label the specific phe-
tion or disease phenotype will, in fact, appear notype of interest as Pi (Pi might refer to either
when a given genotype is present. If every per- the round or wrinkled seeds) and the specific
son carrying a gene for a dominantly inherited genotype among many possibilities as G j. The
disorder has the mutant phenotype, then the penetrance would then be the probability of
gene is said to have 100 percent penetrance. If P i given G j. These penetrances can all be ex-
Complete Penetrance:
Variable Penetrance:
pressed using the mathematical notation of will be affected. In humans, the dominant al-
conditional probabilities as follows: lele P produces polydactylyextra toes and/or
fingers. Matings between two normal appear-
Case 1: Pr(round|G)
Case 2: Pr(wrinkled|G)
ing parents sometimes produce offspring with
Case 3: Pr(Pi|Gj) polydactyly. The parent with the Pp genotype
exhibits reduced penetrance for the P allele.
A 100 percent penetrance means that all in- Manjit S. Kang
dividuals who possess a particular genotype ex- See also: Hereditary Diseases; Pedigree
press the phenotype (common in all homozy- Analysis.
gous lethal genes). Tay-Sachs disease shows
complete, or 100 percent, penetrance, as all Further Reading
homozygotes for this allele develop the disease Fairbanks, Daniel J., and W. Ralph Anderson.
and die. Genetics: The Continuity of Life. New York:
An allele, Fu, in mice causes fusion in the tail Brooks/Cole, 1999. This is one of the rare
in heterozygotes, Fufu, and extremely fused books that contains a good discussion, in
and abnormal tails in the homozygotes, FuFu. Chapter 13, of the concepts of penetrance
From testcross matings of Fufu fufu, 87 fused- and expressivity.
tailed mice and 129 nonfused-tailed mice re- Kang, Manjit S. Using Genotype-by-Environ-
sulted. Genetic analyses of the 129 nonfused- ment Interaction for Crop Cultivar Develop-
tailed mice revealed that 22 were genotypically ment. Advances in Agronomy 62 (November,
Fufu. The number of fused-tailed mice was 87 1997): 199-252. This paper discusses envi-
and the number of mice with the Fufu genotype ronmental influences on heredity.
but nonfused tails was 22. The total number of Kang, Manjit S., and Hugh G. Gauch, Jr. Geno-
fused-tailed mice expected was (87 + 22) = 109. type-by-Environment Interaction. Boca Raton,
Therefore, penetrance was calculated at 87/ Fla.: CRC Press, 1996. For those interested in
109 = 0.798 in-depth treatment of the interactions be-
tween genotypes and environments.
Expressivity
Whereas penetrance describes the frequency
that a genotype is expressed as a specified phe-
notype, expressivity describes the range of vari- Phenylketonuria (PKU)
ation in the phenotype when expression is
observed. Expressivity is variation in allelic ex- Field of study: Diseases and syndromes
pression when the allele is penetrant. Not all Significance: Phenylketonuria is a relatively com-
traits are expressed 100 percent of the time mon genetic disease affecting about one in every
even though the allele is present. Expressivity is ten thousand newborn babies. If the disease is not
the range of variation in a phenotype; it refers detected and treatment is not begun within the first
to the degree of expression of a given trait or few weeks of life, the child will develop various neu-
combination of traits that is associated with a rological symptoms including retardation. If the
gene. Affected individuals may have severe or disease is detected shortly after birth and dietary
mild symptoms; they may have symptoms that treatment is instituted, symptoms characteristic of
show up in one organ or combination of organs the disease usually will not develop.
in one individual but not in the same locations
in other individuals. Key terms
Phenotype may be altered by heterogeneity phenylalanine: an essential amino acid that
of other genes that affect the expression of a accumulates in those affected by PKU; phe-
particular locus in question, or by environmen- nylalanine and tyrosine, another essential
tal influence. Variable expressivity is a common amino acid, can be converted into various
feature of a variety of cancers. The lower the compounds such as melanin, epinephrine,
penetrance, the fewer number of individuals norepinephrine, and dopamine
Phenylketonuria (PKU) 605
The variety of different defects in the PKU See also: Biochemical Mutations; Genetic
gene leads to variability in the activity of PAH Screening; Genetic Testing; Hereditary Dis-
and the severity of the disease. eases; Inborn Errors of Metabolism; Model Or-
ganism: Mus musculus.
PKU Screening
In 1957 Willard Centerwall introduced fer- Further Reading
ric chloride as a screening technique by im- Koch, Jean Holt. Robert Guthrie, the PKU Story: A
pregnating babies diapers with ferric chloride. Crusade Against Mental Retardation. Pasa-
If the babies urine contained phenylpyruvic dena, Calif.: Hope, 1997. A longtime friend
acid, the diaper would turn green. Since the profiles the scientific work and personal life
test was reliable only after the baby was several work of Robert Guthrie.
weeks old and after brain damage may already National PKU News. This newsletter, published
have occurred, a new, more reliable and more in Seattle, Washington, three times per year,
sensitive test was needed. provides the latest information about PKU.
Robert Guthrie developed a more sensitive Parker, James N. The Official Parents Sourcebook
test. In the Guthrie test, bacteria are grown on on Phenylketonuria. San Diego, Calif.: ICON
an agar medium that contains an inhibitor of Health Publications, 2002. This resource,
growth that can be overcome by exogenously created for parents with PKU children, tells
added phenylalanine. If a small piece of filter parents how and where to look for informa-
paper containing blood is placed on the agar tion about PKU.
medium with the bacteria, the phenylalanine
in the blood leaches out of the filter paper and Web Site of Interest
stimulates growth of the bacteria. The extent of National Organization for Rare Disorders.
the growth around the filter paper is directly http://www.rarediseases.org. Searchable
proportional to the amount of phenylalanine site by type of disorder. Includes back-
in the blood. Guthrie published his procedure ground information on PKU, a list of other
in 1961. In 1963 Massachusetts became the first names for the disease, and a list of related or-
state to legislate mandatory PKU screening of ganizations.
all newborns. It is now mandatory in all fifty
states.
Treatment Plasmids
The treatment of choice for PKU is dietary
or nutritional intervention. PKU babies placed Field of study: Molecular genetics
on very low phenylalanine diets show normal Significance: Plasmids are DNA molecules that ex-
cognitive development. The PKU diet elimi- ist separately from the chromosome. Plasmids exist
nates high-protein foods, which are replaced in a commensal relationship with their host and
with low-phenylalanine foods and supple- may provide the host with new abilities. They are
mented with a nutritional formula. In 1954, used in genetic research as vehicles for carrying
Horst Bickel was the first to treat PKU with diet genes. In the wild, they promote the exchange of
therapy. genes and contribute to the problem of antibiotic re-
It is recommended that dietary intervention sistance.
begin as soon as possible after birth and con-
tinue for life. It is especially important that Key terms
pregnant PKU women adhere closely to the commensalism: a relationship in which two or-
diet, or their babies will be mentally retarded. ganisms rely on each other for survival
Studies have shown that if children or adults gene: a region of DNA containing instructions
are taken off the diet, some PKU symptoms for the manufacture of a protein
may develop. transposon: a piece of DNA that can copy it-
Charles L. Vigue self from one location to another
Plasmids 607
Plasmid Transfer Between Cells the ability to survive is the human body. A num-
Propagation of plasmids can occur through ber of pathogenic microorganisms gain their
the spread of plasmids from parent cells to ability to inhabit the human body, and thus
their offspring (referred to as vertical trans- cause disease, from genes contained on plas-
fer), but propagation can also occur between mids. An example of this is Bacillus anthracis,
two different cells (referred to as horizontal the agent that causes anthrax. Many of the
transfer). Many plasmids are able to transfer genes that allow this organism to cause disease
themselves from one host to another through are contained on one of two plasmids, called
the process of conjugation. Conjugal plas- pXO1 and pXO2. Yersinia pestis, the causative
mids contain a collection of genes that direct agent of bubonic plague, also gains its disease-
the host cell that contains them to attach to causing ability from plasmids.
other cells and transfer a copy of the plasmid.
In this manner, the plasmid can spread itself to R Factors
other hosts and is not limited to spreading itself Another example of plasmids conferring on
only to the descendants of the original host their hosts the ability to survive in a hostile en-
cell. vironment is antibiotic resistance. Plasmids
One of the first plasmids to be identified was known as R factors contain genes that make
discovered because of its ability to conjugate. their bacterial hosts resistant to antibiotics.
This plasmid, known as the F plasmid, or F fac- These R factors are usually conjugal plasmids,
tor, is a plasmid found in the bacterium Esche- so they can move easily from cell to cell. Be-
richia coli. Cells harboring the F plasmid are cause the antibiotic resistance genes they carry
designated F+ cells and can transfer their plas- are usually parts of transposons, they can
mid to other E. coli cells that do not contain the readily copy themselves from one piece of DNA
F plasmid (called F cells). to another. Two different R factors that hap-
Conjugal plasmids can be very specific and pened to be together in one cell could ex-
transfer only between closely related members change copies of each others antibiotic resis-
of the same species (such as the F plasmid), or tance genes. A number of R factors exist that
they can be very promiscuous and allow trans- contain multiple antibiotic resistance genes.
fer between unrelated species. An extreme ex- Such plasmids can result in the formation of
ample of cross-species transfer is the Ti plasmid multi-drug resistant (MDR) strains of patho-
of the bacterial species Agrobacterium tumefaciens. genic bacteria, which are difficult to treat.
The Ti plasmid is capable of transferring part There is much evidence to suggest that the
of itself from A. tumefaciens into the cells of widespread use of antibiotics has contrib-
dicotyledonous plants. Plant cells that receive uted to the development of MDR pathogens,
parts of the Ti plasmid are induced to grow and which are emerging as an important health
form a tumorlike structure, called a gall, that concern.
provides a hospitable environment for A. tume-
faciens. Role of Plasmids in Evolution
Through conjugation, plasmids can transfer
Host Benefits from Plasmids genetic information from one species of bacte-
In most commensal relationships, there is an rial cell to another. During its stay in a particu-
exchange of benefits between the two partners. lar host, a plasmid may acquire some of the
The same is true for plasmids and their hosts. chromosomal genes of the host, which it then
In many cases, plasmids provide their host cells carries to a new host by conjugation. These
with a collection of genes that enhance the abil- genes can then be transferred from the plas-
ity of the host cell to survive. Enhancements in- mid to the chromosome of the new host. If the
clude the ability to metabolize a wider range of new host and the old host are different species,
materials for food and the ability to survive in this gene transfer can result in the introduction
hostile environments. One particular hostile of new genes, and thus new traits, into a cell.
environment in which plasmids can provide Bacteria, being asexual, produce daughter cells
Polygenic Inheritance 609
(n = 2) model, the number and frequency of Diabetes and cancer are considered to be
phenotypic classes (2n + 1 = 5) can be deter- threshold traits because all individuals can be
mined by expanding the binomial (a + b)4, classified as affected or unaffected (qualita-
where a represents number of favorable alleles tive). They are also continuous traits because
and b represents number of nonfavorable al- severity varies from nearly undetectable to ex-
leles. tremely severe (quantitative). Because it is vir-
Subsequently, Nilsson-Ehle crossed a differ- tually impossible to determine the exact geno-
ent variety of red-grained wheat with white- type for such traits, it is difficult to control
grained wheat. He found that one-sixty-fourth defects with a polygenic mode of inheritance.
of the plants produced dark red kernels and
one-sixty-fourth produced white kernels. Detection of Genes Controlling Polygenic
There were a total of seven phenotypic (color) Traits
classes instead of five. The segregation ratio The detection of genes controlling polygenic
corresponded to three genes: (a + b)6 = 1a6 + traits is challenging and complex because:
6a 5b 1 + 15a 4b 2 + 20a 3b 3 + 15a 2b 4 + 6a 1b 5 + 1b 6.
(1) The expression of genes controlling such
Here, a 6 means that one of sixty-four individu-
traits is modified by fluctuations in envi-
als possessed six favorable alleles, 20a 3b 3 means
ronmental and/or management factors.
that twenty of sixty-four individuals had three
(2) A quantitative trait is usually a composite
favorable and three nonfavorable alleles, and
of many other traits, each influenced by
b 6 means that one individual had six non-
many genes with variable effects.
favorable alleles. An assumption was that each
(3) Effects of allele substitution are small be-
of the alleles had an equal, additive effect.
cause many genes control the trait.
These experiments led to what is known as the
(4) Expression of an individual gene may be
multiple-factor hypothesis, or polygenic inheri-
modified by the expression of other genes
tance (Kenneth Mather coined the terms
and environment.
polygenes and polygenic traits). Around
1920, Ronald Aylmer Fisher, Sewall Green Polygenic traits are best analyzed with statistical
Wright, and John Burdon Sanderson Haldane methods, the simplest of which are estimation
developed methods of quantitative analysis of of arithmetic mean, standard error, variance,
genetic effects. and standard deviation. Two populations can
Polygenic traits are characterized by the have the same mean, but their distribution may
amount of some attribute that they possess but be different. Thus, one needs information on
not by presence or absence, as is the case with variances for describing the two populations
qualitative traits that are controlled by one or more fully. From variances, effects of genes can
two major genes. Environmental factors gener- be ascertained in the aggregate rather than as
ally have little or no effect on the expression of individual genes.
a gene or genes controlling a qualitative trait, The issues in quantitative genetics are not
whereas quantitative traits are highly influenced only how many and which genes control a trait
by the environment and genotype is poorly rep- but also how much of what is observed (pheno-
resented by phenotype. Genes controlling poly- type) is attributable to genes (heritability) and
genic traits are sometimes called minor genes. how much to the environment. The concept of
heritability in the broad sense is useful for
Examples and Characteristics of quantitative traits, but heritability itself does
Polygenic Traits not give any clues to the total number of genes
Quantitative genetics encompasses analyses involved. If heritability is close to 1.0, the vari-
of traits that exhibit continuous variation ance for a trait is attributable entirely to genet-
caused by polygenes and their interactions ics, and when it is close to zero, the popula-
among themselves and with environmental fac- tions phenotype is due entirely to the variation
tors. Such traits include height, weight, and in the underlying environment. Environmen-
some genetic defects. tal effects mask or modify genetic effects.
Polymerase Chain Reaction 611
specified by the location at which the primer The PCR reaction is made more efficient by
anneals to the template. The primers are cho- the use of heat-stable DNA polymerases, iso-
sen to flank the DNA to be amplified. This an- lated from bacteria that live at very high tem-
nealing is done at a lower temperature (about peratures in hot springs or deep-sea vents, and
30-65 degrees Celsius, or about 86-149 degrees by the use of a programmable water bath
Fahrenheit). The final step is the synthesis by (called a thermal cycler) to change the temper-
DNA polymerase of a new strand of DNA com- atures of samples quickly to each of the temper-
plementary to the template starting from the atures needed in each of the steps of a cycle.
primers. This step is carried out at tempera-
tures about 65-75 degrees Celsius (149-167 de- Impact and Applications
grees Fahrenheit). These three steps are re- PCR is extremely rapid. One billion copies
peated many times (for many cycles) to amplify of a specific DNA can be made in a few hours. It
the template DNA. The time for each of the is also extremely sensitive. It is possible to copy
three steps is typically one to two minutes. If, in a single DNA molecule. Great care must be
each cycle, one copy is made of each of the taken to avoid contamination, however, for
strands of the template, the number of DNA even trace contaminants can readily be ampli-
molecules produced doubles each cycle. Be- fied by this method.
cause of this doubling, more than one million PCR is a useful tool for many different appli-
copies of the template DNA are made at the cations. It is used in basic research to obtain
end of twenty cycles. DNA for sequencing and other analyses. PCR is
A technician performs polymerase chain reaction testing of anthrax samples. (AP/Wide World Photos)
Polyploidy 613
used in disease diagnosis, in prenatal diagnosis, major scientific development of the year,
and to match donor and recipient tissues for the polymerase chain reaction, noting that
organ transplants. Because a specific sequence the technique, although introduced earlier,
can be amplified greatly, much less clinical ma- truly burgeoned in 1989.
terial is needed to make a diagnosis. The assay Innis, Michael A., David H. Gelfand, and John
is also rapid, so results are available sooner. J. Sninsky, eds. PCR Applications: Protocols for
PCR is used to detect pathogens, such as the Functional Genomics. San Diego: Academic
causative agents for Lyme disease or for ac- Press, 1999. Discusses gene discovery, ge-
quired immunodeficiency syndrome (AIDS), nomics, and DNA array technology. Entries
that are difficult to culture. PCR can even be on nomenclature, expression, sequence anal-
used to amplify DNA from ancient sources such ysis, structure and function, electrophysiol-
as mummies, bones, and other museum speci- ogy, parmacology, and information retrieval.
mens. PCR is an important tool in forensic in- Illustrations, bibliography, index.
vestigations. Target DNA from trace amounts Kochanowski, Bernd, and Udo Reischl, eds.
of biological material such as semen, blood, Quantitative PCR Protocols. Methods in Mo-
and hair roots can be amplified. There are lecular Medicine 26. Totowa, N.J.: Humana
probes for regions of human DNA that show Press, 1999. Outlines protocols and includes
hypervariability in the population and there- methodological and process notes. Illustra-
fore make good markers to identify the source tions, bibliography, index.
of the DNA. PCR can therefore be used to eval- Lloyd, Ricardo V., ed. Morphology Methods: Cell
uate evidence at the scene of a crime, help and Molecular Biology Techniques. Totowa,
identify missing people, and resolve paternity N.J.: Humana Press, 2001. Includes an over-
cases. view of PCR. Black-and-white and color illus-
Susan J. Karcher trations, bibliography, index.
See also: Ancient DNA; Anthrax; Bioin- McPherson, M. J., and S. G. Mller. PCR Basics.
formatics; Blotting: Southern, Northern, and Oxford, England: BIOS Scientific, 2000.
Western; Central Dogma of Molecular Biology; Provides introductory information about
Cloning Vectors; DNA Fingerprinting; DNA Se- PCR theory, background, and protocols. Il-
quencing Technology; Forensic Genetics; Ge- lustrations, bibliography, index.
netic Engineering: Historical Development; Mullis, Kary B. The Unusual Origin of the
Human Genome Project; In Vitro Fertilization Polymerase Chain Reaction. Scientific Ameri-
and Embryo Transfer; Mitochondrial Diseases; can 262 (April, 1990). Nobel laureate Mullis
Molecular Genetics; Paternity Tests; Repetitive describes the initial development of the
DNA; RFLP Analysis; RNA Isolation; Swine Flu. technique for the general audience.
Watson, James D., et al. Recombinant DNA. New
Further Reading York: Scientific American Books, 1992. Sum-
Budowle, Bruce, et al. DNA Typing Protocols: Mo- marizes polymerase chain reaction and its
lecular Biology and Forensic Analysis. Natick, applications. Full-color illustrations, dia-
Mass.: Eaton, 2000. Discussion includes grams, bibliography, index.
DNA extraction and PCR-based analyses. Il-
lustrations, bibliography, index.
Chen, Bing-Yuan, and Harry W. Janes, eds. PCR
Cloning Protocols. Rev. 2d ed. Totowa, N.J.:
Humana Press, 2002. Presents helpful intro-
Polyploidy
ductory chapters with each section and Field of study: Population genetics
guidelines for PCR cloning. Illustrations, Significance: Polyploids have three or more com-
bibliographies, index. plete sets of chromosomes in their nuclei instead of
Guyer, Ruth L., and Daniel E. Koshland, Jr. the two sets found in diploids. Polyploids are espe-
The Molecule of the Year. Science 246 (De- cially common in plants, with some examples also
cember 22, 1989): 1543-1546. Reviews the existing in animals, and have a prominent role in
614 Polyploidy
the evolution of species. Some tissues of diploid or- applied primarily to plants, in which polyploidy
ganisms are polyploid, while the remaining cells in is better studied. Hybrids between two species
the organism are diploid. are often sterile, but occasionally a diploid ga-
mete from one of the species joins with a nor-
Key terms mal haploid gamete from the other species,
allopolyploid: a type of polyploid species which produces a triploid hybrid. Triploids are
that contains genomes from more than one also sterile, for the most part, but do produce a
ancestral species small number of gametes, many of which are
aneuploid: a cell or an organism with one or diploid. This makes the probability that two
more missing or extra chromosomes; the op- diploid gametes will join, to form a tetraploid,
posite is euploid, a cell with the normal much higher. This hypothesis is supported by
chromosome number the discovery of triploid hybrid plants that do
autopolyploid: a type of polyploid species produce a small number of viable gametes.
that contains more than two sets of chromo- This type of polyploid, formed as a result of hy-
somes from the same species bridization between two species, is called an al-
homologous chromosomes: chromosomes lopolyploid. Allopolyploids are typically fertile
that are structurally the same and have the and represent a new species.
same gene loci, although they may have dif- Polyploidy can also occur within a single spe-
ferent alleles (alternative forms of a gene) at cies, without hybridization, in which case it is
many of their shared loci called an autopolyploid. Autopolyploids can
form in the same way as allopolyploids, but they
The Formation of Polyploidy can also occur as the result of a failure in cell di-
Most animals are diploid, meaning that they vision in a bud. If a cell in the meristematic re-
have two homologous sets of chromosomes in gion (a rapidly dividing group of cells at the tip
their cells; and their gametes (eggs and sperm) of a bud) completes mitosis but not cytokinesis,
are haploid, that is, having one set of chromo- it will be a tetraploid cell. All daughter cells
somes. Plants, a variety of single-celled eukary- from this cell will also be tetraploid, so that any
otes, and some insects have individual or parts flowers borne on this branch will produce dip-
of an individuals life cycle when they are hap- loid gametes. If the plant is self-compatible, it
loid. In any case, when there are more than two can then produce tetraploid offspring from
sets of homologous chromosomes, the cell or these flowers. Autopolyploids are often a little
organism is considered polyploid. A triploid or- larger and more robust than the diploids that
ganism has three sets of homologous chromo- produce them, but they are often so similar
somes, a tetraploid has four sets, a dodecaploid they cannot be easily distinguished. An auto-
has twelve sets, and there are organisms known polyploid, when formed, represents a new spe-
to have many more than a dozen sets of homol- cies but is not generally recognized as such un-
ogous chromosomes. less it looks different enough physically from
How polyploids are formed in nature is still diploids.
debated. Regardless of what theory is accepted,
the first step certainly involves a failure during The Genetics of Polyploids
cell division, in either meiosis or mitosis. For A polyploid has more copies of each gene
example, if cytokinesis (division of the cyto- than a diploid. For example, a tetraploid has
plasm) fails at the conclusion of meiosis II, the four alleles at each locus, which means tetra-
daughter cells will be diploid. If, by chance, a ploids can contain much more individual vari-
diploid sperm fertilizes a diploid egg, the re- ability than diploids. This has led some evolu-
sulting zygote will be tetraploid. Although poly- tionists to suggest that polyploids should have
ploidy might occur this way, biologists have pro- higher fitness than the diploids from which
posed an alternative model involving a triploid they came. With more variation, the individual
intermediate stage. would be preadapted to a much wider range of
The triploid intermediate model has been conditions. Because there are so many extra
Polyploidy 615
copies of genes, a certain amount of gene si- because the chromosomes from the two species
lencing (loss of genes through mutation or are unable to pair properly.
other processes) occurs, with no apparent det-
riment to the plant. Polyploid Plants and Animals
The pairing behavior of chromosomes in In the plant kingdom, it is estimated by some
polyploids is also unique. In a diploid, during that 95 percent of pteridophytes (plants, in-
meiosis, homologous chromosomes associate cluding ferns, that reproduce by spores) and
in pairs. In an autotetraploid there are four perhaps as many as 80 percent of angiosperms
homologous chromosomes of each type which (flowering plants that form seeds inside an
associate together in groups of four. In an ovary) are polyploid, although there is high
allotetraploid, the chromosomes from the two variability in its occurrence among families of
species from which they are derived are com- angiosperms. In contrast, polyploidy is uncom-
monly not completely homologous and do not mon in gymnosperms (plants that have naked
associate together. Consequently, the pairs of seeds that are not within specialized struc-
homologous chromosomes from one parent tures). Extensive polyploidy is observed in
species associate together in pairs, as do the chrysanthemums, in which chromosome num-
chromosomes from the other parent species. bers range from 18 to 198. The basic chromo-
For this reason, sometimes allopolyploids are some number (haploid or gamete number of
referred to as amphidiploids, because their chromosomes) is 9. Polyploids from triploids
pairing behavior looks the same as it does in a (with 27 chromosomes) to 22-ploids (198 chro-
diploid. This is also why an allopolyploid is fer- mosomes) are observed. The stonecrop Sedum
tile (because meiosis occurs normally), but a suaveolens, which has the highest chromosome
hybrid between two diploids commonly is not, number of any angiosperm, is believed to be
616 Polyploidy
about 80-ploid (720 chromosomes). Many im- an allohexaploid and contains chromosome
portant agricultural crops, including wheat, sets that are derived from three different an-
corn, sugarcane, potatoes, coffee, apples, and cient types. Compared to the species from
cotton, are polyploid. which it evolved, T. aestivum is far more produc-
Polyploid animals are less common than tive and produces larger grains of wheat.
polyploid plants but are found among some Triticum aestivum was not developed by humans
groups, including crustaceans, earthworms, but appears to have arisen by a series of chance
flatworms, and insects such as weevils, sawflies, events in the past, humans simply recognizing
and moths. Polyploidy has also been observed the better qualities of T. aestivum. Another for-
in some vertebrates, including tree frogs, liz- tuitous example involves three species of mus-
ards, salamanders, and fish. It has been sug- tard that have given rise to black mustard, tur-
gested that the genetic redundancy observed nips, cabbage, broccoli, and several other
in vertebrates may be caused by ancestral poly- related crops, all of which are allotetraploids.
ploidy. Polyploids may be induced by the use of
drugs such as colchicine, which halts cell divi-
Polyploidy in Tissues sion. Because of the advantages of the natural
Most plants and animals contain particular polyploids used in agriculture, many geneti-
tissues that are polyploid or polytene, while the cists have experimented with artificially pro-
rest of the organism is diploid. Polyploidy is ob- ducing polyploids to improve crop yields. One
served in multinucleate cells and in cells that prime example of this approach is Triticale,
have undergone endomitosis, in which the which represents an allopolyploid produced by
chromosomes condense but the cell does not hybridizing wheat and rye. Producing artificial
undergo nuclear or cellular division. For exam- polyploids often produces a new variety that
ple, in vertebrates, liver cells are binucleate and has unexpected negative characteristics, so that
therefore tetraploid. In addition, in humans, only a few such polyploids have been success-
megakaryocytes can have polyploidy levels of ful. Nevertheless, research on polyploidy con-
up to sixty-four. A megakaryocyte is a giant tinues.
bone-marrow cell with a large, irregularly Susan J. Karcher, updated by Bryan Ness
lobed nucleus that is the precursor to blood See also: Cell Division; Cytokinesis; High-
platelets. A megakaryocyte does not circulate, Yield Crops; Gene Families; Genome Size; He-
but forms platelets by budding. A single mega- reditary Diseases; Nondisjunction and Aneu-
karyocyte can produce three thousand to four ploidy.
thousand platelets. A platelet is an enucleated,
disk-shaped cell in the blood that has a role in Further Reading
blood coagulation. In polytene cells, the repli- Adams, Keith L., Richard Cronn, Ryan Perci-
cated copies of the chromosomal DNA remain field, and Jonathan F. Wendel. Genes Du-
associated to produce giant chromosomes that plicated by Polyploidy Show Unequal Con-
have a continuously visible banding pattern. tributions to the Transcriptome and Organ-
The trophoblast cells of the mammalian pla- Specific Reciprocal Silencing. Proceedings of
centa are polytene. the National Academy of Sciences 100 (April 15,
2003): 4649-4654. This article shows that
Importance of Polyploids to Humans with multiple copies of a gene due to poly-
Most human polyploids die as embryos or fe- poidy, some of the copies are silenced.
tuses. In a few rare cases, a polyploid infant is Hunter, Kimberley L., et al. Investigating Poly-
born that lives for a few days. In fact, polyploidy ploidy: Using Marigold Stomates and Fin-
is not tolerated in most animal systems. Plants, gernail Polish. American Biology Teacher 64
on the other hand, show none of these prob- (May, 2002). A guide to exploring poly-
lems with polyploidy. Some crop plants are ploidy through hands-on learning. Experi-
much more productive because they are poly- ment supports National Science Education
ploid. For example, wheat (Triticum aestivum) is Standards.
Population Genetics 617
Leitch, Illia J., and Michael D. Bennett. Poly- neutral theory of evolution: Motoo
ploidy in Angiosperms. Trends in Plant Sci- Kimuras theory that nucleotide substitu-
ence 2 (December, 1997). Describes the role tions in the DNA often have no effect on fit-
of polyploidy in the evolution of higher ness, and thus changes in allele frequencies
plants. in populations are caused primarily by ge-
Lewis, Ricki. Human Genetics: Concepts and Appli- netic drift
cations. 5th ed. Boston: McGraw-Hill, 2003.
Gives an overview of polyploidy and aneu- The Hardy-Weinberg Law
ploidy in humans. Color ilustrations, maps, The branch of genetics called population
and CD-ROM with this edition. genetics is based on the application of nine-
teenth century Austrian botanist Gregor Men-
dels principles of inheritance to genes in a
population. (Although, for some species, pop-
Population Genetics ulation can be difficult to define, the term
generally refers to a geographic group of inter-
Field of study: Population genetics breeding individuals of the same species.)
Significance: Population genetics is the study of Mendels principles can be used to predict the
how genes behave in populations. It is concerned expected proportions of offspring in a cross be-
with both theoretical and experimental investiga- tween two individuals of known genotypes,
tions of changes in genetic variation caused by where the genotype describes the genetic con-
various forces; therefore, the field has close ties to tent of an individual for one or more genes. An
evolutionary biology. Population genetics models individual carries two copies of all chromo-
can be used to explore the evolutionary histories of somes (except perhaps for the sex chromo-
species, make predictions about future evolution, somes, as in human males) and therefore has
and predict the behavior of genetic diseases in hu- two copies of each gene. These two copies may
man populations. be identical or somewhat different. Different
forms of the same gene are called alleles. A ge-
Key terms notype in which both alleles are the same is
allele: one of the different forms of a particu- called a homozygote, while one in which the
lar gene (locus) two alleles are different is a heterozygote. Al-
fitness: a measure of the ability of a genotype though a single individual can carry no more
or individual to survive and reproduce com- than two alleles for a particular gene, there may
pared to other genotypes or individuals be many alleles of a gene present in a popula-
gene pool: all of the alleles in all the gametes tion.
of all the individuals in a population It would be essentially impossible to track
genetic drift: random changes in genetic the inheritance patterns of every single mating
variation caused by sampling error in small pair in a population, in essence tracking all the
populations alleles in the gene pool. However, by making
genotype: the pair of alleles carried by an indi- some simplifying assumptions about a popula-
vidual for a specific gene locus tion, it is possible to predict what will happen to
Hardy-Weinberg law: a mathematical model the gene pool over time. Working indepen-
that predicts, under particular conditions, dently in 1908, the British mathematician God-
that allele frequencies will remain constant frey Hardy and the German physiologist Wil-
over time, with genotypes in specific predict- helm Weinberg were the first to formulate a
able proportions simple mathematical model describing the be-
modern synthesis: the merging of the Dar- havior of a gene (locus) with two alleles in a pop-
winian mechanisms for evolution with Men- ulation. In this model, the numbers of each al-
delian genetics to form the modern fields lele and of each genotype are not represented
of population genetics and evolutionary bi- as actual numbers but as proportions (known
ology as allele frequencies and genotype frequencies,
618 Population Genetics
respectively) so that the model can be applied of genetic variation, meaning that for a fairly
to any population regardless of its size. By as- large proportion of genes (loci) that are ana-
suming Mendelian inheritance of alleles, Hardy lyzed, there are multiple alleles, and therefore
and Weinberg showed that allele frequencies multiple genotypes, within populations. For
in a population do not change over time and example, in the common fruit fly Drosophila me-
that genotype frequencies will change to spe- lanogaster (an organism that has been well stud-
cific proportions, determined by the allele fre- ied genetically since the very early 1900s), be-
quencies, within one generation and remain at tween one-third and two-thirds of the genes
those proportions in future generations. This that have been examined by protein electro-
result is known as the Hardy-Weinberg law, and phoresis have been found to be variable. Ge-
the stable genotype proportions predicted by netic variation can be measured as allele fre-
the law are known as Hardy-Weinberg equilib- quencies (allelic variation) or genotype
rium. It was shown in subsequent work by oth- frequencies (genotypic variation). A major task
ers that the Hardy-Weinberg law remains true of population geneticists has been to describe
in more complex models with more than two such variation, to try to explain why it exists,
alleles and more than one locus. and to predict its behavior over time.
In order for the Hardy-Weinberg law to The Hardy-Weinberg law predicts that if ge-
work, certain assumptions about a population netic variation exists in a population, it will re-
must be true: main constant over time, with genotypes in spe-
cific proportions. However, the law cannot
(1) the gene pool must be infinite in size;
begin to explain natural variation, since geno-
(2) mating among individuals (or the fusion
types are not always found in Hardy-Weinberg
of gametes) must be completely random;
proportions, and studies that involve sam-
(3) there must be no new mutations;
pling populations over time often show that
(4) there must be no gene flow (that is, no al-
genetic variation can be changing. The histori-
leles should enter or leave the population;
cal approach to explaining these observations
and
has been to formulate more complex mathe-
(5) there should be no natural selection.
matical models based on the simple Hardy-
Since real populations cannot meet these con- Weinberg model that violate one or more of
ditions, it may seem that the Hardy-Weinberg the implicit Hardy-Weinberg conditions.
model is too unrealistic to be useful, but, in Beginning in the 1920s and 1930s, a group
fact, it can be useful. First, the conditions of a of population geneticists, working indepen-
natural population may be very close to Hardy- dently, began exploring the effects of violating
Weinberg assumptions, so the Hardy-Weinberg Hardy-Weinberg assumptions on genetic varia-
law may be approximately true for at least some tion in populations. In what has become known
populations. Second, if genotypes in a popula- as the modern synthesis, Ronald A. Fisher,
tion are not in Hardy-Weinberg equilibrium, it J. B. S. Haldane, and Sewall Wright merged
is an indication that one or more of these as- Darwins theory of natural selection with Men-
sumptions is not met. The Hardy-Weinberg dels theory of genetic inheritance to create a
law has been broadly expanded, using sophisti- field of population genetics that allows for ge-
cated mathematical modeling, and with ade- netic change. They applied mathematics to the
quate data can be used to determine why a pop- problem of variation in populations and were
ulations allele and genotype frequencies are eventually able to incorporate what happens
out of Hardy-Weinberg equilibrium. when each, or combinations, of the Hardy-
Weinberg assumptions are violated.
Genetic Variation and Mathematical
Modeling Assortative Mating and Inbreeding
Sampling and genetic analyses of real popu- One of the implicit conditions of the Hardy-
lations of many different types of organisms re- Weinberg model is that genotypes form mating
veal that there is usually a substantial amount pairs at random. In most cases mates are not se-
Population Genetics 619
rare, making the hypothesis of evolution by domly in the pattern of genetic variation from
mutation alone unsatisfactory. generation to generation. These random
The action of mutation in conjunction with changes in allele and genotype frequencies
other forces, such as selection, may account for are called genetic drift. The situation is analo-
the low-frequency persistence of clearly harm- gous to coin tossing. With a fair coin, the expec-
ful alleles in populations. For example, one tation is that half of the tosses will result in
might expect that alleles that can result in ge- heads and half in tails. On average, this will be
netic diseases (such as cystic fibrosis) would be true, but in practice a small sample will not
quickly eliminated from human populations by show the expectation. For example, if a coin
natural selection. However, low rates of muta- is tossed ten times, it is unlikely that the re-
tion can continually introduce these alleles sult will be exactly five heads and five tails. On
into populations. In this mutation-selection the other hand, with a thousand tosses, the re-
balance, mutation tends to introduce alleles sults will be closer to half and half. This higher
while selection tends to eliminate them, with a deviation from the expected result in small
net result of continuing low frequencies in the samples is called a sampling error. In a small
population. population, there is an expectation of the pat-
tern of genetic variation based on the Hardy-
Genetic Drift Weinberg law, but sampling error during the
Real populations are not, of course, infinite union of sex cells to form offspring genotypes
in size, though some are large enough that this will result in random deviations from that ex-
Hardy-Weinberg condition is a useful approxi- pectation. The effect is that allele frequencies
mation. However, many natural populations increase or decrease randomly, with corre-
are small, and any population with less than sponding changes in genotype frequencies. The
about one thousand individuals will vary ran- smaller the population, the greater the sam-
Genetic Drift
Aa Aa Aa Aa
Females Males
3 progeny
produced carrying
A alleles
AA AA AA
In this small population, the a allele has disappeared as a result of random chance and is lost to future generations.
Population Genetics 621
pling error and the more pronounced genetic genotype has the highest fitness. In the simple
drift will be. one-gene, two-allele model, there are three
Genetic drift has an effect on genetic varia- possible genotypes: two homozygotes and one
tion that is similar to that of other factors. Over heterozygote. If one homozygote has the high-
the long term, allele frequencies will drift until est fitness, it will be favored, and the genetic
all alleles have been eliminated but one, elimi- composition of the population will gradually
nating variation. (For the moment, ignore the shift toward more of that genotype (and its cor-
action of other forces that increase variation.) responding allele). This is called directional
Over a period of dozens of generations, how- selection. If both homozygotes have higher fit-
ever, drift can allow variation to be maintained, ness than the heterozygote (disruptive selec-
especially in larger populations in which drift is tion), one or the other will be favored, depend-
minimal. ing on the starting conditions. Both of these
In the early days of population genetics, the situations will decrease genetic variation in the
possibility of genetic drift was recognized but population, because eventually one allele will
often considered to be a minor consideration, prevail. Although each of these types of selec-
with natural selection as a dominant force. tion (particularly directional) may be found
Fisher in particular dismissed the importance for genes in natural populations, they cannot
of genetic drift, engaging over a number of explain why genetic variation is present, and is
years in a published debate with Wright, who al- perhaps increasing, in nature.
ways felt that drift would be important in small Heterozygote advantage, in which the heter-
populations. Beginning in the 1960s with the ozygote has higher fitness than either homozy-
acquisition of data on DNA-level population gote, is the other possible situation in this
variation, the role of drift in natural popula- model. In this case, because the heterozygote
tions became more recognized. It appears to be carries both alleles, both are expected to be fa-
an especially strong force in cases in which a vored together and therefore maintained. This
small number of individuals leave the popula- is the only condition in this simple model in
tion and migrate to a new area where they es- which genetic variation may be maintained or
tablish a new population. Large changes can increased over time. Although this seems like a
occur, especially if the number of migrants is plausible explanation for the observed levels of
only ten or twenty. This type of situation is now natural variation, studies in which fitness values
referred to as a founder effect. are measured almost never show heterozygote
advantage in genes from natural populations.
Natural Selection As a general explanation for the presence of ge-
Natural selection in a simple model of a netic variation, this simple model of selection is
gene with two alleles in a population can be eas- unsatisfactory.
ily represented by assuming that genotypes dif- Studies of more complex theoretical models
fer in their ability to survive and produce off- of selection (for example, those with many
spring. This ability is called fitness. In applying genes and different forms of selection) have re-
natural selection to a theoretical population, vealed conditions that allow patterns of varia-
each genotype is assigned a fitness value be- tion very similar to those observed in natural
tween zero and one. Typically, the genotype in populations, and in some cases it seems clear
a population that is best able to survive and can, that natural selection is a major factor deter-
on average, produce more offspring than other mining patterns of genetic change. However,
genotypes is assigned a fitness value of one, and in many cases, selection does not seem to be the
genotypes with lower fitness are assigned fit- most important factor or even a factor at all.
nesses with fractional values relative to the high-
fitness genotype. Experimental Population Genetics and the
The study of this simple model of natural se- Neutral Theory
lection has revealed that it can alter genetic Population genetics has always been a field
variation in different ways, depending on which in which the understanding of theory is ahead
622 Population Genetics
oped with a large deletion that includes the than 95 percent of cases. For cases caused by
SNRPN region and the PWS imprinting center uniparental disomy, polymerase chain reaction
and shows a phenotype similar to that of infants (PCR) testing can be used.
with PWS.
It is probable that the hypothalamic prob- Relevance to Geneticists
lems (such as overeating) associated with PWS Few examples of known parental imprinting
might result from a loss of SNRPN. The produc- occur in the human, so AS and PWS provide
tion of this protein is found mainly in the hypo- rare opportunities for geneticists and biolo-
thalamic regions of the brain and in the olfac- gists to study this important phenomenon. Ex-
tory cortex. Thus, disruption of hypothalamic amples of nonhuman parental imprinting are
functions such as satiety are a likely result of well known, but the genetic and biochemical
this defect. Prader-Willi syndrome is the most mechanisms have not been established. De-
common genetic cause of obesity. In addition tailing the IC for chromosome 15 will be key to
to its role in satiety, the hypothalamus regulates understanding how imprinting occurs and how
growth, sexual development, metabolism, the effects of AS and PWS are manifested.
body temperature, pigmentation, and mood The suggestion has been made that PWS
all functions that are affected in those with (and therefore disruption of the IC) may also,
PWS. at least in some cases, have an environmental
PWS may also be caused by uniparental di- trigger. A high association of PWS with fathers
somy, as seen in AS. However, in PWS both cop- employed in hydrocarbon-related occupations
ies of chromosome 15 are derived from the (such as factory workers, lumbermen, machin-
mother instead of from the father. ists, chemists, and mechanics) at the time of
As mentioned above, the imprinting center conception has been reported by one investiga-
may be involved in at least some cases of both tive team. This is an area that needs further ex-
syndromes. This chromosome 15 IC is about ploration.
100 kilobase pairs (kb) long and includes exon Kerry L. Cheesman
1 of the SNRPN gene. Mutations in this area See also: Amniocentesis and Chorionic Vil-
appear to prevent the paternal-to-maternal im- lus Sampling; Chromosome Structure; Con-
printing switch in the AS families and prevents genital Defects; Down Syndrome; Fragile X
the maternal-to-paternal switch in PWS fami- Syndrome; Hereditar y Diseases; Human
lies. Therefore, it is possible that the IC is Growth Hormone; Huntingtons Disease; In-
needed to regulate alternate RNA splicing in telligence; Polymerase Chain Reaction; Prena-
the SNRPN gene transcripts. tal Diagnosis.
Preimplantation genetic diagnosis (PGD) has been While this early form of prenatal diagnosis allows
used since 1988 to screen for genetic disorders. The the elimination of many embryos carrying major ge-
most common type of PGD involves embryo biopsy netic defects prior to implantation, it is still recom-
at the 6-8 cell stage after fertilization has occurred in mended that followup prenatal diagnosis (using
vitro. This early form of prenatal diagnosis is typi- chorionic villus sampling or amniocentesis) be done
cally performed on day 3 embryos. One to two on resulting pregnancies. It must be realized that in
blastomeres (cells) are removed from the embryo order to employ preimplantation diagnostic testing,
(either by aspiration or by extrusion) using a fine a couple must undergo in vitro fertilization even if
glass needle. The biopsied embryo is then returned they are fertile. This is an expensive, time-consuming
to culture, where the lost cells are replenished. Ge- process, and generally results in only a 20 percent
netic testing is then carried out on the biopsied cells pregnancy rate per cycle. For couples with fertility
using either a technique known as fluorescent in situ problems, this is an easy path to choose as they try
hybridization (FISH) or a second technique known to ensure implantation of normal, healthy embryos
as fluorescent polymerase chain reaction (PCR). leading to healthy babies.
The FISH technique can be used to determine the This technique has been used increasingly by cou-
presence of chromosomes 13, 16, 18, 21, 22, X, and Y. ples who have a history of genetic disorders. In the
Aneuploidies (abnormal numbers of chromosomes) past, couples who had a history of genetic abnormal-
involving these chromosomes account for the major- ities could decide (1) not to have children, (2) be-
ity of first-trimester miscarriages and for 95 percent come pregnant and knowingly risk and accept ab-
of all postnatal chromosomal abnormalities. PCR in- normalities, or (3) become pregnant and rely on
volves amplification of DNA and allows diagnosis of chorionic villus sampling or amniocentesis to diag-
single-gene diseases. nose genetic problems and terminate (abort) prob-
By enabling very early diagnosis of these abnor- lem pregnancies.
malities, PGD allows physicians to determine which To date, PGD has been used to detect cases of cys-
embryos are most likely to be chromosomally nor- tic fibrosis, Tay-Sachs disease, beta-thalassemia, Hun-
mal prior to placement in the uterus. This increases tingtons disease, myotonic dystrophy, X-linked dis-
the probability of a successful pregnancy and a orders, and aneuploidies such as trisomy 13, 18, or
healthy baby. Genetic testing generally takes only six 21, Turner syndrome, or Klinefelter syndrome. The
to eight hours to complete, so that intrauterine number of detectable genetic defects has greatly in-
transfer of the chromosomally normal embryo can creased since 1988. In that time, hundreds of healthy
take place within one day. If more normal embryos children have been born to parents undergoing pre-
are obtained than one wishes to implant, the extra implantation diagnosis.
embryos may be preserved for future use by cryo- Robin Kamienny Montvilo
preservation. The survival rate of frozen embryos
is thought to be about 50 percent.
family, or if the parents have already produced lected by amniocentesis can be grown in cul-
one child with a genetic disorder. ture; then the fluid around the cells is collected
and analyzed for enzymes produced by the cells.
Maternal Blood Tests and Ultrasound If an enzyme is missing (as in the case of Tay-
Screening maternal blood for the presence Sachs disease), the fetus may be diagnosed with
of alpha fetoprotein (AFP) is offered to preg- the disorder before it is born. Because disorders
nant women who are about eighteen weeks such as Tay-Sachs disease are untreatable and
into a pregnancy. Although AFP is produced by fatal, a woman who has had one Tay-Sachs child
the fetal liver, some will cross the placenta into may not wish to give birth to another. Early di-
the mothers blood. Elevated levels of AFP can agnosis of a second Tay-Sachs fetus would per-
indicate an open neural tube defect (such as mit her to have a therapeutic abortion.
spina bifida), although it can also indicate twins. Chromosomes in the cells obtained by am-
Unusual AFP findings are usually followed up niocentesis may be stained to produce a karyo-
by ultrasound examination of the fetus. type. In a normal karyotype, the chromosomes
Other tests of maternal blood measure the will be present in pairs. If the fetus has Down
amounts of two substances that are produced syndrome (trisomy 21), there will be three cop-
by the fetal part of the placenta: hCG and UE3. ies of chromosome 21. Other types of chromo-
Lower-than-average levels of AFP and UE3, some abnormalities that also appear in karyo-
combined with a higher-than-average amount types are changes within a single chromosome.
of hCG, increases the risk that the woman is If a chromosome has lost a piece, it is said to
carrying a Down syndrome (trisomy 21) fetus. contain a deletion. Large deletions will be obvi-
For example, a nineteen-year-old woman has a ous when a karyotype is analyzed because the
baseline risk of conceiving a fetus with Down chromosome will appear smaller than normal.
syndrome of 1 in 1,193. When blood-test results Sometimes the deletion is so small that it is not
show low AFP and UE3 along with high hCG, visible on a karyotype.
the probability of Down syndrome rises to 1 in If chromosome analysis is needed early in
145. pregnancy before the volume of amniotic fluid
During an ultrasound examination, harm- is large enough to permit amniocentesis, the
less sound waves are bounced off the fetus from mother and doctor may opt for chorionic villus
an emitter placed on the surface of the sampling (CVS). The embryo produces finger-
mothers abdomen or in her vagina. They are like projections (villi) into the uterine lining.
used to make a picture of the fetus on a televi- Because these projections are produced by the
sion monitor. Measurements on the monitor embryo, their cells will have the same chromo-
can often be used to determine the overall size, some number as the rest of the embryonic
the head size, and the sex of the fetus, and cells. After growing in culture, the cells may be
whether all the arms and legs are formed and karyotyped in the same way as those obtained
of the proper length. Successive ultrasound by amniocentesis. Both amniocentesis and CVS
tests will indicate if the fetus is growing nor- carry risks of infection and miscarriage. Nor-
mally. Certain ultrasound findings, such as mally these procedures are not offered unless
shortened long bones, may indicate an in- the risk of having an affected child is found to
creased probability for a Down syndrome baby. be greater than the risk of complications from
Because Down syndrome is a highly variable the procedures.
condition, normal ultrasound findings do not If the doctor is convinced that the fetus has a
guarantee that the child will be born without tiny chromosomal defect that is not visible on a
Down syndrome. Only a chromosome analysis karyotype, it will then be necessary to probe (or
can determine this for certain. FISH) the fetal chromosomes; the initials
FISH stand for fluorescent in situ hybridiza-
Amniocentesis, Karyotyping, and FISH tion. A chromosome probe is a piece of DNA
Amniocentesis is the process of collecting fe- that is complementary to DNA within a gene.
tal cells from the amniotic fluid. Fetal cells col- Complementary pieces of DNA will stick to-
Prenatal Diagnosis 629
gether (hybridize) when they come in contact. somes to appear as green spots and number 21
The probe also has an attached molecule that chromosomes to appear as red spots. Cells
will glow when viewed under fluorescent light. from a girl with trisomy 21 would have two
A probe for a particular gene will stick to the green spots and two aqua spots, but no red spot
part of the chromosome where the gene is lo- when the first set of probes is used. Some other
cated and make a glowing spot. If the gene is cells from the same girl will show two red spots,
not present because it has been lost, no spot but three green ones, when the second set of
will appear. Probes have been developed for probes is used.
many individual genes that cause developmen- More recently, tests for many more genetic
tal abnormalities when they are deleted from defects using advanced molecular genetics
the chromosomes. tests have been developed. DNA can be isolated
Cells obtained by amniocentesis can be from fetal cells, obtained by one of the meth-
probed in less time than it takes to grow and ods already described, which is then probed for
prepare them for karyotyping. Probes have single gene defects. Hundreds of potential ge-
been developed for the centromeres of the netic defects can be detected in this way, al-
chromosomes that are frequently present in ex- though only a few such tests are generally avail-
tra copies, such as 13, 18, 21, X, and Y. Y chro- able. Another barrier to their use is their high
mosomes that have been probed appear as red cost. Costs will likely drop in the future as the
spots, X chromosomes as green spots, and tests are perfected and are used more widely.
number 18 chromosomes as aqua spots. A sec- These same tests may be performed on the par-
ond set of probes attached to other cells from ents to determine whether they are carriers of
the same fetus will cause number 13 chromo- certain genetic diseases.
Yury Verlinsky (right), known for his cutting-edge work in prenatal testing, and Ridvan Seckin Ozen examine human chromosomes
at the Reproductive Genetics Institute in Chicago. (AP/Wide World Photos)
630 Prenatal Diagnosis
In 1972, Stanley B. Prusiner, then a resident in neu- hundred nucleotides and would have to be smaller
rology at the University of California School of Medi- than any known virus.
cine at San Francisco, lost a patient to Creutzfeldt- Prusiner and his collaborators subsequently
Jakob disease. He resolved to learn more about the learned that the gene for the prion protein was
condition. He read that it and related diseases, scra- found in chromosomes of hamsters, mice, humans,
pie and kuru, could be transmitted by injecting ex- and all other mammals that have been examined.
tracts from diseased brain into the brains of healthy Furthermore, most of the time these animals make
animals. At the time, the diseases were thought to be the prion protein without getting sicka startling
caused by a slow-acting virus, but it had not been observation. Prusiner and his team subsequently
identified. He was intrigued by a study from the labo- showed that the prion protein existed in two forms,
ratory of Tikvah Alper that suggested that the scrapie one harmless and the other leading to disease. The
agent lacked nucleic acid. When he started his own latter proved to be highly resistant to degradation by
lab in 1974, Prusiner decided to pursue the nature of proteolytic enzymes and accumulated in the brain
the infectious agent. tissue of affected animals and people. In infectious
He and his associates determined to purify the disease, the harmful form of the prions appears to
causative agent in scrapie-infected brains and, by convert the harmless form to the harmful form, al-
1982, had a highly purified preparation. They sub- though the mechanism is not understood. In inher-
jected it to extensive analysis, and all of their results ited disease, mutations in the prion may cause it to
indicated that it indeed lacked DNA or RNA and that adopt the harmful form spontaneously or after some
it consisted mainly, if not exclusively, of protein. The unknown signal, leading eventually to the disease
infectivity was lost when treated with procedures that state. While questions remain, research since the
denatured protein, but not when treated with those 1980s has established the involvement of prions in
detrimental to nucleic acids. He named the agent a various spongiform encephalopathies.
prion, an abbreviation for proteinaceous infec- In 1997, Prusiner was awarded the Nobel Prize in
tious particle. Shortly afterward, he showed that it Physiology or Medicine for his pioneering discovery
consisted of a single protein. This was a highly un- of prions and their role in various neurological dis-
orthodox discovery because all pathogens studied eases. The Nobel Committee also noted his persever-
to date contained nucleic acid. Skeptics were con- ance in pursuing an unorthodox hypothesis in the
vinced that a very small amount of nucleic acid must face of major skepticism.
be contaminating the prions, although the limits on James L. Robinson
detection showed that it contained fewer than one
one thousand Fore died of Kuru each year. An- fear. Thousands of cattle were killed to prevent
thropologists recording their customs de- human consumption of contaminated beef.
scribed their practice of eating the brains of The cows were infected by supplemental feed-
their dead relatives in order to gain the knowl- ings tainted by infected sheep meat. Animal-to-
edge they contained. Clearly, some infectious human transmission of these diseases appears
agent was being transmitted during this ritual. to occur, and research has shown that human-
Such cannibalism has since stopped, and Kuru to-animal infection is possible as well.
has declined markedly. Kuru, like Creutzfeldt- Both Kuru and Creutzfeldt-Jakob syndrome,
Jakob syndrome, shows the same spongiform as well as the animal forms, have no known
changes and protein deposits in the brain after treatment or cure. Because of the long incuba-
death. Similarly, early symptoms include intel- tion period, decades may pass before symp-
lectual deterioration, spastic movements, and toms appear, but once they do, the central ner-
visual problems. Within a year, the patient be- vous system is rapidly destroyed, and death
comes unresponsive and dies. comes quickly. It is likely that many more peo-
The outbreak of mad cow disease in the ple die of these disorders than is known be-
mid-1990s in Great Britain led to widespread cause they are so rarely diagnosed.
Prion Diseases: Kuru and Creutzfeldt-Jakob Syndrome 633
Protein Structure
Field of study: Molecular genetics
Significance: Proteins have three-dimensional
structures that determine their functions,
and slight changes in overall structure may A three-dimensional image of the ras protein. (U.S. Department
of Energy Human Genome Program, http://www.ornl.gov/
significantly alter their activity. Correlation
hgmis)
of protein structure and function can pro-
vide insights into cellular metabolism and
its many interconnected processes. Because
amino acid that gives each amino acid its
most diseases result from improper protein func-
unique properties
tion, advances in this field could lead to effective
molecular-based disease treatments.
Protein Structure and Function
Proteins consist of strings of individual sub-
Key terms units called amino acids that are chemically
amino acid: the basic subunit of a protein; bonded together with peptide bonds. Once
there are twenty commonly occurring amino acids are bonded, the resulting mole-
amino acids, any of which may join together cule is called a polypeptide. The properties and
by chemical bonds to form a complex pro- arrangement of the amino acids in the poly-
tein molecule peptide cause it to fold into a specific shape or
enzymes: proteins that are able to increase the conformation that is required for proper pro-
rate of chemical reactions in cells without tein function. Proteins have been called the
being altered in the process workhorses of t0he cell because they perform
hydrogen bond: a weak bond that helps stabi- most of the activities encoded in the genes of
lize the folding of a protein the cell. Proteins function by binding to other
polypeptide: a chain of amino acids joined by molecules, frequently to other proteins. The
chemical bonds precise three-dimensional shape of a protein
R group: a functional group that is part of an determines the specific molecules it will be
Protein Structure 635
able to bind to, and for many proteins binding central carbon atom (known as the alpha car-
is specific to just one other specific type of mol- bon, or C) as shown in the following figure:
ecule.
In 1973, Christian B. Anfinsen performed
experiments that showed that the three-dimen- H O
sional structure of a protein is determined by
the sequence of its amino acids. He used a pro- H2N C C OH
tein called ribonuclease (RNase), an enzyme
that degrades RNA in the cell. The ability of R
ribonuclease to degrade RNA is dependent
upon its ability to fold into its proper three-
dimensional shape. Anfinsen showed that if the The uniqueness of each of the twenty amino ac-
enzyme was completely unfolded by heat and ids is determined by the R group. This group
chemical treatment (at which time it would not may be as simple as a hydrogen atom (in the
function), it formed a linear chain of amino ac- case of the amino acid glycine) or as complex as
ids. Although there were 105 possible confor- a ring-shaped structure (as found in the amino
mations that the enzyme could take upon re- acid phenylalanine). It may be charged, either
folding, it would refold into the single correct positively or negatively, or it may be uncharged.
functional conformation upon removal of heat Cells join amino acids together to form pep-
and chemicals. This established that the amino tides (strings of up to ten amino acids), poly-
acid sequences of proteins, which are specified peptides (strings of ten to one hundred amino
by the genes of the cell, carry all of the informa- acids), or proteins (single or multiple polypep-
tion necessary for proteins to fold into their tides folded and oriented to one another so
proper three-dimensional shapes. they are functional). The amino acids are
To understand protein conformation better, joined together by covalent bonds, called pep-
it is helpful to analyze the underlying levels of tide bonds (in the box in the following figure),
structure that determine the final three-di- between the carbon atom of the carboxyl
mensional shape. The primary structure of a group of one amino acid (COOH) and the
polypeptide is the simplest level of structure nitrogen atom of the amino group (NH2) of
and is, by definition, its amino acid sequence. the next adjacent amino acid:
Because primary structure of polypeptides ulti-
mately determines all succeeding levels of
structure, knowing the primar y structure H O H O
should theoretically allow scientists to predict
the final three-dimensional structure. Building H2N C C N C C OH
on a detailed knowledge of the structure of
many proteins, scientists can now develop com- R H R
puter programs that are able to predict three-
dimensional shape with some degree of accu-
racy, but much more research will be required During the formation of the peptide bond, a
to increase the accuracy of these methods. molecule of water (H2O) is lost (an -OH from
the carboxyl group and an -H from the amino
Primary Protein Structure group), so this reaction is also called a dehy-
There are twenty naturally occurring amino dration synthesis. The result is a dipeptide (a
acids that are commonly found in proteins, peptide made of two amino acids joined by a
and each of these has a common structure con- peptide bond) that has a backbone of nitro-
sisting of a nitrogen-containing amino group gens and carbons (NCCNCC) with
(NH2), a carboxyl group (COOH), a hy- other elements and R groups protruding from
drogen atom (H), and a unique functional the backbone. An amino acid may be joined to
group referred to as an R group, all bonded to a the growing peptide chain by formation of a
636 Protein Structure
peptide bond between the carbon atom of the pleated sheets. An alpha helix is a rigid struc-
free carboxyl group (on the right of the preced- ture shaped very much like a telephone cord; it
ing figure) and the nitrogen atom of the amino spirals around as the oxygen of one amino acid
acid being added. The end of a polypeptide of the chain forms a hydrogen bond with the
with an exposed carboxyl group is called the hydrogen atom of an amino acid five amino ac-
C-terminal end, and the end with an exposed ids away on the protein strand. The rigidity of
amino group is called the N-terminal end. the structure is caused by the large number of
The atoms and R groups that protrude from hydrogen bonds (individually weak but collec-
the backbone are capable of interacting with tively strong) and the compactness of the helix
each other, and these interactions lead to that forms. Many alpha helices are found in
higher-order secondary, tertiary, and quater- proteins that function to maintain cell struc-
nary structures. ture.
Beta sheets are formed by hydrogen bond-
Secondary Structure ing between amino acids in different regions
The next level of structure is secondary (often very far apart on the linear strand) of a
structure, which involves the formation of hy- polypeptide. The shape of a beta-pleated sheet
drogen bonds between the oxygen atoms in may be likened to the bellows of an accordion
carboxyl groups with the hydrogen atoms of or a sheet of paper that has been folded multi-
amino groups from different parts of the poly- ple times to form pleats. Because of the large
peptide. Hydrogen bonds are weak bonds that number of hydrogen bonds in them, beta
form between atoms that have a very strong at- sheets are also strong structures, and they form
traction for electrons (such as oxygen or nitro- planar regions that are often found at the bot-
gen), and a hydrogen atom that is bound to an- tom of pockets inside proteins to which other
other atom with a very strong attraction for molecules attach.
electrons. Secondary structure does not in- In addition to alpha helices or beta-pleated
volve the formation of bonds with R groups or sheets, other regions of the protein may have
atoms that are parts of R groups, but involves no obvious secondary structure; these regions
bonding just between amino and carboxyl are said to have a random coil shape. It is the
groups that are in the peptide bonds making combinations of random coils, alpha helices,
up the backbone of polypeptides. and beta sheets that form the secondary struc-
ture of the protein.
H O H O Tertiary Structure
The final level of protein shape (for a single
H2N C C N C C OH polypeptide or simple protein) is called ter-
tiary structure. Tertiary structure is caused by
R H R the numerous interactions of R groups on the
amino acids and of the protein with its environ-
Hydrogen bond ment, which is usually aqueous (water based).
Various R groups may either be attracted to and
H O H O form bonds with each other, or they may be re-
pelled from each other. For example, if an R
H2N C C N C C OH group has an overall positive electrical charge,
it will be attracted to R groups with a negative
R H R charge but repelled from other positively
charged R groups. For a polypeptide with one
hundred amino acids, if amino acid number 6
These hydrogen bonds between backbone is negatively charged, it could be attracted to a
molecules lead to the formation of two major positively charged amino acid at position 74,
types of structures: alpha helices and beta- thus bringing two ends of the protein that are
Protein Structure 637
information, whereas protein is its active form. RNA serves as the intermediate form from
Although there are thousands of different pro- which proteins are synthesized. RNA plays
teins in cells, they either serve a structural role three roles during protein synthesis. Messen-
or are enzymes that catalyze the biosynthetic re- ger RNA (mRNA) contains the information for
actions of a cell. Following the discovery of the the amino acid sequence of a protein. Transfer
structure of DNA in 1953 by James Watson and RNAs (tRNAs) are small RNA molecules that
Francis Crick, scientists began to study the pro- serve as adapters that decipher the coded in-
cess by which the information stored in this formation present within an mRNA and bring
molecule is converted into protein. the appropriate amino acid to the polypeptide
Proteins are linear, functional molecules as it is being synthesized. Ribosomal RNAs
composed of a unique sequence of amino ac- (rRNAs) act as the engine that carries out most
ids. Twenty different amino acids are used as of the steps during protein synthesis. Together
the protein building blocks. Although the in- with a specific set of proteins, rRNAs form ribo-
formation for the amino acid sequence of each somes that bind the mRNA, serve as the plat-
protein is present in DNA, protein is not syn- form for tRNAs to decode an mRNA, and cata-
thesized directly from this source. Instead, lyze the formation of peptide bonds between
The fundamental steps in protein synthesis. (U.S. Department of Energy Human Genome Program, http://www.ornl.gov/
hgmis)
640 Protein Synthesis
amino acids. Each ribosome is composed of synthesis of an mRNA from its DNA template,
two subunits: a small (or 40s) and a large (or one guanine is added to the 5 end of the
60s) subunit, each of which has its own func- mRNA in an inverted orientation and is the
tion. The s in 40s and 60s is an abbreviation only nucleotide in the entire mRNA present in
for Svedberg units, which are a measure of how a 3 to 5 orientation. It is referred to as the cap.
quickly a large molecule or complex molecular A long stretch of adenosine is added to the 3
structure sediments (or sinks) to the bottom of end of the mRNA to make what is called the
a centrifuge tube while being centrifuged. The poly-A tail.
larger the number, the larger the molecule. Typically, mRNAs have a stretch of nucleo-
Like all RNA, mRNA is composed of just four tide sequence that lies between the cap and the
types of nucleotides: adenine (A), guanine coding region. This is referred to as the leader
(G), cytosine (C), and uracil (U). Therefore, sequence and is not translated. Therefore, a
the information in an mRNA is contained in a signal is necessary to indicate where the coding
linear sequence of nucleotides that is con- region initiates. The codon AUG usually serves
verted into a protein molecule composed of a as this initiation codon; however, other AUG
linear sequence of amino acids. This process is codons may be present in the coding region.
referred to as translation, since it converts Any one of three possible codons (UGA, UAG,
the language of nucleotides that make up an or UAA) can serve as stop codons that signal
mRNA into the language of amino acids that the ribosome to terminate translation. Several
make up a protein. This is achieved by a three- accessory proteins assist ribosomes in binding
letter genetic code in which each amino acid in mRNA and help carry out the required steps
a protein is specified by a three-nucleotide se- during translation.
quence in the mRNA called a codon. The four
possible letters means that there are sixty- The Translation Process: Initiation
four possible three-letter words. As there are Translation occurs in three phases: initia-
only twenty amino acids used to make proteins, tion, elongation, and termination. The func-
most amino acids are encoded by several differ- tion of the 40s ribosomal subunit is to bind to
ent codons. For example, there are six differ- an mRNA and locate the correct AUG as the
ent codons (UCU, UCC, UCA, UCG, AGU, and initiation codon. It does this by binding close to
AGC) that specify the amino acid serine, the cap at the 5 end of the mRNA and scanning
whereas there is only one codon (AUG) that the nucleotide sequence in its 5 to 3 direction
specifies the amino acid methionine. The in search of the initiation codon. Marilyn
mRNA, therefore, is simply a linear array of Kozak identified a certain nucleotide sequence
codons (that is, three-nucleotide words that surrounding the initiator AUG of eukaryotic
are read by tRNAs together with ribosomes). mRNAs that indicates to the ribosome that this
The region within an mRNA containing this se- AUG is the initiation codon. She found that the
quence of codons is called the coding region. presence of an A or G three nucleotides prior
Before translation can occur in eukaryotic to the AUG and a G in the position immediately
cells, mRNAs undergo processing steps at both following the AUG were critical in identifying
ends to add features that will be necessary for the correct AUG as the initiation codon. This is
translation (These processing steps do not oc- referred to as the sequence context of the ini-
cur in prokaryotic cells.) Nucleotides are struc- tiation codon. Therefore, as the 40s ribosomal
tured such that they have two ends, a 5 and a 3 subunit scans the leader sequence of an mRNA
end, that are available to form chemical bonds in a 5 to 3 direction, it searches for the first
with other nucleotides. Each nucleotide pres- AUG in this context and may bypass other
ent in an mRNA has a 5 to 3 orientation that AUGs not in this context.
gives a directionality to the mRNA so that the Nahum Sonenberg demonstrated that the
RNA begins with a 5 end and finishes in a 3 scanning process by the 40s subunit can be im-
end. The ribosome reads the coding region of peded by the presence of stem-loop structures
an mRNA in a 5 to 3 direction. Following the present in the leader sequence. These form
Protein Synthesis 641
Protein Synthesis
mRNA chain
UGGAGGC
UGUU GU
A A
U AGUUA
Glycine
ine
Glyc Va
li End
ne
Serine chain
e
in
M
an
et codon
al
hi
yl
on
en
in
Ph
Protein chain
Protein synthesis is directed by messenger RNA (mRNA). The order of the amino acids in the protein chain is controlled by the order
of the bases in the mRNA chain. It takes a codon of three bases to specify one amino acid.
from base pairing between complementary nu- Through the combined action of eIF4G and
cleotides present in the leader sequence. Two eIF3, the 40s subunit is bound to the mRNA,
nucleotides are said to be complementary and through the action of eIF4A and eIF4B, the
when they join together by hydrogen bonds. mRNA is prepared for 40s subunit scanning. As
For instance, the nucleotide (or base) A is com- the cellular concentration of eIF4E is very low,
plementary to U, and these two can form what mRNAs must compete for this protein. Those
is called a base pair. Likewise, the nucleotides that do not compete well for eIF4E will not
C and G are complementary. Several accessory be translated efficiently. This represents one
proteins, called eukaryotic initiation factors means by which a cell can regulate protein
(eIFs), aid the binding and scanning of 40s sub- synthesis. One class of mRNA that competes
units. The first of these, eIF4F, is composed of poorly for eIF4E encodes growth-factor pro-
three subunits called eIF4E, eIF4A, and eIF4G. teins. Growth factors are required in small
The protein eIF4E is the subunit responsible amounts to stimulate cellular growth. Sonen-
for recognizing and binding to the cap of the berg has shown that the overproduction of
mRNA. The eIF4A subunit of eIF4F, together eIF4E in animal cells leads to a reduction in the
with another factor called eIF4B, functions to competition for this protein, and mRNAs such
remove the presence of stem-loop structures in as growth-factor mRNAs that were previously
the leader sequence through the disruption of poorly translated when the concentration of
the base pairing between nucleotides in the eIF4E was low are now translated at a higher
stem loop. The protein eIF4G is the large sub- rate when eIF4E is abundant. This in turn re-
unit of eIF4F, and it serves to interact with sev- sults in the overproduction of growth factors,
eral other proteins, one of which is eIF3. It is which leads to uncontrolled growth, a charac-
this latter initiation factor that the 40s subunit teristic typical of cancer cells.
first associates with during its initial binding to A protein that specifically binds to the poly-A
an mRNA. tail at the 3 end of an mRNA is called the poly-
642 Protein Synthesis
A-binding protein (PABP). Discovered in the otic elongation factor 1 (eEF1). A codon is de-
1970s, the only function of this protein was coded by the appropriate tRNA through base
thought to be to protect the mRNA from attack pairing between the three nucleotides that
at its 3 end by enzymes that degrade RNA. Dan- make up the codon in the mRNA and three
iel Gallie demonstrated another function for complementary nucleotides within a specific
PABP by showing that the PABP-poly-A-tail region (called the anticodon) within the tRNA.
complex was required for the function of the The tRNA binding sites in the 80s ribosome are
eIF4F-cap complex during translation initia- located in the 60s subunit. The ribosome moves
tion. The idea that a protein located at the 3 over the coding region one codon at a time, or
end of an mRNA should participate in events in steps of three nucleotides, in a process re-
occurring at the opposite end of an mRNA ferred to as translocation. When the ribo-
seemed strange initially. However, RNA is quite some moves to the next codon to be decoded,
flexible and is rarely present in a straight, linear the tRNA containing the appropriate antico-
form in the cellular environment. Conse- don will bind tightly in the open site in the 60s
quently, the poly-A tail can easily approach the subunit (the A site). The tRNA that bound to
cap at the 5 end. Gallie showed that PABP in- the previous codon is present in a second site in
teracts with eIF4G and eIF4B, two initiation fac- the 60s subunit (the P site). Once a new tRNA
tors that are closely associated with the cap, has bound to the A site, the ribosomal RNA it-
through protein-to-protein contacts. The con- self catalyzes the formation of a peptide bond
sequence of this interaction is that the 3 end of between the growing polypeptide and the new
an mRNA is held in close physical proximity to amino acid. This results in the transfer of the
its cap. The interaction between these proteins polypeptide attached to the tRNA present in
stabilizes their binding to the mRNA, which in the P site to the amino acid on the tRNA pres-
turn promotes protein synthesis. Therefore, ent in the A site. A second elongation factor,
mRNAs can be thought of as adopting a circu- eEF2, catalyzes the movement of the ribosome
lar form during translation that looks similar to to the next codon to be decoded. This process
a snake biting its own tail. This idea is now is repeated one codon at a time until a stop
widely accepted by scientists. codon is reached.
One additional factor, called eIF2, is needed The termination phase of translation begins
to bring the first tRNA to the 40s subunit. when the ribosome reaches one of the three
Along with the initiator tRNA (which decodes termination or stop codons. These are also re-
the AUG codon specifying the amino acid ferred to as nonsense codons as the cell does
methionine), eIF2 aids the 40s subunit in iden- not produce any tRNAs that can decode them.
tifying the AUG initiation. Once the 40s sub- Accessory factors, called release factors, are
unit has located the initiation codon, the 60s also required to assist this stage of translation.
ribosomal subunit joins the 40s subunit to They bind to the empty A site in which the stop
form the intact 80s ribosome. (Svedberg units codon is present, and this triggers the cleavage
are not additive; therefore, a 40s and 60s unit of the bond between the completed protein
joined together do not make a 100s unit.) This from the last tRNA in the P site, thereby re-
marks the end of the initiation phase of trans- leasing the protein. The ribosome then dissoci-
lation. ates into its 40s and 60s subunits, the latter of
which diffuses away from the mRNA. The close
The Translation Process: Elongation and physical proximity of the cap and poly-A tail of
Termination an mRNA maintained by the interaction be-
During the elongation phase, tRNAs bind to tween PABP and the initiation factors (eIF4G
the 80s ribosome as it passes over the codons of and eIF4B) is thought to assist the recycling
the mRNA, and the amino acids attached to the of the 40s subunit back to the 5 end of the
tRNAs are transferred to the growing polypep- mRNA to participate in a subsequent round of
tide. Binding of the tRNAs to the ribosome is translation.
assisted by an accessory protein called eukary-
Proteomics 643
Although such methods provide valuable comes almost unrecognizable from the parent
information in analyzing the structure of pro- gene. A lack of protein amplification meth-
teins, they suffer from the loss of spatial infor- odstechniques that would produce more
mation that occurs when tissues are homoge- copies of a protein to aid in studyrequires
nized, when the protein is obtained from a sensitive analysis methods and increasingly
manufactured, bacterial environment, or when strong detectors. Currently new methods are
it is otherwise isolated. Matrix-assisted laser being developed, but the limit of study is as
desorption/ionization time-of-flight (MALDI- large as 1 nanometer.
TOF) mass spectrometry is a complementary
method of analysis that does not yield struc- Disease
tural information but provides protein profiles Proteins often act as markers for disease. As
from intact tissue, allowing comparison of dis- researchers study proteins, they have found
eased versus normal tissue. that disease may be characterized by some pro-
Large databases of mass spectroscopic data teins that are being overproduced, not being
are being assembled to assist in future identifi- produced at all, or being produced at inappro-
cation of know proteins. Further databases of priate times. As the correlation of proteins to
proteome information include particular mo- disease becomes clearer, better diagnostic tests
lecular masses, charges, and, in some cases, and drugs are being explored. For example,
connections to the genes regulated or the par- Alzheimers disease and Down syndrome are
ent gene of the peptide in question. Scientists associated with a common protein fragment as
hope to relate regulators and the complex web the major extracellular protein component of
of peripheral proteins that affect the function senile plaques.
of each gene. Researchers are investigating changes in
protein expression in heart disease and heart
Challenges and Limitations of Current failure, and several hundred cardiac proteins
Methods have already been identified. The study of
The amount of data being obtained by pro- proteomics in immunological diseases has re-
teomics research poses a problem in organiz- vealed that there is a connection between the
ing and processing the information obtained human neutrophil -defensins (HNPs) and
on proteins. The Human Proteome Organiza- human immunodeficiency virus, HIV-1. HNPs
tion (HUPO) and the European Bioinformatics are small, cysteine-rich, cationic antimicrobial
Institute (EBI) are two organizations whose proteins that are stored in the azurophilic gran-
purposes include the management and organi- ules of neutrophils and released during
zation of proteomics information and data- phagocytosis to kill ingested foreign microbes.
bases, and the facilitation of the advancement To date, the three most abundant forms of the
of this scientific endeavor. protein have been implicated in suppressing
Analyzing MS data from proteins and relat- HIV-1 in vivo.
ing the complex array of proteins within a sin- Similarly, cancer is being studied to find a
gle cell to the linear genetic material of DNA roster of proteins that are present in cancerous
present challenges to researchers that they are cells but not in normal cells. A joint effort from
tackling through computer algorithms, pro- the National Cancer Institute and the Food
grams, and databases. The SWISS-PROT data- and Drug Administration is searching for the
base, for example, is an annotated protein- differences between cancerous and normal
sequence database maintained by the Swiss cells, and also for protein markers.
Bioinformatics Institute.
Other obstacles to relating proteins to par- Possible Future Directions
ent genes include the loss of quaternary struc- Although proteomics is a relatively new area
ture during separation and the presence of of genetic research, the importance of the
post-translation processing, which can alter the sugar coatings of proteins and cells is gaining
amino acid sequence to the extent that it be- attention, under the name glycomics. This
646 Pseudogenes
more quickly. It may change to produce a dif- pseudogene. Because the introns of a gene are
ferent, functional polypeptide (and effectively removed from the RNA transcript, processed
become a new gene), or it may remain non- pseudogenes are not exact copies of the origi-
functional as a pseudogene. There are two nal DNA sequence; the introns are missing.
types of pseudogenes, defined by how they Copies of protein-coding genes copied by this
were produced: nonprocessed and processed. mechanism are members of a type of repetitive
DNA called LINES (for long interspersed se-
Nonprocessed Pseudogenes quences) and exist in multiple copies scattered
Nonprocessed (or duplicated) pseudogenes around the genome, each up to several thou-
arise when a portion of the original gene is du- sand base pairs in length. Short processed
plicated, with portions necessary for proper pseudogenes are members of another class of
functioning missing or altered or when the repetitive DNA called SINES (short inter-
complete original gene is duplicated. They can spersed sequences of up to several hundred
be identified by the presence of introns and base pairs in length) and result from the retro-
may have mutations in the promoter that pre- transposon-mediated copying of tRNA or
vent transcription or the correct removal of in- rRNA genes. SINES of this type are sometimes
trons, or they may have other mutations (such very abundant in genomes because they may
as premature stop codons) within exons that have internal promoters, so that they are more
result in translation of a nonfunctional poly- easily transcribed, and therefore transposed.
peptide. A series of tandem duplications of The most prominent of SINES are those that
a gene can result in clustered gene families, are members of the Alu family, which occur an
which can include expressed genes, expressed average of once every six thousand base pairs in
pseudogenes (which are transcribed but pro- the human genome.
duce no functional polypeptide), and nonex-
pressed pseudogenes that are not transcribed. Pseudogenes and Neutral Evolution
The alpha-globulin and beta-globulin clusters In 2003, Japanese researchers reported the
are examples of such gene families. Other ex- discovery of a mouse pseudogene that is in-
amples of nonprocessed pseudogenes include volved in regulating the expression of its re-
members of the immunoglobulin (Ig) and ma- lated functional gene. This discovery sug-
jor histocompatibility complex (MHC) gene gested that at least some pseudogenes may
families. have important functions. Although pseudo-
genes are very commonly found across ge-
Processed Pseudogenes nomes, most do not appear to serve any func-
Processed pseudogenes originate from tran- tion, and until further research uncovers more
scribed RNA copies of genes that are copied functional pseudogenes this assumption ap-
back to DNA by the enzyme reverse transcrip- pears warranted. Their abundance can be
tase. Processed pseudogenes are usually inte- explained by the tendency of duplicated se-
grated into the genome in a different location quences to be further copied. Retrotranspo-
from the original gene. Reverse transcriptase is sition increases the number of copies of pro-
an enzyme produced by retroviruses, which cessed pseudogenes, and gene duplication
have RNA genomes that are reverse tran- leading to unprocessed pseudogenes favors
scribed to DNA when the viruses infect host mechanisms that generate additional copies,
cells. Retrotransposons, which are related to leading to clustered gene families. Natural se-
retroviruses, are DNA sequences that transpose lection does not tend to eliminate these addi-
or duplicate themselves by reverse transcrip- tional copies because their presence does not
tion of a transcribed RNA copy of the se- harm the organism as long as there is at least
quence. one functional copy of the original gene. In
Often, retrotransposons will carry along a other words, pseudogenes are selectively neu-
copy of the surrounding host DNA, resulting in tral.
the duplication of that sequencea processed Because of their selective neutrality, pseudo-
648 Pseudohermaphrodites
genes are especially useful for estimating neu- medical evaluation and appropriate medical in-
tral mutation rates in genomes. The neutral tervention to help ensure a healthy, well-adjusted
theory of evolution predicts that, because of life.
the constraints of selection, functional regions
of the genome (such as the exons, or coding se- Key terms
quences, of genes) will evolve more slowly than ambiguous genitalia: external sexual organs
less critical sequences, such as introns, or non- that are not clearly male or female
functional sequences like pseudogenes. The genotype: the sum total of the genes present
number of nucleotide differences between in an individual
homologous sequences of related species can gonads: organs that produce reproductive
be used to calculate estimates of evolutionary cells and sex hormones, for example, testes
rates, and such estimates support the neutral in males and ovaries in females
theory: the greatest rates of divergence occur karyotype: the number and kind of chromo-
within pseudogenes. Using comparisons from somes present in every cell of the body (nor-
several pseudogenes, researchers can establish mal female karyotype is 46,XX and normal
the baseline neutral mutation rate for a group male karyotype is 46,XY)
of species. phenotype: the physical appearance and phys-
Stephen T. Kilpatrick iological characteristics of an individual,
See also: Gene Families; Repetitive DNA. which depends on the interaction of geno-
type and environment
Further Reading
Graur, Dan, and Wen-Hsiung Li. Fundamentals Normal Fetal Development
of Molecular Evolution. 2d ed. Sunderland, Prior to nine weeks gestational age, a male
Mass.: Sinauer Associates, 1999. A detailed and a female fetus have identical external geni-
review of the topic, including the impor- talia (sexual organs) consisting of a phallus and
tance of pseudogenes in determining ge- labioscrotal folds. The phallus develops into a
nomic rates of neutral evolution. penis in males and a clitoris in females;
Lewin, Benjamin. Genes VII. New York: Oxford labioscrotal folds become the scrotum in males
University Press, 2001. Provides several exam- and the labial folds in females. Early in develop-
ples of clustered gene families that include ment, the gonads can develop into either testes
pseudogenes, and describes the mechanism or ovaries. In a fetus with a normal male
for the origin of processed pseudogenes. karyotype (46,XY), the primitive gonads be-
Li, Wen-Hsiung, Takashi Gojobori, and Masa- come testes, which produce testosterone. Tes-
toshi Nei. Pseudogenes as a Paradigm of tosterone in turn causes enlargement of the
Neutral Evolution. Nature 292, no. 5820 primitive phallus into a penis. It is the presence
(1981): 237-239. Discusses the predictions of of the Y chromosome, and in particular a small,
the neutral theory, how rates of nucleotide sex-determining region of the Y chromosome
substitution may be calculated, and how termed the SRY locus, that drives the forma-
data from pseudogenes support the neutral tion of the testes. The presence of the SRY lo-
theory. cus appears to be essential for development of a
normal male.
Pseudohermaphroditism
Pseudohermaphrodites A true hermaphrodite is born with both
ovarian and testicular tissue. A male pseudo-
Field of study: Diseases and syndromes hermaphrodite has a 46,XY karyotype with ei-
Significance: Pseudohermaphrodites are individu- ther female genitalia or ambiguous genitalia
als born with either ambiguous genitalia or exter- (but only testicular tissue); a female pseudo-
nal genitalia that are the opposite of their chromo- hermaphrodite has a 46,XX karyotype with ei-
somal sex. These individuals need a thorough ther male genitalia or ambiguous genitalia (but
Pseudohermaphrodites 649
only ovarian tissue). Ambiguous genitalia typi- duction of testosterone. These individuals may
cally consist of a small, abnormally shaped, actually develop into nearly normal-appearing
phalluslike structure, often with hypospadias males. Abnormalities of the testosterone recep-
(in which urine comes from the base of the pe- tor can also result in a range of different con-
nis instead of the tip) and abnormal develop- ditions in affected males, from normal female
ment of the labioscrotal folds (not clearly a appearance (a totally defective receptor) to
scrotum or labia). A vaginal opening may be ambiguous genitalia (partially defective recep-
present. tor) in a 46,XY male. These individuals will not
Most cases of pseudohermaphroditism re- masculinize at puberty because no matter how
sult from abnormal exposure to increased or much testosterone or DHT they produce, their
decreased amounts of sex hormones during bodies cannot respond to the hormones.
embryonic development. The most common Both male and female pseudohermaphro-
cause of female pseudohermaphroditism is ex- ditism can result from chromosomal abnor-
posure of a female fetus to increased levels of malities. The absence or dysfunction of the
testosterone during the first half of pregnancy. SRY locus produces an individual with nor-
Maternal use of anabolic steroids can cause this mal female genitalia but a 46,XY karyotype.
condition, but the most common genetic cause Individuals with a 46,XX karyotype who have
of increased testosterone exposure is congeni- the SRY locus transposed to one of their X
tal adrenal hyperplasia (CAH). CAH results chromosomes will have a normal male appear-
from an abnormality in the enzymatic pathways ance.
of the fetus that make both cortisol (a stress
hormone) and the sex steroids (such as testos- Impact and Applications
terone). At several points in these pathways, Some forms of pseudohermaphroditism are
there may be a nonfunctioning enzyme that re- life threatening, and so early diagnosis is im-
sults in too little production of cortisol and too perative. Both males and females with CAH are
much production of the sex steroids. This will at risk for sudden death caused by low cortisol
result in partial masculinization of the external levels and other hormone deficiencies. Early
genitalia of a female embryo. Females with diagnosis is relatively easy in affected females
CAH are usually born with an enlarged clitoris since their genital abnormalities are noticeable
(often mistakenly thought to be a penis) and at birth. Affected males are often not recog-
partial fusion of the labia. Males can also have nized until they have a life-threatening event,
CAH, but the excess testosterone does not af- which usually occurs in the first two weeks of
fect their genital development since a relatively life. Treatment of CAH consists of appropriate
high level of testosterone exposure is a normal hormone supplementation that, if instituted
part of their development. early in life, can help prevent serious problems.
The most common causes of male pseudo- CAH is inherited in an autosomal recessive
hermaphroditism are abnormalities of testos- manner, so parents of an affected individual
terone production or abnormalities in the tes- have a 25 percent chance of having another af-
tosterone receptor at the cellular level. One fected child with each pregnancy.
example is a deficiency in 5-alpha-reductase, The sex of rearing of a child with ambiguous
the enzyme that converts testosterone to dihy- genitalia is usually determined by the childs
drotestosterone (DHT). When there is a defi- type of pseudohermaphroditism. Typically, sex
ciency of this enzyme, there will be a deficiency of rearing will be based on the chromosomal
of DHT, which is the hormone primarily re- sex of the child. These children may need sex
sponsible for masculinization of external geni- hormone supplementation or surgery to assist
talia. A male who lacks DHT will have female- in developing gender-appropriate genitalia.
appearing external genitalia or ambiguous Children with pseudohermaphroditism with
genitalia at birth. Often these individuals are normal-appearing genitalia at birth may not be
reared as females, but at puberty they will recognized until puberty, when abnormal
masculinize because of greatly increased pro- masculinization or feminization may occur.
650 Punctuated Equilibrium
These individuals need medical evaluation and sia, Klinefelter syndrome, androgen insensi-
karyotype determination to guide the proper tivity, and testicular feminization.
medical treatment. Johns Hopkins University, Division of Pediatric
Patricia G. Wheeler Endocrinology, Syndromes of Abnormal
See also: Biological Clocks; Gender Iden- Sex Differentiation. http://www.hopkins
tity; Hermaphrodites; Homosexuality; Human medicine.org/pediatricendocrinology. Site
Genetics; Metafemales; RNA Transcription provides a guide to the science and genetics
and mRNA Processing; Steroid Hormones; of sex differentiation, including a glossary.
Testicular Feminization Syndrome; X Chromo- Click on patient resources.
some Inactivation; XYY Syndrome. National Organization for Rare Disorders
(NORD). http://www.rarediseases.org. Of-
Further Reading fers information and articles about rare ge-
Hunter, R. H. F. Sex Determination, Differentia- netic conditions and diseases, including XYY
tion, and Intersexuality in Placental Mammals. syndrome, in several searchable databases.
New York: Cambridge University Press, 1995.
Discusses the genetic determination of sex
in mammals. Illustrations (some color), bib-
liography, index. Punctuated Equilibrium
Meyer-Bahlburg, Heino. Intersexuality and the
Diagnosis of Gender Identity Disorder. Ar- Fields of study: Evolutionary biology;
chives of Sexual Behavior 23 (1994). Addresses Population genetics
gender identity and its relation to pseudo- Significance: Punctuated equilibrium is a model of
hermaphroditism. evolutionary change in which new species origi-
Simpson, J. L. Disorders of the Gonads, Geni- nate abruptly and then exist through a long period
tal Tract, and Genitalia. In Emer y and of stasis. This model is important as an explana-
Rimoins Principles and Practice of Medical Ge- tion of the stepwise pattern of species change seen
netics, edited by David L. Rimoin et al. 3 vols. in the fossil record.
New York: Churchill Livingstone, 2002. A de-
tailed account of male and female pseudo- Key terms
hermaphroditism. Illustrations, bibliogra- allopatric speciation: a theory that suggests
phy, index. that small parts of a population may become
Speiser, Phyllis W., ed. Congenital Adrenal Hyper- genetically isolated and develop differences
plasia. Philadelphia: W. B. Saunders, 2001. that would lead to the development of a new
Contents address prenatal treatment, new- species
born screening, new treatments, surgery, heterochrony: a change in the timing or rate
gender, sexuality, cognitive function, and of development of characters in an organ-
pregnancy outcomes. Illustrated. ism relative to those same events in its evolu-
tionary ancestors
Web Sites of Interest phyletic gradualism: the idea that evolu-
Intersex Society of North America. http:// tionary change proceeds by a progression of
www.isna.org. The society is a public aware- tiny changes, adding up to produce new spe-
ness, education, and advocacy organization cies over immense periods of time
which works to create a world free of shame,
secrecy, and unwanted surgery for intersex Evolutionary Patterns
people (individuals born with anatomy or Nineteenth centur y English naturalist
physiology which differs from cultural ideals Charles Darwin viewed the development of
of male and female). Includes links to infor- new species as occurring slowly by a shift of
mation on such conditions as clitoromegaly, characters within populations, so that a gradual
micropenis, hypospadias, ambiguous geni- transition from one species to another took
tals, early genital surgery, adrenal hyperpla- place. This is now generally referred to as
Punctuated Equilibrium 651
Stephen Jay Gould in his office on the Harvard campus in 1997. Together with Niles Eldredge, Gould developed the theory of punc-
tuated equilibrium to explain gaps in the fossil record. (AP/Wide World Photos)
place. One of these, termed allopatric specia- be affected by a mutation, perhaps resulting in
tion, was first proposed by Ernst Mayr in 1963. the descendant growing for much longer than
He pointed out that a reproductive isolating the ancestral form, thus producing a giant ver-
mechanism is needed to provide a barrier to sion. These changes would be essentially in-
gene flow and that this could be provided by stantaneous and thus would show as abrupt
geographic isolation. Allopatric or geograph- changes of species in the fossil record.
ical isolation could result when the normal
range of a population of organisms is reduced Impact and Applications
or fragmented. Parts of the population become The publication of the idea of punctuated
separated in peripheral isolates, and if the pop- equilibrium ignited a storm of controversy that
ulation is small, it may become modified rap- still persists. It predicts that speciation can be
idly by natural selection or genetic drift, partic- very rapid, but more important, it is consistent
ularly if it is adapting to a new environment. with the prevalence of stasis over long periods
This type of process is commonly called the of time so often observed in the fossil record.
founder effect, because it is the characteris- Species had long been viewed as flexible and
tics of the small group of individuals that will responsive to the environment, but fossil spe-
overwhelmingly determine the possible char- cies showed no change over long periods de-
acteristics of their descendants. As the initial spite a changing environment. Biologists have
members of the peripheral isolate may be few thus had to review their ideas about the con-
in number, it might take only a few genera- cept of species and the processes that operate
tions for the population to have changed on them. Species are now seen as real entities
enough to become reproductively isolated that have characteristics that are more than the
from the parent population. In the fossil re- sum of their component populations. Thus the
cord, this will be seen as a period of stasis repre- tendency of a group to evolve rapidly or slowly
senting the parent population, followed by a may be intrinsic to the group as a whole and not
rapid morphological change as the peripheral dependent on the individuals that compose it.
population is isolated from it and then replaces This debate has helped show that the fossil
it, either competitively or because it has be- record can be important in detecting phenom-
come extinct or has moved to follow a shifting ena that are too large in scale for biologists to
habitat. Because this is thought to take place observe.
rapidly in small populations, fossilization po- David K. Elliott
tential is low, and unequivocal examples are See also: Artificial Selection; Consanguin-
not common in the fossil record. However, ity and Genetic Disease; Evolutionary Biology;
in 1981, Peter Williamson published a well- Genetic Load; Hardy-Weinberg Law; In-
documented example from the Tertiary period breeding and Assortative Mating; Molecular
of Lake Turkana in Kenya, which showed epi- Clock Hypothesis; Natural Selection; Popula-
sodes of stasis and rapid change in populations tion Genetics; Speciation.
of freshwater mollusks. The increases in evolu-
tionary rate were apparently driven by severe Further Reading
environmental change that caused parts of the Eldredge, Niles. Time Frames: The Rethinking of
lake to dry up. Darwinian Evolution and the Theory of Punctu-
Punctuated changes may also have taken ated Equilibria. New York: Simon & Schuster,
place because of heterochrony, which is a 1985. The theorys coauthor explains how
change in the rate of development or timing punctuated equilibria complements Dar-
of appearance of ancestral characters. Paedo- wins thesis. Illustrations, bibliography,
morphosis, for example, would result in the index.
retention of juvenile characters in the adult, Eldredge, Niles, and Stephen Jay Gould. Punc-
while its opposite, peramorphosis, would result tuated Equilibria: An Alternative to Phyletic
in an adult morphologically more advanced Gradualism. In Models in Paleobiology, ed-
than its ancestor. Rates of development could ited by Thomas J. M. Schopf. San Francisco:
Punctuated Equilibrium 653
Freeman, Cooper, 1972. The 1972 paper (1977). A follow-up to the original exposi-
that introduced the theory of punctuated tion of the theory.
equilibrium to the scientific community. Il- Prothero, Donald R. Bringing Fossils to Life:
lustrations, bibliography. An Introduction to Paleobiology. New York:
Gould, Stephen Jay. The Meaning of Punctu- McGraw-Hill, 2003. Includes an introduc-
ated Equilibria and Its Role in Validating a tory discussion of punctuated equilibrium.
Hierarchical Approach to Macroevolution. Bibliography, index.
In Perspectives on Evolution, edited by Roger Somit, Albert, and Steven A. Peterson, eds. The
Milkman. Sunderland, Mass.: Sinauer Asso- Dynamics of Evolution: The Punctuated Equilib-
ciates, 1982. The founder of the theory ex- rium Debate in the Natural and Social Sciences.
pands on its implications for evolution. Ithaca, N.Y.: Cornell University Press, 1992.
Gould, Stephen Jay, and Niles Eldredge. Punc- Provides an overview of the punctuated
tuated Equilibrium: The Tempo and Mode equilibrium debate, including updates by
of Evolution Reconsidered. Paleobiology 3 Gould and Eldredge. Bibliography, index.
Quantitative Inheritance was described early in the twentieth century
Field of study: Population genetics when Swedish plant breeder Herman Nilsson-
Significance: Quantitative inheritance involves Ehle crossed red and white wheat. The resulting
metric traits. These traits are generally associated progeny were light red in color. When matings
with adaptation, reproduction, yield, form, and were made within the progeny, the resulting
function. They are thus of great importance to evo- kernels of wheat ranged in color from white to
lution, conservation biology, psychology, and espe- red. He was able to categorize the wheat into
cially to the improvement of agricultural organ- five colors: red, intermediate red, light red,
isms. pink, and white. Intermediate colors occurred
with greater frequency than extreme colors.
Key terms Nilsson-Ehle deduced that particulate genetic
genotype: the genetic makeup of an organism factors (now known as alleles) were involved,
at all loci that affect a quantitative trait with red wheat inheriting four red alleles, inter-
heritability: the proportion of phenotypic mediate red inheriting three red alleles, light
differences among individuals that are a re- red inheriting two red alleles, pink inheriting
sult of genetic differences one red allele, and white inheriting no red al-
metric traits: traits controlled by multiple leles. These results were consistent with Men-
genes with small individual effects and con- dels findings, except that two sets of factors
tinuously varying environmental effects, re- (now known as loci) were controlling this trait
sulting in continuous variation in a popula- rather than the single locus observed for the
tion traits considered by Mendel. Further, these re-
phenotype: the observed expression of a ge- sults could be generalized to account for addi-
notype that results from the combined ef- tional inheritance patterns controlled by more
fects of the genotype and the environment than two loci. Quantitative inheritance was
to which the organism has been exposed mathematically described by British statistician
and geneticist Ronald A. Fisher.
The Genetics Underlying Metric Traits Under many circumstances, the environ-
An understanding of the genetics affecting ment also modifies the expression of traits. A
metric traits came with the unification of the combination of many loci with individually
Mendelian and biometrical schools of genetics small effects alone would produce a rough bell-
early in the 1900s. The statistical relationships shaped distribution for a quantitative trait. En-
involved in inheritance of metric traits such as vironmental effects are continuous and are in-
height of humans were well known in the late dependent of genetic effects. Environmental
1800s. Soon after that, Gregor Mendels break- effects blur the boundaries of the genetic cate-
through on particulate inheritance, obtained gories and can make it difficult or impossible to
from work utilizing traits such as colors and identify the effects of individual loci for many
shapes of peas, was rediscovered. However, quantitative traits. The distribution of pheno-
some traits did not follow Mendelian inheri- types, reflecting combined genetic and envi-
tance patterns. As an example, Francis Galton ronmental effects, is typically a smooth, bell-
crossed pea plants having uniformly large shaped curve.
seeds with those having uniformly small seeds. Genetic and environmental effects jointly
The seed size of the progeny was intermediate. influence the value of most metric traits. The
However, when the progeny were mated relative magnitudes of genetic and environ-
among themselves, seed size formed a distribu- mental effects are measured using heritability
tion from small to large with many intermedi- statistics. Although essentially equivalent, heri-
ate sizes. tability has several practical definitions. One
How could particulate genetic factors ex- definition states that heritability is equal to the
plain a continuous distribution? The solution proportion of observed differences among or-
Quantitative Inheritance 655
ganisms for a trait due to genetic differences. regarding incestuous relationships in humans
For example, if one-quarter of the differences and for the dispersal systems for some other
among cows for the amount of milk they pro- species of mammals such as wolves. Physiologi-
duce are caused by differences among their ge- cal barriers have evolved to prevent fertiliza-
notypes, the heritability of milk production is tion between close relatives in many species of
25 percent. The remaining 75 percent of differ- plants. Some mechanisms function as an ana-
ences among the animals are attributed to envi- tomical inhibitor to prevent union of pollen
ronmental effects. An alternative definition is and ova from the same plant; in maize, for ex-
that heritability is equal to the proportion of ample, the male and female flower are widely
differences among sets of parents that are separated on the plant. Indeed, in some spe-
passed on to their progeny. For example, if the cies such as asparagus and holly trees, the sexes
average height of a pair of parents is 8 inches are separated in different individuals; thus all
(20 centimeters) more than the mean of their seeds must consequently result from cross-
population and the heritability of height is 50 pollination. In other systems, cross-pollination
percent, their progeny would be expected to is required for fertile seeds to result. The pol-
average 4 inches (10 centimeters) taller than len must originate from a plant genetically dif-
their peers in the population. ferent from the seed parent. These phenom-
ena are known as self-incompatibility and are
Fundamental Relationships of present in species such as broccoli, radishes,
Quantitative Genetics some clovers, and many fruit trees.
Two relationships are fundamental to the The corollary to inbreeding depression is
understanding and application of quantitative hybrid vigor, a phenomenon of improved fit-
genetics. First, there is a tendency for likeness ness that is often evident in progeny resulting
among related individuals. Although similari- from the mating of individuals less related than
ties of human stature and facial appearance the average in a population. Hybrid vigor has
within families are familiar to most people, sim- been utilized in breeding programs to achieve
ilar relationships hold for such traits in all or- remarkable productivity of hybrid seed corn as
ganisms. Correlation among relatives exists for well as crossbred poultry and livestock. Hybrid
such diverse traits as blood pressure, plant vigor results in increased reproduction and
height, grain yield, and egg production. These efficiency of nutrient utilization. The mule,
correlations are caused by relatives sharing a which results from mating a male donkey to a
portion of genes in common. The more closely female horse, is a well-known example of a hy-
the individuals are related, the greater the pro- brid that has remarkable strength and hardi-
portion of genes that are shared. Identical ness compared to the parent species, but which
twins share all their genes, and full brothers is, unfortunately, sterile.
and sisters or parent and offspring are ex-
pected to share one-half their genes. This rela- Quantitative Traits of Humans
tionship is commonly utilized in the improve- Like other organisms, many traits of humans
ment of agricultural organisms. Individuals are are quantitatively inherited. Psychological
chosen to be parents based on the perfor- characteristics, intelligence quotient (IQ), and
mance of their relatives. For example, bulls of birth weight have been studied extensively. The
dairy breeds are chosen to become widely used heritability of IQ has been reported to be high.
as sires based on the milk-producing ability of Other personality characteristics such as inci-
their sisters and daughters. dence of depression, introversion, and enthusi-
The second fundamental relationship is asm have been reported to be highly heritable.
that, in organisms that do not normally self- Musical ability is another characteristic under
fertilize, vigor is depressed in progeny that some degree of genetic control. These results
result from the mating of closely related indi- have been consistent across replicated studies
viduals. This effect is known as inbreeding de- and are thus expected to be reliable; however,
pression. It may be the basis of the social taboos some caution must be exercised when consid-
656 Quantitative Inheritance
ering the reliability of results from individual access to high-quality grain rations, and protec-
studies. Most studies of heritability in humans tion from extremes of heat and cold, may not
have involved likeness of twins reared together be ideal under conditions in New Zealand in
and apart. The difficulty in obtaining such data which cattle are required to compete with
results in a relatively small sample size, at least herdmates for high-quality pasture forage. Nei-
relative to similar experiments in animals. An ther of these animals may be ideal under tropi-
unfortunate response to studies of quantitative cal conditions where extremely high tempera-
inheritance in humans was the eugenics move- tures, disease, and parasites are common.
ment. Remarkable progress has been made in
Birth weight of humans is of interest because many important food crops. Grain yield has re-
it is both under genetic control and subject to sponded to improvement programs. Develop-
influence by well-known environmental fac- ment of hybrid corn increased yield several-
tors, such as smoking by the mother. Birth fold over the last few decades of the twentieth
weight is subject to stabilizing selection, in century. Development of improved varieties of
which individuals with intermediate values small grains resulted in an increased ability of
have the highest rates of survival. This results in many developing countries to be self-sufficient
genetic pressure to maintain the average birth in food production. Grain breeder Norman
weight at a relatively constant value. Borlaug won the Nobel Peace Prize in 1970 for
his role in developing grain varieties that con-
Quantitative Characters in Agricultural tributed to the Green Revolution.
Improvement Can breeders continue to make improve-
The ability to meet the demand for food by a ments in the genetic potential for crops, live-
growing world population is dependent upon stock, and fish to yield enough food to support
continuously increasing agricultural produc- a growing human population? Tools of bio-
tivity. Reserves of high-quality farmland have technology are expected to increase the rate at
nearly all been brought into production, and a which breeders can make genetic change. Ulti-
sustainable increase in the harvest of fish is mately, the answer depends upon the genetic
likely impossible. Many countries that struggle variation available in the global populations of
to meet the food demands of their populations food-producing organisms and their wild rela-
are too poor to increase agricultural yields tives. The potential for genetic improvement of
through increased inputs of fertilizer and some species has been relatively untapped. Do-
chemicals. Increased food production will, mestication of fish for use in aquaculture and
therefore, largely depend on genetic improve- utilization of potential crop species such as am-
ment of the organisms produced by farmers aranth are possible food reserves. Wheat, corn,
worldwide. and rice provide a large proportion of the calo-
Most characteristics of economic value in ag- ries supporting the world population. The yields
riculturally important organisms are quantita- of these three crop species have already bene-
tively inherited. Traits such as grain yield, bak- fited from many generations of selective breed-
ing quality, milk and meat production, and ing. For continued genetic improvement, it is
efficiency of nutrient utilization are under the critical that variation not be lost through the
influence of many genes as well as the produc- extinction of indigenous strains and wild rela-
tion environment. The task of breeders is not tives of important food-producing organisms.
only to identify organisms with superior ge-
netic characteristics but also to identify those Impact and Applications
breeds and varieties well adapted to the specific Molecular genetics and biotechnology have
environmental conditions in which they will be also added new tools for analyzing the genetics
produced. The type of dairy cattle that most ef- of quantitative traits. In any organism that has
ficiently produces milk under the normal pro- had its genome adequately mapped, genetic
duction circumstances in the United States, markers can be used to determine the number
which includes high health status, unlimited of loci involved in a particular trait. In carefully
Quantitative Inheritance 657
constructed crosses geneticists look for statisti- versy surrounds them, and ethicists continue to
cal correlations between markers and the trait worry that conclusions from such research will
of interest. When a high correlation is found, be used in a new wave of eugenics. In spite of
the marker is said to represent a quantitative the risk of misusing an improved understand-
trait locus (QTL). Often a percentage effect for ing of human quantitative traits, human biol-
each QTL can be determined and because the ogy and medicine stand to benefit.
location of markers is typically known, the po- William R. Lamberson, updated by Bryan Ness
tential location of the gene can also be inferred See also: Artificial Selection; Biofertilizers;
(that is, somewhere near the marker). A good Consanguinity and Genetic Disease; Epistasis;
understanding of the QTLs involved in the ex- Genetic Load; Hardy-Weinberg Law; Hybridi-
pression of a quantitative trait can help deter- zation and Introgression; Inbreeding and Assor-
mine the best way to improve the organism. tative Mating; Mendelian Genetics; Polygenic
Although QTLs are much easier to discover Inheritance; Population Genetics; Speciation;
in organisms where controlled crosses are pos- Twin Studies.
sible, studies have also been carried out in hu-
mans. In humans, geneticists must rely on
whatever matings have happened, and due to Further Reading
ethical limitations, cannot set up specific Falconer, D. S., and Trudy F. MacKay. Introduc-
crosses. Studies in humans have attempted to tion to Quantitative Genetics. 4th ed. Reading,
quantify the number of QTLs responsible for Mass.: Addison-Wesley, 1996. The standard
such things as IQ and various physical traits. text on the subject, outlining the genetics of
One study even purported to show that homo- differences in quantitative phenotypes and
sexuality is genetically based. Although there is their applications to animal breeding, plant
some support for such studies, much contro- improvement, and evolution.
4=?A races were chiefly caused by differences in envi-
Field of study: Human genetics and social ronment. Therefore, his scheme sought to show
issues a gradual change in bodily appearance, all devi-
Significance: Humans typically have been catego- ating from an original type. Blumenbach main-
rized into a small number of races based on common tained that the original forms, which he named
traits, ancestry, and geography. Knowledge of hu- Caucasian, were those primarily of European
man genomic diversity has increased awareness of ancestry. His final classification, published in
ambiguities associated with traditional racial 1795 in On the Natural Variety of Mankind, con-
groups. The sociopolitical consequences of using ge- sisted of five races: Caucasian, Malay, Ethio-
netics to devalue certain races are profound, and pian, American, and Mongolian. Two races di-
based on the available data, are completely baseless. rectly radiated from the Caucasians: the Malay
and the American. The Malay (Pacific island-
Key terms ers) then generated the Ethiopian (Africans),
eugenics: a movement concerned with the im- while the American (from the New World) gave
provement of human genetic traits, predom- rise to the Mongolian (East Asians). The fifth
inantly by the regulation of mating race, the Malay, was added to Linnaeuss classi-
Human Genome Diversity Project: an ex- fication to show a step-by-step change from the
tension of the Human Genome Project in original body type.
which DNA of native people around the After Linnaeus and Blumenbach, many vari-
world is collected for study ations of their categories were formulated,
population: a group of geographically local- chiefly by biologists and anthropologists. Clas-
ized, interbreeding individuals sification lumpers combined people into
race: a collection of geographically localized only a few races (for example, black, white, and
populations with well-defined genetic traits Asian). Splitters separated the traditional
groups into many different races. One classifi-
History of Racial Classification cation scheme divided all Europeans into Al-
Efforts to classify humans into a number of pine, Nordic, and Mediterranean races. Others
distinct types date back at least to the ancient split Europeans into ten different races. No
Greeks. Applying scientific principles to sepa- one scheme of racial classification came to be
rate people into races has been a goal for more accepted throughout the scientific community.
than two centuries. In 1758, the founder of bio-
logical classification, Swedish botanist Carolus Genetic Diversity Among Races
Linnaeus, arranged humans into four princi- The genetic components of a population are
pal races: Americanus, Europeus, Asiaticus, and produced by three primary factors: natural se-
Afer. Although geographic location was his pri- lection, nonadaptive genetic change, and mat-
mary organizing factor, Linnaeus also de- ing between neighboring populations. The first
scribed the races according to subjective traits two factors may result in differences between
such as temperament. Despite his use of ar- populations, and reproductive isolation, either
chaic criteria, Linnaeus did not give superior voluntary or because of geographic isolation,
status to any of the races. perpetuates the distinctions. Natural selection
Johann Friedrich Blumenbach, a German refers to the persistence of genetic traits favor-
naturalist and admirer of Linnaeus, developed able in a specific environment. For example, a
a classification with lasting influence. Many widely held assumption concerns skin color,
of his contemporaries believed that different primarily a result of the pigment melanin. Mel-
groups of humans arose separately in several anin offers some shielding from ultraviolet so-
regions of the world. Blumenbach, on the other lar rays. According to this theory, people living
hand, strongly believed in one form of human in regions with concentrated ultraviolet expo-
and believed that physical variations among sure have increased melanin synthesis and,
Race $#'
therefore, dark skin color conferring additional Africa is unequaled with respect to cumulative
protection against skin cancer. Individuals with genetic diversity. If overall genetic distinctness
genes for increased melanin have enhanced is evaluated, numerous races are found in Af-
survival rates and reproductive opportunities. rica, Khoisan Africans of southern Africa being
The reproductive opportunities produce off- the most distinct. According to one theory, the
spring that inherit those same genes for in- remainder of the human species (including
creased melanin. This process results in a higher Asians, Europeans, and aboriginal Australians)
percentage of the population with elevated mel- corresponds to only one other race.
anin production genes. Therefore, genes cod-
ing for melanin production are favorable and Conflicts Concerning Definitions of Race
persist in these environments. Linnaeus developed a scientific system of
The second factor contributing to the ge- classification that is fundamentally still in use.
netic makeup of a population is nonadaptive This approach involves separating all organisms
genetic change. This process involves random first into broad groups based on general charac-
genetic mutations. Mutations are changes re- teristics. These large groups are broken down
sulting in modified forms of the same gene. For further into smaller and smaller groups, each
example, certain genes are responsible for eye subdivision containing individuals with more
color. Individuals contain alternate forms of similarities. For example, humans are found
these genes, or alleles, which result in observed within the large kingdom containing all types of
differences in eye color. Alleles resulting from animals. Animals are separated based on the for-
nonadaptive genetic change may remain in the mation of a backbone. Of those animals con-
population because of their neutral nature. In taining a backbone, humans are placed into a
other words, they are not harmful or beneficial. set with all mammals and then further cataloged
Because these traits are impartial to environ- with other primates. Each succeeding classifica-
mental influences, they may endure from gen- tion unit contains individuals more alike, since
eration to generation. Different populations the characteristics used to define each subdivi-
will spontaneously produce, persist, and delete sion are more specific. Eventually, all organisms
them. Genetic difference between populations are placed into a species category. Humans be-
caused by these random mutations and isola- long in the species Homo sapiens. By definition, a
tion is called genetic drift. sexually reproducing species contains all indi-
The third factor, mating between individuals viduals that can mate and produce fertile off-
from neighboring groups, tends to merge traits spring. Race is analogous to a more specific unit,
from several populations. This genetic mixing the subspecies, a fundamentally distinct sub-
often results in offspring with blended charac- group within one species.
teristics and only moderate variations between For a racial or subspecies classification
adjacent groups. scheme to be objective and biologically mean-
Several studies have compared the overall ingful, researchers must decide carefully which
genetic complement of various human popula- heritable characteristics (passed to future gen-
tions. On average, any two people of the same erations genetically) will define, or separate,
or a different race diverge genetically by a mere the races. Several principles are considered.
0.2 percent. It is estimated that only 0.012 per- First, the discriminating traits must be discrete.
cent contributes to traditional racial variations. In other words, differences among races must
Hence, most of the genetic dissimilarities be- be distinguishable, not continually changing
tween a person of African descent and a person by small degrees between populations. Second,
of European descent are also different between everyone placed within a specific race must
two individuals with the same ancestry. The possess the selected traits defining variant.
genes do not differ. It is the proportion of indi- Features used to describe a race must agree.
viduals expressing a specific allele of a gene This means that all of the selected characteris-
that varies from population to population. tics are found consistently in each member. For
Upon closer examination, it was found that example, if blue eyes and brown hair are cho-
660 Race
sen as defining characteristics, everyone desig- principles of subspecies classification. For ex-
nated as belonging to that race must share both ample, the traits used to define traditional hu-
of those characteristics. Individuals placed in man races are rarely discrete. Skin color, a
other races should not exhibit this particular prominent characteristic employed, is not a
combination. The purpose of using these char- well-defined trait. Approximately five genes in-
acteristics is to distinguish groups. Conse- fluence skin color significantly, but fifty or so
quently, if traits are shared by members of two likely contribute. Pigmentation in humans re-
or more races, their defining value is poor. sults from a complex series of biochemical
Third, individuals of the same race must have pathways regulated by amounts of enzymes
descended from a common ancestor, unique to (molecules that control chemical reactions)
those people. Many shared characteristics pres- and enzyme inhibitors, along with environ-
ent in individuals of a race may be traced to that mental factors. Like most complex traits involv-
ancestor by heredity. Based on the preceding ing many genes, human skin color varies on a
defining criteria (selection of discrete traits, continuous gradation. From lightest to darkest,
agreement of traits, and common ancestry), all intermediate pigmentations are repre-
pure representatives of each racial category sented. Color may vary widely even within the
should be detectable. same family. The boundary between black and
Many researchers maintain that traditional white is an arbitrary, human-made border, not
races do not conform to accepted scientific one imposed by nature.
On average, any two people of the same or a different race diverge genetically by a mere 0.2 percent, and only 0.012 percent contribute
to traditional racial variations. Allelic variations account for most of the superficial differences perceived as race. (U.S. Depart-
ment of Energy Human Genome Program, http://www.ornl.gov/hgmis)
Race 661
In addition, traditional defining racial char- drion contains a single, circular DNA molecule
acteristics, such as skin color and facial charac- accounting for approximately 0.048 percent of
teristics, are not found in all members of a race; the entire genetic complement. In 1987, genet-
they are not in agreement. For example, many icist Rebecca L. Cann compared mitochon-
Melanesians, indigenous to Pacific islands, drial DNA from many populations: African,
have pigmentation as dark as any human but Asian, Caucasian, Australian, and New Guinean.
are not classified as black. Another example Agreeing with other mitochondrial and nu-
concerns unclassifiable populations. For exam- clear DNA studies, the results indicated that
ple, many individuals native to India have Africans were the most genetically variable by
Caucasoid facial features and very dark skin, a significant extent. The results suggested to
yet live in Asia. When traditional racial charac- Cann that Africa was the root of all humankind
teristics are examined closely, many groups are and that humans first arose there 100,000 to
left with no conventional race. No pure ge- 200,000 years ago. Several lines of research, in-
netic representatives of any traditional race cluding DNA analysis of humanoid fossils, pro-
exist. vide evidence for this theory.
Common ancestry, or evolutionary relation- Many scientists are using genetic markers to
ships, must also be considered. Genetic studies decipher the migrations that fashioned past
have shown that Africans do not belong to a sin- and present human populations. For example,
gle black heritage. In fact, several lineages are DNA comparisons revealed three Native Amer-
found in Africa. An even greater variance is ican lineages. Some scientists believe one mi-
found in African Americans. Besides a diverse gration crossed the Bering Strait, most likely
African ancestry, it is estimated that, on aver- from Mongolia. Only after further migration
age, 20 to 30 percent of African American heri- throughout the Americas were the three Amer-
tage is European or Native American. Yet all ican Indian lineages formed. Another theory
black Americans are consolidated into one states that three separate Asian migrations oc-
race. curred, each bringing a different lineage. An-
The true diversity found in humans is not other example is the South African Lemba
patterned according to accepted standards of community. DNA analysis gives credence to
the subspecies. Only at extreme geographical their claim as one of the lost tribes of Israel.
distances are notable differences found. How- Considering the cumulative evidence, many
ever, in-between populations have always scientists regard a more correct depiction of
been in existence because of mating, and human populations to be a roughly inverted
therefore gene flow, between neighboring version of Blumenbachs. Asians arose from Af-
groups. Consequently, human populations in ricans, and Europeans are Asian and North Af-
close proximity have more genetic similarities rican hybrids. However, interpretations of
than distant populations. It is the population it- DNA analyses are, almost inevitably, controver-
self that best illustrates the pattern of human sial. Multiple theories abound and are revised
diversity. Well-defined genetic borders be- as additional research is performed.
tween human populations are not observed,
and racial boundaries in classification schemes Sociopolitical Implications
are often formed arbitrarily. Race is often portrayed as a natural, biologi-
cal division, the result of geographic isolation
Theories of Human and Racial Evolution and adaptation to local environment. However,
Advances in DNA technology have greatly confusion between biological and cultural clas-
aided researchers in their quest to reconstruct sification obscures perceptions of race. When
the history of Homo sapiens and its various sub- individuals describe themselves as black,
groups. Analysis of human DNA has been per- white, or Hispanic, for example, they are
formed on both nuclear and mitochondrial usually describing cultural heredity as well as
DNA. Mitochondria are organelles responsible biological similarities. The relative importance
for generating cellular energy. Each mitochon- of perceived cultural affiliations or genetics
662 Race
Descendants of Sally Hemings, an African American slave of Thomas Jefferson who is known by DNA evidence to have had children
by him, pose at Jeffersons home, Monticello, during a July, 2003, reunion. (AP/Wide World Photos)
undertaking, has requested that researchers single intelligence and that cognitive ability
collect and store DNA from indigenous popu- is shaped through education. Bibliography,
lations around the world. These samples will be index.
available to all qualified scientists. Results of Fraser, Steven, ed. The Bell Curve Wars: Race,
the studies may include gene therapy treat- Intelligence, and the Future of America. New
ments and greater success with organ trans- York: Basic Books, 1995. Brief, critical re-
plantation. A more thorough understanding of sponse to the book by Herrnstein and
the genetic diversity and unity in the species Murray by scholars from a variety of disci-
Homo sapiens will as a result be possible. plines and backgrounds. Bibliography.
Stacie R. Chismark Gates, E. Nathaniel, ed. The Concept of Race in
See also: Biological Determinism; Eugen- Natural and Social Science. New York: Gar-
ics; Eugenics: Nazi Germany; Evolutionary Bi- land, 1997. Argues that the concept of race,
ology; Genetic Engineering: Social and Ethical as a form of classification based on physical
Issues; Heredity and Environment; Intelligence; characteristics, was arbitrarily conceived dur-
Miscegenation and Antimiscegenation Laws; ing the Enlightenment and is without scien-
Sociobiology; Sterilization Laws. tific merit. Illustrations, map, bibliography.
Gould, Stephen Jay. The Mismeasure of Man. Rev.
Further Reading ed. New York: W. W. Norton, 1996. Presents
Cavalli-Sforza, Luigi L. The Great Human Diaspo- a historical commentary on racial categori-
ras: A History of Diversity and Evolution. Trans- zation and a refutation of theories espousing
lated by Serah Thorne. Reading, Mass.: a single measure of genetically fixed intelli-
Addison-Wesley, 1995. Argues that humans gence. Bibliography, index.
around the world are more similar than dif- Graves, Joseph L., Jr. The Emperors New Clothes:
ferent. Basing his discussion on a study of ge- Biological Theories of Race at the Millennium.
netic data of fifteen populations from five New Brunswick, N.J.: Rutgers University
continents, the author explains how human Press, 2001. Argues for a more scientific ap-
groups colonized the earth 100,000 years proach to debates about race, one that takes
ago. Illustrations, maps, bibliography, index. human genetic diversity into account. Illus-
Cavalli-Sforza, Luigi L., et al. The History and trations, bibliography, index.
Geography of Human Genes. Princeton, N.J.: Herrnstein, Richard J., and Charles Murray.
Princeton University Press, 1996. Often re- The Bell Curve: Intelligence and Class Structure
ferred to as a genetic atlas, this volume con- in America. New York: Free Press, 1994. The
tains fifty years of research comparing heri- authors maintain that IQ is a valid measure
table traits, such as blood groups, from more of intelligence, that intelligence is largely a
than one thousand human populations. Il- product of genetic background, and that dif-
lustrations, maps, bibliography, index. ferences in intelligence among social classes
Devlin, Bernie, et al. Intelligence, Genes, and Suc- play a major part in shaping American soci-
cess: Scientists Respond to The Bell Curve. New ety. Illustrations, bibliography, index.
York: Springer, 1997. Presents a scientific Kevles, Daniel J. In the Name of Eugenics: Genetics
and statistical reinterpretation of the argu- and the Uses of Human Heredity. Cambridge,
ments by Richard Herrnstein and Charles Mass.: Harvard University Press, 1995. Dis-
Murray, in their book The Bell Curve (see be- cusses genetics both as a science and as a so-
low), about the heritability of intelligence cial and political perspective, and how the
and about IQ and social success. Bibliogra- two often collide to muddy the boundaries
phy, index. of science and opinion.
Fish, Jefferson M., ed. Race and Intelligence: Sepa- Valencia, Richard R., and Lisa A. Suzuki. Intelli-
rating Science from Myth. Mahwah, N.J.: Law- gence Testing and Minority Students: Founda-
rence Erlbaum, 2002. An interdisciplinary tions, Performance Factors, and Assessment Issues.
collection disputing race as a biological cate- Thousand Oaks, Calif.: Sage, 2000. Histori-
gory and arguing that there is no general or cal and multicultural perspective on intelli-
664 Repetitive DNA
gence and its often assumed relation with so- variable number tandem repeat (VNTR): a
cioeconomic status, home environment, test type of DNA sequence in which a short se-
bias, and heredity. Illustrations, bibliogra- quence is repeated over and over; chromo-
phy, index. somes from different individuals frequently
have different numbers of the basic repeat,
Web Sites of Interest and if many of these variants are known, the
Genetics and Identity Project. http://www.bio sequence is termed a hypervariable
ethics.umn.edu/genetics_and_identity. Proj-
ect looks at the ways genetic research affects
racial, ethnic, and familial identities. Types of Repetitive DNA
Human Genome Project Research Institute, The nuclear genomes of eukaryotes are
Minorities, Race, and Genomics. http://www characterized by repetitive DNA elements con-
.ornl.gov/techresources/human_genome/ sisting of nucleotide sequences that vary in
elsi/minorities.html. Site provides informa- length and base composition and that are local-
tion on race and genetic research, particu- ized to a particular region of the genome or dis-
larly on how that research affects minority persed throughout the genome (for example,
communities. on different chromosomes). Some repetitive
National Academies Press, Evaluating Human DNA elements are found in the genome a few
Genetic Diversity. http://www.nap.edu. A times, whereas others may be repeated millions
free, downloadable book on human genetic or billions of times; thus, the percentage of the
diversity, which includes the chapter Hu- total genome represented by repetitive DNA
man Rights and Human Genetic-Variation varies widely among taxa.
Research. There are two major classes of tandem repet-
itive DNAs (TR-DNAs): those that are localized
to a particular region (or regions) of the ge-
nome and those that are dispersed throughout
Repetitive DNA the genome. TR-DNAs are composed of repeat-
ing units that are oriented in head-to-tail ar-
Field of study: Molecular genetics rays. The repetitive units of an array may in-
Significance: Eukaryotic nuclei contain repetitive clude genes, promoters, and intergenic spacers
DNA elements of different origin, which constitute or repeats of simple nucleotide sequences. For
between 20 and 90 percent of the genome depend- example, in the kangaroo rat the simple se-
ing on the species. The presence and type of repeti- quence AAG is repeated 2.4 billion times.
tive DNA elements have provided insights into Localized TR-DNA is often composed of
gene flow, forensic investigations, biomedicine, members of multigene families. For example,
and genomic mapping. in humans there are 350 copies of the ribo-
somal RNA (rRNA) genes on five different
Key terms chromosomes that occur as tandemly repeated
nucleotide: the basic unit of DNA, consisting arrays. Transfer RNA (tRNA) and immuno-
of a five-carbon sugar, a nitrogen-containing globin genes represent other examples of
base, and a phosphate group multigene families that are tandemly repeated.
polymorphism: the presence of many differ- However, most localized TR-DNA consists of
ent alleles for a particular locus in individu- simple, noncoding repetitive DNA sequences
als of the same species that often, but not always, can be found in
retrotransposition: a subset of the repli- heterochromatic or centromeric regions.
cative transposable elements that transpose Dispersed TR-DNA sequences are scattered
through an RNA intermediate throughout the genome and can be divided
tandem repetitive DNA (TR-DNA): DNA are into two major groups: short interspersed ele-
composed of repeating units that are ori- ments (SINEs) and long interspersed repeats
ented in head-to-tail arrays (LINEs).
Repetitive DNA 665
Origin and Evolution of Dispersed DNA that is typically found in centromeric regions.
Elements Units of between nine and one hundred nucle-
SINEs are nonviral retropseudogenes that otides that are tandemly repeated ten to one
were derived from genes encoding small, un- hundred times and scattered throughout the
translated RNAs (for example, tRNAs). The genome are known as minisatellites. Microsat-
RNA transcript was reverse transcribed into ellites are also dispersed elements composed of
DNA and then was inserted into the genome. short repeats of a basic unit one to six nucleo-
In their current state, although they resemble tides in length that is tandemly repeated ten to
the genes they were from which they derived, one hundred times at each locus. The most
they no longer function properly. SINEs are common microsatellite loci in humans are di-
also examples of transposable elements capa- nucleotide arrays of (CA)N. However, on aver-
ble of jumping from one locus to another via age there is at least one tri- or tetranucleotide
an RNA intermediate. microsatellite locus per 10 kb of human ge-
The best-characterized SINEs in humans are nomic DNA. Finally, the basic unit of dispersed
highly repetitive Alu sequences, so named be- Alu sequences is one to five nucleotides in
cause they are cleaved multiple times by the length, and this unit is repeated ten to forty
endonuclease AluI, derived from the bacte- times per locus.
rium Arthrobacter luteus. Between 500,000 and
1 million Alu copies are scattered across the hu- Polymorphism at Loci Composed of
man genome, each approximately three hun- Simple Tandem Repeats
dred nucleotides in length. Alu sequences may For purposes of convenience, the four
constitute as much as 5 percent of the human groups of simple tandem repeats discussed
genome. above (satellite DNA, minisatellites, microsat-
LINEs are derived from a viral ancestor and ellites, and Alu sequences) are sometimes col-
are also capable of transposition. The most lectively referred to as variable number tandem
common LINE element in humans, constitut- repeats (VNTRs).
ing 5 percent of the human genome, is termed Separate VNTR loci are thought of as alleles;
L1. There are about 200,000 copies of L1 in therefore, in humans each VNTR locus will be
each diploid cell. Full-length, functional (that represented by two alleles, one paternal and
is, transpositionally competent) L1 elements the other maternally inherited. All VNTR loci
are approximately 6 kilobase pairs (kb) in exhibit high rates of mutation. For these rea-
length, but most copies of L1 are truncated at sons, VNTR loci are highly polymorphic, that
the 5 end and incapable of moving. Full-length is, there are a large number of alleles at any
L1 copies contain two protein-coding regions, given locus. This polymorphism can be assayed
or open reading frames (ORFs): ORF-1 and using laboratory techniques such as polymer-
ORF-2. ORF-1 encodes an RNA-binding pro- ase chain reaction (PCR) or Southern blotting
tein, and ORF-2 codes for reverse transcriptase. to examine the differences in the lengths of
the alleles (repetitive elements) at a particular
Classification of Simple Tandem Repeats locus.
Simple sequences that are tandemly re- Length differences at VNTR loci arise as a re-
peated are classified into four major groups sult of mispairing of repeats during replication,
based on three characteristics: the number of mitosis, or meiosis theoretically resulting in the
nucleotides in the repetitive unit, the number loss or gain of one to many of the repeat units.
of times the unit is repeated, and whether or Empirical studies and computer-based model-
not the element is localized or scattered across ing experiments have demonstrated that each
the genome. Satellite DNA is composed of ba- mutation usually increases or decreases the
sic units, ranging from two to hundreds of nu- number of repeated units of an allele in a one-
cleotides in length, that are repeated more step manner. In other words, most mutations
than one thousand times. Satellite DNA repre- result in the loss or gain of only one repeated
sents an example of a localized simple repeat unit.
666 Repetitive DNA
The multiallelic variation that arises through Transposable Elements and Human
variation in repeat copy number provides ge- Disease
netic markers useful for many different appli- Retrotranspositions of LINEs and SINEs
cations. For example, under conditions of ran- into coding or noncoding genomic DNAs rep-
dom mating and because of high mutation resent major insertional mutations. The effects
rates at VNTR loci, most individuals within the of such insertions vary but are usually deleteri-
human population are heterozygous at any se- ous, leading to debilitating human diseases.
lected VNTR locus. This observation directly Among a growing list of diseases known in
led to the origin of DNA fingerprinting (or some cases to be caused by the insertion of
DNA profiling), which is now considered ad- LINEs or SINEs are Duchenne muscular dys-
missible forensic evidence in many judicial sys- trophy, Glanzmann thrombasthenia, hemo-
tems worldwide. Length variation of VNTRs philia, hypercholesterolemia, neurofibromato-
creates a powerful tool for identity analysis (for sis, Sandhoff disease, and Tay-Sachs disease.
example, paternity testing) and is routinely Translocation of repeated sequences has also
used by population geneticists to examine gene been demonstrated to turn on tumorogenic
flow among populations. In the fields of ge- oncogenes (for example, one type of colon
nomics and biomedicine, VNTR loci are use- cancer).
ful genetic landmarks for mapping the loca- Other studies have shown that unstable
tion of other genes of interest, that is, those minisatellite, microsatellite, and Alu loci can
with a particular function or others implicated also cause disease. In short, there seems to be a
in disease. threshold number of repeats of the basic nucle-
otide unit that can be accommodated at a given
locus. When this threshold is exceeded by
Are Interspersed Repeated Elements overamplification of the basic repeated unit,
Junk DNA? serious diseases may arise. Among those dis-
Repeated DNA elements were once believed eases attributed to overamplification of tan-
to be selfish or junk DNA, concerned only dem repeats of simple sequences are fragile X
with their own proliferation within the host syndrome and Huntingtons disease.
cells genome. Recent studies, however, reveal J. Craig Bailey
that repetitive elements interact with the ge- See also: Aging; Anthrax; Chromosome
nome with profound evolutionar y conse- Structure; Chromosome Walking and Jump-
quences. For example, satellite DNA found ing; DNA Fingerprinting; Gene Families; Ge-
near the centromere may play a role in assem- nome Size; Genomics; Human Genetics; Model
bling and fusing chromosomal microtubules Organism: Neurospora crassa; Molecular Clock
during cell division. It is also now clear that Hypothesis; Pseudogenes; RFLP Analysis; Telo-
transposable genetic elements such as SINEs, meres.
LINEs, and Alu sequences may have played a
significant role in the evolution of particular Further Reading
proteins. For example, Alu elements flanking Li, Wen-Hsiung. Molecular Evolution. Sunder-
the primordial human growth hormone gene land, Mass.: Sinauer Associates, 1997. Pro-
are responsible for the evolution of a relatively vides a basic introduction to the different
new member of the gene family, the chorionic types of variable tandem repeats, their uses
somatomammotropin gene. Transposable re- in the biological sciences, and how they af-
peated elements may have contributed sub- fect genome organization.
stantially to the origin of new gene functions by Maichele, A. J., N. J. Farwell, and J. S. Cham-
initiating a copy of an existing gene (which, berlain. A B2 Repeat Insertion Generates
over time, can acquire a different function) or Alternate Structures of the Mouse Muscle
by creating composite genes composed of do- Gamma-phosphorylase Kinase Gene. Ge-
mains from two or more previously unrelated nomics 16, no. 1 (1993): 139-149. An excellent
genes. example of how retrotransposition of repeti-
Restriction Enzymes 667
tive DNA elements may alter the function of, dictable pattern. This nuclease, HindII, was the
or give rise to, new structural proteins. first restriction endonuclease or restriction en-
Maraia, Richard J., ed. The Impact of Short Inter- zyme. Smith was working with the bacterium
spersed Elements (SINEs) on the Host Genome. Haemophilus influenzae (H. influenzae) when he
Austin, Tex.: R. G. Landes, 1995. A compre- discovered this enzyme, which was capable of
hensive treatise on the origin, evolution, and destroying DNA from other bacterial species
functional roles that SINEs play in the biol- but not the DNA of H. influenzae itself. The
ogy of organisms and in biomedicine. term restriction refers to the apparent role
these enzymes play in destroying the DNA of
invading bacteriophages (bacterial viruses),
while leaving the bacterial cells own DNA un-
Restriction Enzymes touched. A bacterium with such an enzyme was
said to restrict the host range of the bacterio-
Fields of study: Genetic engineering and phage.
biotechnology; Molecular genetics As more restriction enzymes from a wide va-
Significance: Restriction enzymes are bacterial en- riety of bacterial species were discovered in the
zymes capable of cutting DNA molecules at specific 1970s, it became increasingly clear that these
nucleotide sequences. Discovery of these enzymes enzymes could be useful for creating and ma-
was a pivotal event in the development of genetic nipulating DNA fragments in unique ways.
engineering technology, and they are routinely and What was not clear, however, was how these en-
widely used in molecular biology. zymes were able to distinguish between bacte-
riophage DNA and the bacterial cells own
Key terms DNA. A chemical comparison between DNA
enzyme: a molecule, usually a protein, that is that could and could not be fragmented re-
used by cells to facilitate and speed up a vealed that the DNA molecules differed slightly
chemical reaction at the restriction sites (the locations the en-
methylation: the process of adding a methyl zyme recognized and cut). Nucleotides at the
chemical group (one carbon atom and three restriction site were found to have methyl (CH3)
hydrogen atoms) to a particular molecule, groups attached to them, giving this phenome-
such as a DNA nucleotide non the name DNA methylation.
nuclease: a type of enzyme that breaks down The conclusion was that the methylation
the sugar-phosphate backbone of nucleic ac- somehow protected the DNA from attack, and
ids such as DNA and RNA this could account for Smiths observation that
nucleotides: the building blocks of nucleic H. influenzae DNA was not destroyed by its own
acids, composed of a sugar, a phosphate restriction enzyme; presumably the enzyme
group, and nitrogen-containing bases recognized a specific methylation pattern on
the DNA molecule and left it alone. Foreign
Discovery and Role of Restriction DNA (from another species, for example)
Enzymes in Bacteria would not have the correct methylation pat-
Nucleases are a broad class of enzymes that tern, or it might not be methylated at all, and
destroy nucleic acids by breaking the sugar- could therefore be fragmented by the restric-
phosphate backbone of the molecule. Until tion enzyme. Hence, restriction enzymes are
1970, the only known nucleases were those that now regarded as part of a simple yet effective
destroyed nucleic acids nonspecificallythat bacterial defense mechanism to guard against
is, in a random fashion. For this reason, these foreign DNA, which can enter bacterial cells
enzymes were of limited usefulness for working with relative ease.
with nucleic acids such as DNA and RNA. In
1970, molecular biologist Hamilton Smith dis- Mechanism of Action
covered a type of nuclease that could fragment To begin the process of cleaving a DNA mol-
DNA molecules in a specific and therefore pre- ecule, a restriction enzyme must first recognize
668 Restriction Enzymes
spread use of restriction enzymes. On the most with DNA fragments from other molecules.
basic level, restriction enzymes allow scientists This technology has led to advances such as the
to create recombinant DNA molecules (hybrid production of human insulin by bacterial cells
molecules containing DNA from different such as Escherichia coli.
sources, such as humans and bacteria). No mat- The DNA of most organisms is relatively
ter what the source, DNA molecules can be cut large and complex; it is usually so large, in fact,
with restriction enzymes to produce fragments that it becomes difficult to manipulate and
that can then be rejoined in new combinations study the DNA of some organisms, such as hu-
mans. Restriction enzymes provide a conve-
nient way to cut large DNA molecules very spe-
cifically into smaller fragments that can then be
used more easily in a variety of molecular ge-
netics procedures.
Another area of genetic engineering that is
possible because of restriction enzymes is the
production of restriction maps. A restriction
map is a diagram of a DNA molecule showing
where particular restriction enzymes cut the
molecule and the molecular sizes of fragments
Chromosomal DNA
that are generated. The restriction sites can
digested with EcoRI then be used as markers for further study of the
restriction enzyme DNA molecule and to help geneticists locate
important genetic regions. Use of restriction
enzymes has also revealed other interesting
and useful markers of the human genome,
Cutting site called restriction fragment length polymorph-
isms (RFLP). RFLP refers to changes in the size
of restriction fragments caused by mutations in
the recognition site for a particular restriction
enzyme. More specifically, the recognition site
is mutated so that the restriction enzyme no
Restriction fragments longer cuts there; the result is one long frag-
ment where, before the mutation, there would
have been two shorter fragments. These
changes in fragment length can then be used as
markers for the region of DNA in question. Be-
cause they result from mutations in the DNA se-
quence, they are inherited from one genera-
tion to the next. Thus these mutations have
been a valuable tool for molecular biologists in
producing a map of human DNA and for those
Gel electrophoresis scientists involved in fingerprinting individu-
als by means of their DNA.
Randall K. Harris, updated by Bryan Ness
See also: Bacterial Genetics and Cell Struc-
ture; Bioinformatics; Biopharmaceuticals;
Blotting: Southern, Northern, and Western;
The process of cutting DNA with restriction enzymes. (U.S. Cloning; Cloning Vectors; DNA Finger-
Department of Energy Human Genome Program, printing; Forensic Genetics; Gender Identity;
http://www.ornl .gov/hgmis) Genetic Engineering; Genetic Engineering:
670 Reverse Transcriptase
Historical Development; Genetic Engineering: provide a start point for extension by a DNA
Social and Ethical Issues; Genomic Libraries; polymerase
Model Organism: Xenopus laevis; Molecular Ge- proofreading activity: enzyme activity in
netics; Population Genetics; RFLP Analysis; DNA polymerase that fixes errors made in
Shotgun Cloning; Synthetic Genes. copying templates
retroviruses: viruses that possess RNA ge-
Further Reading nomes with genetic information that flows
Drlica, Karl. Understanding DNA and Gene Clon- from RNA to host DNA via reverse transcrip-
ing: A Guide for the Curious. 4th ed. New York: tases
John Wiley & Sons, 2003. Provides basic in-
formation about restriction enzymes and Genetic Information Flow and
their use in cloning. Illustrations, bibliogra- Retroviruses
phy, index. The central dogma of molecular genetics
Lewin, Benjamin. Genes VII. Oxford, N.Y.: Ox- states that information flow is from DNA to
ford University Press, 2001. Provides a de- RNA to proteins. RNA polymerase transcribes
tailed yet highly readable explanation of RNA using a DNA template. For structural
restriction and methylation in bacteria. Illus- genes, the transcribed RNA is a messenger
trations, bibliography, index. RNA (mRNA), which is used by ribosomes to
Watson, James D., et al. Recombinant DNA. New produce a protein. To maintain and reproduce
York: Scientific American Books, 1992. An its DNA, an organism uses RNA to make DNA,
excellent resource for the general reader via DNA polymerase. It was long believed by ge-
wishing to understand the basics of genetic neticists that there were no exceptions to the
engineering. Full-color illustrations, dia- central dogma.
grams, bibliography, index. Some viruses, retroviruses, possess RNA ge-
nomes with genetic information flow from
RNA to DNA (via reverse transcriptases), and
back, before translation. Retroviruses have
been isolated from cancers and cancer tissue
Reverse Transcriptase cultures from birds, rodents, primates, and hu-
mans, and some retroviruses cause a high inci-
Fields of study: Genetic engineering and dence of certain cancers. Flow of retroviral ge-
biotechnology; Molecular genetics netic information from RNA to DNA was
Significance: Retroviruses infect eukaryotic cells, proposed in 1964 by Howard Temin (1934-
using reverse transcriptases (RTs) to turn their 1994) for Rous sarcoma virus. Temin, along
RNA genomes to DNA that enables their host to use with David Baltimore, jointly received the No-
the DNA to make new virus particles. Retroviral bel Prize in Physiology or Medicine in 1975 for
DNA, often dormant for years before new virus independently discovering the enzyme reverse
particles are released, can be oncogenic, giving in- transcriptase (RT).
fected cells high incidences of cancer. Purified RTs Rous sarcoma virus causes tumors in birds.
are used to make RNA into DNA for biotechnology. Temins hypothesis was based on effects of nu-
cleic acid synthesis inhibitors on replication of
Key terms the virus. First, the process was inhibited by
deoxyribonucleoside triphosphate actinomycin D, an inhibitor of DNA-dependent
(dNTP): one of four monomers (dATP, RNA synthesis. Furthermore, DNA synthesis in-
dCTP, dGTP, dTTP) incorporated into DNA hibition by cytosine arabinoside, early after in-
DNA polymerase: an enzyme that catalyzes the fection, stopped viral replication. Therefore, a
formation of a DNA strand using a template DNA intermediate seemed involved in viral
DNA or RNA molecule as a guide replication. The expected process was termed
primer: A short piece of single-stranded DNA reverse transcription because RNA becomes
that can hybridize to denatured DNA and DNA instead of DNA becoming RNA.
Reverse Transcriptase 671
wide variety of RNAs in vitro. This has been very OConnell, Joe, ed. RT-PCR Protocols. Totowa,
useful in molecular biology, especially in pro- N.J.: Humana Press, 2002. Collects several
duction of exact DNA copies of purified RNAs. papers on the use of reverse transcription
Once the copies are made by RT, they can be polymerase chain reaction in analysis of
cloned into bacterial expression vectors, where mRNA, quantitative methodologies, detec-
mass quantities of the gene product can be pro- tion of RNA viruses, genetic analysis, and im-
duced. It has also been shown that RT activity munology. Tables, charts, index.
takes part in making telomeres (protective chro- Shippen-Lentz, D., and E. H. Blackburn. Func-
mosome ends). Telomere formation and main- tional Evidence for an RNA Template in
tenance are essential cell processes, related to Telomerase. Science 247 (1990): 546-552.
life span and deemed important to understand- Points to the RT activity in telomerases. Illus-
ing cancer. trated.
RTs are also important in treatment of ac- Varmus, Harold. Retroviruses. Science 240
quired immunodeficiency syndrome (AIDS). (1988): 1427-1435. The discoverer of onco-
The drugs most useful for AIDS treatment are genes describes properties of different ret-
RT inhibitors such as zidovudine, didanosine, roviruses, including the mechanism of re-
zalcitabine, and stavudine. RTs are also associ- verse transcription.
ated with the difficulty in maintaining success-
ful long-term AIDS treatment, due to rapid de-
velopment of resistant HIV in individual AIDS
patients. The resistance is postulated to be due RFLP Analysis
to RTs lack of a proofreading component. In-
adequate proofreading in sequential replica- Field of study: Techniques and
tion of HIV viral particles from generation to methodologies
generation is believed to cause the rapid muta- Significance: RFLP analysis was the first simple
tion of the viral genome. method available for distinguishing individuals
Sanford S. Singer based on DNA sequence differences. The concep-
See also: cDNA Libraries; Central Dogma tual basis for this technique is still widely used in
of Molecular Biology; Model Organism: Chla- genetics, although RFLP analysis has been largely
mydomonas reinhardtii; Pseudogenes; Repetitive supplanted by other, faster and more powerful tech-
DNA; RNA Isolation; RNA Structure and Func- niques for the comparison of genetic differences.
tion; RNA World; Shotgun Cloning.
Key terms
Further Reading gel electrophoresis: a method for separat-
Goff, S. P. Retroviral Reverse Transcriptase: ing DNA molecules by size by applying elec-
Synthesis, Structure, and Function. JAIDS 3 tric current to force DNA through a matrix
(1990): 817-831. A solid, well-illustrated of agarose, which inhibits the migration of
paper. larger DNA fragments more than small DNA
Joklik, Wolfgang K., ed. Microbiology: A Cente- fragments
nary Perspective. Washington, D.C.: ASM restriction enzymes: proteins that recognize
Press, 1999. Thoroughly reviews important specific DNA sequences and then cut the
microbiology issues, including reverse tran- DNA, normally at the same sequence recog-
scriptase papers by Howard Temin and Da- nized by the enzymes
vid Baltimore. Southern blotting: a method for transfer-
Litvack, Simon. Retroviral Reverse Transcriptases. ring DNA molecules from an agarose gel to a
Austin, Tex.: R. G. Landes, 1996. Describes nylon membrane; once the DNA is on the
discovery, biosynthesis, structure, inhibitors, membrane, it is incubated with a DNA con-
and action mechanistics of reverse transcrip- taining an identifiable label and is then used
tase. Illustrations and bibliographic refer- to detect similar or identical DNA sequences
ences. on the membrane
RFLP Analysis 673
hemoglobin alleles. This method allowed for See also: Blotting: Southern, Northern, and
the identification of affected fetuses using DNA Western; Chromosome Theory of Heredity;
from cells isolated from amniotic fluid (a much DNA Fingerprinting; Gender Identity; Genetic
simpler and safer procedure than the previous Engineering; Genetic Testing; Model Organ-
method of diagnosis, which required isolating ism: Arabidopsis thaliana; Paternity Tests; Poly-
fetal red blood cells). merase Chain Reaction; Prenatal Diagnosis;
Another widely reported use of RFLP analy- Restriction Enzymes.
sis has been in forensic science. RFLP methods
have been critical in helping to identify crimi-
nals, and these methods have also helped exon- Further Reading
erate innocent people. The first application of Chang, J. C., and Y. W. Kan. A Sensitive New
RFLP in forensic analysis was in the case of the Prenatal Test for Sickle-Cell Anemia. New
murders of two young girls in England, in 1983 England Journal of Medicine 307 (1982): 30-
and 1986. Initially, a seventeen-year-old boy 32. A short and readable scientific paper de-
confessed to the murders. RFLP analysis, using scribing one of the first applications of RFLP
DNA from the crime scene, indicated that he analysis to clinical medicine. The same issue
was not the murderer. After extensive investiga- of the journal also has another, somewhat
tion, including RFLP analysis of DNA from more detailed, article on the same topic.
more than forty-five hundred men, a suspect Guilfoile, P. A Photographic Atlas for the Molecular
was identified. Confronted with the evidence, Biology Laboratory. Englewood, Colo.: Mor-
the suspect pleaded guilty to both murders and ton, 2000. An illustrated guide to molecular
was jailed for life. Since then, RFLP analysis has biology techniques, including a substantial
been used in thousands of criminal cases. Other illustrated section on RFLP analysis.
forensic applications of RFLP include its use as Jeffreys, A., V. Wilson, and S. L. Thein. Individ-
evidence in court cases involving paternity de- ual-Specific Fingerprints of Human DNA.
terminations and its role in identifying the bod- Nature 316 (1985): 76-79. A technical article
ies of missing persons who otherwise could not that describes some of the background in-
be identified. formation that led to the use of RFLP analy-
In addition to the clinical and forensic appli- sis in forensic science.
cations described above, RFLP analysis has Orkin, S. H., P. F. Little, H. H. Kazazian, Jr., and
been used in many subdisciplines of biology C. D. Boehm. Improved Detection of the
since the early 1980s. The applications of RFLP Sickle Mutation by DNA Analysis: Applica-
analysis range from the conservation of endan- tion to Prenatal Diagnosis. New England
gered species to the identification of strains of Journal of Medicine 307 (1982): 32-36.
bacteria associated with disease outbreaks to
basic research involving the classification of or-
ganisms.
Although RFLP analysis has been widely used
since its inception, it is increasingly being dis-
RNA Isolation
placed by polymerase chain reaction (PCR) Field of study: Molecular genetics
methods, which typically are much faster and Significance: All cells in an organism or popula-
require much less DNA. RFLP analysis was, tion of organisms of the same species contain the
however, an important step in the introduction same (or nearly the same) set of genes. Therefore,
of modern DNA analysis into the biology labo- understanding which genes are expressed under
ratory and the courtroom. The guiding prin- different conditions is critical to answering many
ciple behind RFLP analysisidentifying indi- questions in biology, including how cells differen-
viduals, strains, and species, based on DNA tiate into tissues, how cells respond to different en-
sequence differencesis still a part of more re- vironments, and which genes are expressed in tu-
cently developed techniques. mor cells. The starting point for answering those
Patrick G. Guilfoile questions is RNA isolation.
RNA Isolation 675
RNA from the nucleus may be more heteroge- Farrell, Robert. RNA Methodologies. 2d ed. San
neous. In this case, cells are lysed using a gentle Diego, Calif.: Academic Press, 1998. Proba-
detergent that disrupts the cytoplasmic mem- bly the definitive book on RNA techniques,
brane, without disturbing the nuclear mem- including RNA isolation. Includes a substan-
brane. Centrifugation is used to separate the tial amount of background information as
nuclei from the cytoplasm, and then the cyto- well as detailed protocols.
plasmic RNA is further purified as described OConnell, Joe, ed. RT-PCR Protocols. Totowa,
above. N.J.: Humana Press, 2002. Collects several
For some procedures, such as RT-PCR, the papers on the use of reverse transcription
RNA sometimes needs to be further purified to polymerase chain reaction in analysis of
ensure that no contaminating DNA is present. mRNA, quantitative methodologies, detec-
In this case, the RNA sample may be treated tion of RNA viruses, genetic analysis, and im-
with the enzyme DNase I, which destroys DNA munology. Tables, charts, index.
but leaves RNA intact. Sambrook, J., and D. W. Russel, eds. Molecular
For other procedures, like cDNA library con- Cloning: A Laboratory Manual. 3d ed. Cold
struction, the RNA is often purified to remove Spring Harbor, N.Y.: Cold Spring Harbor
ribosomal RNA (rRNA), transfer RNA (tRNA), Laboratory Press, 2000. The latest edition of
and other stable RNAs, since the majority of one of the most popular guides to molecular
RNA in the cell (typically more than 90 per- biology protocols. Includes several RNA iso-
cent) is rRNA and tRNA. In this case, the RNA lation procedures.
solution is treated by incubating it with single-
stranded DNA containing a chain of eighteen
to twenty thymine nucleotides, either on a col-
umn or in solution. Messenger RNA (mRNA) RNA Structure and Function
from eukaryotes contains runs of twenty to two
hundred adenine nucleotides that bind to the Field of study: Molecular genetics
single-stranded DNA and allow the mRNA to Significance: Ribonucleic acid (RNA), a molecule
be purified away from the stable RNAs. that plays many roles in the storage and transmis-
Like most techniques in genetics, RNA isola- sion of genetic information, exists in several forms,
tion methods have improved greatly over the each with its own unique function. RNA acts as
years. With advances in methods for studying the messenger between genes in the DNA and their
gene expression such as microarray analysis, protein product, directing the assembly of proteins.
isolating intact RNA is a technique that is more RNA is also an integral part of ribosomes, the site
critical than ever in the modern genetics labo- of protein synthesis, and some RNAs have been
ratory. shown to have catalytic properties. Understanding
Patrick G. Guilfoile the structure and function of RNA is important to
See also: cDNA Libraries; DNA Isolation; a fundamental knowledge of genetics; in addition,
DNA Structure and Function; Polymerase many developing medical therapies will undoubt-
Chain Reaction; Reverse Transcriptase; RNA edly utilize special RNAs to combat genetic dis-
Structure and Function; RNA Transcription eases.
and mRNA Processing.
Key terms
Further Reading messenger RNA: a type of RNA that carries ge-
Ausubel, Fredrick, Roger Brent, Robert King- netic instructions, copied from genes in
ston, David Moore, J. Seidman, and K. Struhl. DNA, to the ribosome to be decoded during
Current Protocols in Molecular Biology. Hobo- translation
ken, N.J.: John Wiley & Sons, 1998. A regu- retrovirus: a special type of virus that carries
larly updated compendium that includes its genetic information as RNA and converts
RNA isolation protocols from several differ- it into DNA that integrates into the cells of
ent laboratories. the viruss host organism
RNA Structure and Function 677
ribosomal RNA: a type of RNA that forms a The Folding of RNA Molecules
major part of the structure of the ribosome The function of an RNA molecule is deter-
ribosomes: organelles that function in protein mined by its nucleotide sequence, which repre-
synthesis and are made up of a large and a sents information derived from DNA. This nu-
small subunit composed of proteins and ri- cleotide sequence is called the primar y
bosomal RNA (rRNA) molecules structure of the molecule. Many RNAs also
ribozyme: an RNA molecule that can function have an important secondary structure, a
catalytically as an enzyme three-dimensional shape that is also important
transcription: the synthesis of an RNA mole- for the function of the molecule. The second-
cule directed by RNA polymerase using a ary structure is determined by hydrogen bond-
DNA template ing between parts of the RNA molecule that are
transfer RNA: a form of RNA that acts to de- complementary. Complementary pairing is al-
code genetic information present in mRNA, ways between A and U ribonucleotides and C
carries a particular amino acid, and is vital to and G ribonucleotides. Hydrogen bonding re-
translation sults in double-stranded regions in the second-
translation: the synthesis of a protein mole- ary structure.
cule directed by the ribosome using infor- Since RNA is single-stranded, it was recog-
mation provided by an mRNA nized shortly after the discovery of some of its
major roles that its capacity for folding is great
The Chemical Nature of RNA and that this folding might play an important
Ribonucleic acid (RNA) is a complex biolog- part in the functioning of the molecule. Base
ical molecule that is classified along with DNA pairing often represents local interactions, and
as a nucleic acid. Chemically, RNA is a polymer a common structural element is a hairpin
(long chain) consisting of subunits called ribo- loop or stem loop. A hairpin loop is formed
nucleotides linked together by phosphodiester when two complementary regions are sepa-
bonds. Each ribonucleotide consists of three rated by a short stretch of bases so that when
parts: the sugar ribose (a five-carbon simple they fold back and pair, some bases are left un-
sugar), a negatively charged phosphate group, paired, forming the loop. The net sum of these
and a nitrogen-containing base. There are four local interactions is referred to as the RNAs
types of ribonucleotides, and the differences secondary structure and is usually important to
among them lie solely in which of four possible an understanding of how the RNA works. All
bases each contains. The four bases are ade- transfer RNAs (tRNAs), for example, are folded
nine (A), guanine (G), cytosine (C), and uracil into a secondary structure that contains three
(U). stem loops and a fourth stem without a loop, a
The structures of DNA and RNA are very structure resembling a cloverleaf in two dimen-
similar, with the following differences. The sions.
sugar found in the nucleotide subunits of DNA Finally, local structural elements may inter-
is deoxyribose, which differs slightly from the act with other elements in long-range interac-
ribose found in the ribonucleotides of RNA. In tions, causing more complicated folding of the
addition, while DNA nucleotides also contain molecule. The full three-dimensional struc-
four possible bases, there is no uracil in DNA; ture of a tRNA molecule from yeast was finally
instead, DNA nucleotides contain a different confirmed in 1978 by several groups indepen-
base called thymine (T). Finally, while DNA ex- dently, using X-ray diffraction. In this process,
ists as a double-stranded helix in nature, RNA is crystals of a molecule are bombarded with X
almost always single-stranded. Like DNA, a sin- rays, which causes them to scatter; an expert
gle RNA strand has a 5-to-3 polarity. These can tell by the pattern of scattering how the dif-
numbers are based on which carbon atom is ex- ferent atoms in the molecule are oriented with
posed at the end of the polymer, each of the respect to one another. The cloverleaf arrange-
carbon atoms being numbered around the ment of a tRNA undergoes further folding so
sugar molecule. that the entire molecule takes on a roughly L-
678 RNA Structure and Function
shaped appearance in three dimensions. An stability (the rate at which it is degraded). Every
understanding of the three-dimensional shape cell contains several enzymes called ribonu-
of an RNA molecule is crucial to understand- cleases (RNases) whose job it is to cut up RNA
ing its function. By the late 1990s, the three- molecules into their ribonucleotides subunits.
dimensional structures of many tRNAs had Some RNAs last only thirty seconds, while others
been worked out, but it had proven difficult to may last up to a day or two. The signals regulat-
do X-ray diffraction analyses on most other ing RNA degradation are being studied, and al-
RNAs because of technical problems. More though much has been learned, many details re-
advanced computer programs and alternate main unclear. It is important to remember that
structure-determining techniques are enabling both the rates of synthesis (transcription) and
research in this field to proceed. degradation ultimately determine the amount
of functional RNA in a cell at any given time.
Synthesis and Stability of RNA
RNA molecules of all types are continually Three Classes of RNA
being synthesized and degraded in a cell; even While all RNAs are produced by transcrip-
the longest-lasting ones exist for only a day or tion, several classes of RNA are created, and
two. Shortly after the structure of DNA was es- each has a unique function. By the late 1960s,
tablished, it became clear that RNA was synthe- three major classes of RNAs had been identi-
sized using a DNA molecule as a template, and fied, and their respective roles in the process of
the mechanism was worked out shortly thereaf- protein synthesis had been identified. In gen-
ter. The entire process by which an RNA mole- eral, protein synthesis refers to the assembly of
cule is constructed using the information in a protein using information encoded in DNA,
DNA is called transcription. An enzyme called with RNA acting as an intermediary to carry in-
RNA polymerase is responsible for assembling formation and assist in protein building. In
the ribonucleotides of a new RNA complemen- 1956, Francis Crick, one of the scientists who
tary to a specific DNA segment (gene). Only had discovered the double-helical structure of
one strand of the DNA is used as a template DNA, referred to this information flow as the
(the sense strand), and the ribonucleotides are central dogma, a term that continues to be
initially arranged according to the base-pairing used, although exceptions to it are now known.
rules. A DNA sequence called the promoter A messenger RNA (mRNA) carries a com-
is a site RNA polymerase can bind initially and plementary copy of the DNA instructions for
allows the process of RNA synthesis to begin. At building a particular protein. In eukaryotes it
the appropriate starting site, RNA polymerase typically represents the information from a sin-
begins to assemble and connect the nucleo- gle gene and carries the information to a ribo-
tides according to the complementary pairing some, the site of protein synthesis. The infor-
rules, such that for every A nucleotide in the mation must be decoded to make a protein.
DNA, RNA polymerase incorporates a U ribo- Nucleotides are read in groups of three (called
nucleotide into the RNA being assembled. The codons). In addition, mRNAs contain signals
remaining pairing rules stipulate that a T in that tell a ribosome where to start and stop
DNA denotes an A in RNA and that a C in DNA translating.
represents a G in RNA (and vise versa). This Ribosomal RNA (rRNA) is part of the struc-
process continues until another sequence, ture of the ribosome. Four different rRNAs in-
called a terminator, is reached. At this point, teract with many proteins to form functional
the RNA polymerase stops transcription, and a ribosomes that direct the events of protein syn-
new RNA molecule is released. thesis. One of the rRNAs interacts with mRNA
Much attention is rightfully focused on tran- to orient it properly so translation can begin at
scription, since it controls the rate of synthesis the correct location. Another rRNA acts to fa-
of each RNA. It has become increasingly clear, cilitate the transfer of the growing polypeptide
however, that the amount of RNA in the cell at a from one tRNA to another (peptidyl transfer-
given time is also strongly dependent on RNA ase activity).
RNA Structure and Function $%'
Transfer RNA (tRNA) serves the vital role of contains several to many introns and is referred
decoding the genetic information. There are at to as immature, or a pre-mRNA. Before it can
least twenty and usually more than forty differ- become mature and functional, three major
ent tRNAs in a cell. On one side, tRNAs contain processing events must occur: splicing, the ad-
an anticodon loop, which can base-pair with dition of a 5 cap, and a tail. The process of
mRNA codons according to their sequence splicing is complex and occurs in the nucleus
and the base-pairing rules. On the other side, with the aid of spliceosomes, large complexes
each contains an amino acid binding site, with of RNAs and proteins that identify intervening
the appropriate amino acid for its anticodon. sequences and cut them out of the pre-mRNA.
In this way, tRNAs recognize the codons and In addition, spliceosomes rejoin the exons to
supply the appropriate amino acids. The pro- produce a complete, functional mRNA. Splic-
cess continues until an entire new polypeptide ing must be extremely specific, since a mistake
has been constructed. causing the removal of even one extra nucleo-
The attachment of the correct amino acids is tide could change the final protein, making it
facilitated by a group of enzymes called tRNA nonfunctional. During splicing, capping and
amino acyl synthetases. Each type of tRNA has a the addition of a poly-A tail take place. A so-
corresponding synthetase that facilitates the at- called cap, which consists of a modified G nu-
tachment of the correct amino acid to the cleotide, is added to the beginning (5 end) of
amino acid binding site. The integrity of this the pre-mRNA by an unconventional linkage.
process is crucial to translation; if only one The cap appears to function by interacting with
tRNA is attached to an incorrect amino acid, the ribosome, helping to orient the mature
the resulting proteins will likely be nonfunc- mRNA so that translation begins at the proper
tional. end. A tail, which consists of many A nucleo-
tides (often two hundred or more), is attached
Split Genes and mRNA Processing in to the 3 end of the pre-mRNA. This so-called
Eukaryotes poly-A tail, which virtually all eukaryotic mRNAs
In bacterial genes, there is a colinearity be- contain, seems to be one factor in determining
tween the segment of a DNA molecule that is the relative stability of an mRNA. These impor-
transcribed and the resulting mRNA. In other tant steps must be performed after transcrip-
words, the mRNA sequence is complementary tion in eukaryotes to produce a functional
to its template and is the same length, as would mRNA.
be expected. In the late 1970s, several groups
of scientists made a seemingly bizarre discovery Other Important Classes of RNA and
regarding mRNAs in eukaryotes (organisms Specialized Functions
whose cells contain a nucleus, including all The traditional roles of RNA in protein syn-
living things that are not bacteria): The se- thesis were originally considered its only roles.
quences of mRNAs isolated from eukaryotes RNA in general, while considered an impor-
were not collinear with the DNA from which tant molecule, was thought of as a helper in
they were transcribed. The coding regions of translation. This all began to change in 1982,
the corresponding DNA were interrupted by when the molecular biologists Thomas Cech
seemingly random sequences that served no and Sidney Altman, working independently
apparent function. These introns, as they and with different systems, reported the exis-
came to be known, were apparently transcribed tence of RNA molecules that had catalytic activ-
along with the coding regions (exons) but were ity. This means that RNA molecules can func-
somehow removed before the mRNA was trans- tion as enzymes; until this time, it was believed
lated. This completely unexpected observation that all enzymes were protein molecules. The
led to further investigations that revealed that importance of these findings cannot be over-
mRNA is extensively processed, or modified, af- stated, and Cech and Altman ultimately shared
ter its transcription in eukaryotes. the 1989 Nobel Prize in Chemistry for the dis-
After a eukaryotic mRNA is transcribed, it covery of these RNA enzymes, or ribozymes.
680 RNA Structure and Function
Both of these initial ribozymes catalyzed reac- was working on the autoimmune disease sys-
tions that involved the cleavage of other RNA temic lupus when she began to characterize the
moleculesthat is, they acted as nucleases. snRNAs. There are six different snRNAs, now
Subsequently, many ribozymes have been found called U1-U6 RNAs. These RNAs exist in the
in various organisms, from bacteria to humans. nucleus of eukaryotic cells and play a vital role
Some of them are able to catalyze different in mRNA splicing. They associate with proteins
types of reactions, and there are new ones re- in the spliceosome, forming so-called ribonu-
ported every year. Thus ribozymes are not a cleoprotein complexes (snRNPs, pronounced
mere curiosity but play an integral role in the snurps), and play a prominent role in detect-
molecular machinery of many organisms. Their ing proper splice sites and directing the pro-
discovery also gave rise to the idea that at one tein enzymes to cut and paste at the proper lo-
point in evolutionary history, molecular sys- cations.
tems composed solely of RNA, performing It has been known since the late 1950s that
many roles, existed in an RNA world. many viruses contain RNA, and not DNA, as
At around the same time as these momen- their genetic material. This is another fascinat-
tous discoveries, still other classes of RNAs were ing role for RNA. The viruses that cause influ-
being discovered, each with its own specialized enza, polio, and a host of other diseases are
functions. In 1981, Jun-ichi Tomizawa discov- RNA viruses. Of particular note are a class of
ered RNA interference (RNAi), the first exam- RNA viruses known as retroviruses. Retrovi-
ple of what would become another major class ruses, which include human immunodeficiency
of RNAs, the antisense RNAs or interference virus (HIV), the virus that causes acquired im-
RNAs. The RNAs in this group are comple- munodeficiency syndrome (AIDS) in humans,
mentary to a target molecule (usually an use a special enzyme called reverse transcrip-
mRNA) and can bind to that target via comple- tase to make a DNA copy of their RNA when
mentary base pairing. RNAi binding usually they enter a cell. The DNA copy is inserted into
plays a regulatory role, often acting to prevent the DNA of the host cell, where it is referred to
translation of the relevant mRNA to modulate as a provirus, and never leaves. This discovery
the expression of the protein for which it represents one of the exceptions to the central
codes. Most of these antisense RNAs are en- dogma. In the central dogma, RNA is always
coded by the same gene as their target, but a made from DNA, and retroviruses have reversed
group called the transencoded antisense this flow of information. Clearly, understand-
RNAs actually have their own genes, which are ing the structures and functions of the RNAs as-
separate and distinct from their target mole- sociated with these viruses will be important in
cules gene. This is especially significant be- attempting to create effective treatments for
cause the complementarity between antisense the diseases associated with them.
RNA and the target is often not perfect, result- An additional role of RNA was noted during
ing in interesting interactions with unique the elucidation of the mechanism of DNA rep-
structural features. The prototype of this class lication. It was found that a small piece of RNA,
of RNAs, micF RNA, was discovered in 1983 by called a primer, must be laid down by the en-
Masayori Inouye and subsequently character- zyme primase, an RNA polymerase, before
ized by Nicholas Delihas. An understanding of DNA polymerase can begin. RNA primers are
the binding of this special type of antisense later removed and replaced with DNA. Also, it
RNA to its target will provide insights into RNA- is worth mentioning that the universal energy-
RNA interactions that may be vital for use in ge- storing molecule of all cells, adenosine triphos-
netic therapy. Research on RNAi molecules phate (ATP), is in fact a version of the RNA nu-
continues, and many new insights into genetic cleotide containing adenine (A).
control after transcription have been gained.
Another major class of RNAs, the small nu- Impact and Applications
clear RNAs (snRNAs), was also discovered in The discovery of the many functions of
the early 1980s. Molecular biologist Joan Steitz RNA, especially its catalytic ability, has radically
RNA Transcription and mRNA Processing 681
changed the understanding of the functioning Function; Genetic Code; Genetic Code, Crack-
of genetic and biological systems and has revo- ing of; Molecular Genetics; Noncoding RNA
lutionized the views of the scientific commu- Molecules; One Gene-One Enzyme Hypothe-
nity regarding the origin of life. The key to un- sis; Protein Structure; Protein Synthesis; Repet-
derstanding how RNA can perform all of its itive DNA; RNA Isolation; RNA Transcription
diverse functions lies in elucidating its many and mRNA Processing; RNA World.
structures, since structure and function are in-
separable. Much progress has been made in es- Further Reading
tablishing the structures of hundreds of RNA Eckstein, Fritz, and David M. J. Lilley, eds. Cata-
molecules; several methods, including ad- lytic RNA. New York: Springer, 1996. Offers a
vanced computer programs, are making it eas- comprehensive overview of ribozyme diver-
ier to predict and analyze RNA structure. Three- sity and function. Illustrations (some color),
dimensional modeling is much more difficult, bibliography, index.
and while the three-dimensional structures of Erickson, Robert P., and Jonathan G. Izant, eds.
several RNAs have been worked out, much Gene Regulation: Biology of Antisense RNA and
work remains. DNA. New York: Raven Press, 1992. Provides
In terms of basic research and genetic engi- both a comprehensive overview of natural
neering, the discovery of antisense RNAs and antisense RNA function and prospects for its
ribozymes has facilitated many procedures, uses in gene therapy. Illustrations, bibliogra-
providing insight at the molecular level of ge- phy, index.
netic processes that would have been difficult Murray, James A. H., ed. Antisense RNA and
to obtain without this knowledge and the tools DNA. New York: Wiley-Liss, 1992. Presents
it has made available. Additionally, plants, bac- experimental approaches. Illustrations, bib-
teria, and animals have been genetically engi- liography, index.
neered to alter the expression of some of their Simons, Robert W., and Marianne Grunberg-
genes, in many cases making use of the new Manago, eds. RNA Structure and Function.
RNA technology. An example is the genetically Cold Spring Harbor, N.Y.: Cold Spring Har-
engineered tomato, which does not ripen until bor Laboratory Press, 1997. An advanced
it is treated at the point of sale. This tomato was text that takes a detailed look at the various
created by inserting an antisense RNA gene; structures of RNA, their relationships to
when it is expressed, it inactivates the mRNA function, and the techniques for determin-
that codes for the enzyme involved in produc- ing RNA structure. Illustrations, bibliogra-
tion of the ripening hormone. phy, index.
Although success in human gene therapy Watson, James D., et al. Molecular Biology of the
has been limited, the usage of retroviruses to Gene. 5th ed. Menlo Park, Calif.: Benjamin
introduce ribozymes, antisense RNAs, or a Cummings, 2003. Discusses RNA structures
combination of both into genetically defective and their relationship to function. Illustra-
cells offers great promise for the future in fight- tions, bibliography, index.
ing a wide variety of diseases, from AIDS and
cancer to cystic fibrosis and sickle-cell disease.
One thing is clear: RNA will play an important
role in increasing the understanding of genet- RNA Transcription and mRNA
ics and in the revolution of gene therapy. RNA
is one of the most structurally interesting and
Processing
functionally diverse of all the biological mole- Field of study: Molecular genetics
cules. Significance: Translation of messenger RNA mole-
Matthew M. Schmidt, updated by Bryan Ness cules (mRNAs) occurs even while transcription is
See also: Ancient DNA; Antisense RNA; taking place in prokaryotes. In eukaryotes the pro-
Chromosome Structure; DNA Isolation; DNA cess is much more complex, with transcription oc-
Repair; DNA Replication; DNA Structure and curring in the nucleus, followed by multiple pro-
682 RNA Transcription and mRNA Processing
cessing steps before a mature mRNA is ready to be RNAs are involved in translation. RNA poly-
translated. All of these extra steps are required for merase II (pol II) transcribes RNA from struc-
mRNAs to be transported out of the nucleus and tural genes, that is, genes that code for polypep-
for recognition by ribosomes in the cytoplasm. tides. Pol II therefore is the primary RNA
polymerase and the one that will be the focus of
Key terms this article when discussing transcription in eu-
messenger RNA (mRNA): the form of RNA karyotes.
that contains the coding instructions used to
make a polypeptide by ribosomes Transcription in Prokaryotes
RNA polymerase: the enzyme that transcribes The first step in transcription is for RNA
RNA using a strand of DNA as a template polymerase to identify the location of a gene.
transcription: the process that converts DNA In prokaryotes many genes are clustered to-
code into a complementary strand of RNA gether in functional groups called operons.
(mRNA) containing code that can be inter- For example, the lactose (lac) operon contains
preted by ribosomes three genes, each coding for one of the en-
translation: the process, mediated by ribo- zymes needed to metabolize the sugar lactose.
somes, in which the genetic code in an At the beginning of each operon are two con-
mRNA is used to produce a polypeptide, the trol sequences, the operator and the promoter.
ultimate product of structural genes The promoter is where RNA polymerase binds,
in preparation for transcription. The operator
RNA Polymerase is a control region that determines whether
Transcription is the process whereby the di- RNA polymerase will be able to bind to the pro-
rections for making a protein are converted moter. The operator interacts with other pro-
from DNA-based instructions to RNA-based in- teins that determine when the associated
structions. This step is required in the process operon should be expressed. They do this by ei-
of expressing a gene as a polypeptide, because ther preventing RNA polymerase from binding
ribosomes, which assemble polypeptides, can to the promoter or by assisting it to bind.
read only RNA-based messages. Although tran- RNA polymerase recognizes promoters by
scription is complicated and involves dozens of the specific base-pair sequences they contain.
enzymes and proteins, it is much simpler in Assuming all conditions are correct, RNA poly-
prokaryotes than in eukaryotes. Because pro- merase binds to the promoter, along with an-
karyotes lack a nucleus, transcription and other protein called the sigma factor (). The
translation are linked processes both occurring beginning of genes are detected with the aid of
in the cytoplasm. In eukaryotes, transcription . Transcription begins at a leader sequence a
and translation occur as completely separate little before the beginning of the first gene and
processes, transcription occurring in the nu- continues until RNA polymerase reaches a ter-
cleus and translation occurring in the cyto- mination signal. If the operon contains more
plasm. (It is now known that some translation than one gene, all of the genes are transcribed
also occurs in the nucleus, but apparently only into a single long mRNA, each gene separated
a small amount, probably less than 10 percent from its neighbors by a spacer region. The
of the translation occurring in a cell.) mRNA is put together by pairing ribonucleo-
In eukaryotes there are three different types tides with their complementary nucleotides in
of RNA polymerase that transcribe RNA using a the DNA template. In place of thymine (T),
strand of DNA as a template (there is a single RNA uses uracil (U); otherwise the same bases
type of RNA polymerase in prokaryotes). Two are present in RNA and DNA, the others being
of them, called RNA polymerase I (pol I) and adenine (A), guanine (G), and cytosine (C).
RNA polymerase III (pol III), specialize in tran- The pairing relationships are as follows, the
scribing types of RNA that are functional prod- DNA base listed first in each pair: A-U, T-A, G-C,
ucts themselves, such as ribosomal RNA and C-G.
(rRNA) and transfer RNA (tRNA). These RNA polymerase catalyzes the joining of
RNA Transcription and mRNA Processing 683
ribonucleotides as they pair with the DNA tem- promoters; (3) transcription occurs in a sepa-
plate. Each mRNA is constructed beginning at rate compartment (the nucleus) from transla-
the 5 end (the phosphate end) and ending tion, most of which occurs in the cytoplasm;
with the 3 end (the hydroxyl end). Even while and (4) initially transcription results in a pre-
transcription is taking place, ribosomes begin messenger RNA (pre-mRNA) molecule that
binding to the mRNA to begin translation. As must be processed before it emerges as a ma-
soon as RNA polymerase has completed tran- ture mRNA ready for translation. Additionally,
scribing the genes of an operon, it releases mRNAs are much longer-lived in eukaryotes.
from the DNA and soon binds to another pro- The first step in transcription is for RNA
moter to begin the process all over again. polymerase to find a gene that needs to be tran-
scribed. Only genes occurring in regions of the
Transcription in Eukaryotes DNA that have been unwound are prepared for
Transcription in eukaryotes differs from the potential transcription. RNA polymerase binds
process in prokaryotes in the following major to an available promoter, which is located just
ways: (1) genes are transcribed individually before a gene and has a region in it called the
instead of in groups; (2) DNA is complexed TATA box (all promoters have the consensus
with many proteins and is highly compacted, sequence TATAAAA in them). RNA polymer-
and therefore must be unwound to expose its ase is unable to bind to the promoter without
DNA
Nucleus
Messenger RNA
(mRNA) Amino acids
Codon
mRNA moves
out of nucleus
mRNA
Cytoplasm
Ribosome
A depiction of the process of RNA transcription. Messenger RNA (mRNA) moves the DNAs template or instructions for protein syn-
thesis (genetic code, or arrangement of bases) from the cell nucleus out into the cytoplasm, where it binds to a ribosome, the cells pro-
tein factory. Transfer RNA molecules then synthesize amino acids by linking to a codon on the mRNA and transferring the resulting
amino acid to a growing chain of amino acids, the protein molecule. (U.S. Department of Energy Human Genome Program,
http://www.ornl.gov/hgmis)
$&" RNA Transcription and mRNA Processing
assistance from over a dozen other proteins, in- the intron out and splices the exons that were
cluding a TATA-binding protein, several tran- on each side of the intron to each other. Genes
scription factors, activators, and coactivators. may have just a few introns, or they may have a
There are other DNA sequences further up- dozen or more. Why eukaryotes have introns at
stream than the promoter that control tran- all is still an open question, as introns, in gen-
scription too, thus accounting for the fact that eral, appear to have no function.
some genes are transcribed more readily, and While intron removal and exon splicing are
therefore more often, than others. taking place, both ends of maturing mRNAs
Once RNA polymerase has bound to the must also be modified. At the 5 end (the end
promoter, it begins assembling an RNA mole- with an exposed phosphate) an enzyme adds
cule complementary to the DNA code in the a modified guanosine nucleotide called 7-
gene. It starts by making a short leader se- methylguanosine. This special nucleotide is
quence, then transcribes the gene, and finishes added so that ribosomes in the cytoplasm can
after transcribing a short trailer sequence. recognize the correct end of mRNAs, and it
Transcription ends when RNA polymerase probably also prevents the 5 end of mRNAs
reaches a termination signal in the DNA. The from being degraded.
initial product is a pre-mRNA molecule which At the 3 end of maturing mRNAs another
is much longer than the mature mRNA will be. enzyme, called polyadenylase, adds a string of
adenine nucleotides. Polyadenylase actually
mRNA Processing in Eukaryotes recognizes a special signal in the trailer se-
Pre-mRNAs must be processed before they quence, at which it cuts and then adds the
can leave the nucleus and be translated at a ri- adenines. The result is what is called a poly-A
bosome. Three separate series of reactions play tail. Initially geneticists did not understand the
a part in producing a mature mRNA: (1) intron function of poly-A tails, but now it appears that
removal and exon splicing, (2) 5 capping, and they protect mRNAs from enzymes in the cyto-
(3) addition of a poly-A tail. Not all transcripts plasm that could break them down. Essentially,
require all three modifications, but most do. poly-A tails are the main reason mRNAs in eu-
The reason pre-mRNAs are much longer karyotes survive so much longer than mRNAs
than their respective mature mRNAs has to do in prokaryotes.
with the structure of genes in the DNA. The Once the modifications have been com-
coding sequences of almost all eukaryotic pleted, mRNAs are ready to be exported from
genes are interrupted with noncoding regions. the nucleus and will now travel through nu-
The noncoding regions are called introns, be- clear pores and enter the cytoplasm, where
cause they represent intervening sequences, awaiting ribosomes will translate them, using
and the coding regions are called exons. For an the RNA code to build polypeptides.
mRNA to be mature it must have all the introns
removed and all the exons spliced together Transcription and Disease
into one unbroken message. Special RNA/pro- Ordinarily transcription works like a well-
tein complexes called small nuclear ribonucle- oiled machine, and only the right genes are
oprotein particles, or snRNPs (pronounced as transcribed at the right time so that just the
snurps by geneticists), carry out this pro- right amount of protein product is produced.
cess. The RNAs in the snRNPs are called small Unfortunately, due to the great complexity of
nuclear RNAs or snRNAs. Several snRNPs the system, problems can occur that lead to dis-
grouped together form a functional splicing ease. It has been estimated that about 15 per-
unit called a spliceosome. Spliceosomes are cent of all genetic diseases may be due to im-
able to recognize short signal sequences in pre- proper intron removal and exon splicing in
mRNA molecules that identify the boundaries pre-mRNA molecules. Improper gene expres-
of introns and exons. When a spliceosome has sion accounts for many other diseases, includ-
found an intron, it binds correctly, and through ing many types of cancer.
formation of a lariat-shaped structure, it cuts Beta-thalassemia, a genetic disorder causing
RNA Transcription and mRNA Processing 685
Cooleys anemia, is caused by a point mutation Overexpression can occur when there is a
(a change in a single nucleotide) that changes mutation in one of the control regions up-
a cutting and splicing signal. As a result, the ma- stream from a gene. For example, a mutation in
ture mRNA has an extra piece of intron, mak- the promoter sequence could cause a tran-
ing the mRNA longer and causing a reading scription factor, and thus RNA polymerase, to
frame shift. A reading frame shift causes every- bind more easily, leading to higher transcrip-
thing from the mutation forward to be skewed, tion rates. Other control regions, such as en-
so that the code no longer codes for the correct hancer sequences, often far removed from the
amino acids. Additionally, as in the case of gene itself, may also affect transcription rates.
Cooleys anemia, a reading frame shift often in- Anything that causes the transcription pro-
troduces a premature stop codon. The gene in- cess to go awry will typically have far-reaching
volved codes for the beta chain of hemoglobin, consequences. Geneticists are just beginning
the protein that carries oxygen in the blood, to understand some of the underlying errors
and this mutation results in a shortened poly- behind a host of genetic diseases, and it should
peptide that does not function properly. be no surprise that some of them involve how
A single point mutation in a splicing site can genes are transcribed. Knowing what the prob-
have even more far-reaching consequences. In lem is, unfortunately, does not usually point to
2000, researchers in Italy discovered an individ- workable solutions. When the primary prob-
ual who was genetically male (having one X lem is an excessive rate of transcription, spe-
and one Y chromosome) but was phenotypi- cially designed antisense RNA molecules (RNA
cally female. She had no uterus or ovaries and molecules that are complementary to mRNA
only superficial external female anatomy, mak- molecules) might be designed that will bind to
ing her a pseudohermaphrodite. This condi- the overexpressed mRNAs and disable them.
tion can be caused by defects either in andro- This approach is still being tested. In the case of
gen production or in the androgen receptor. point mutations that derail the cutting and
In this case, the defect was a simple point mu- splicing process, the only solution may be gene
tation in the androgen receptor gene that led therapy, a technique still not considered tech-
to one intron being retained in the mature nically possible and not expected to be feasible
mRNA. Within the intron was a stop codon, for some time to come.
which meant when the mRNA was translated, Bryan Ness
a shorter, nonfunctional polypeptide was See also: Ancient DNA; Antisense RNA;
formed. The subject did show a very small re- Cancer; Chromosome Structure; DNA Isola-
sponse to androgen, so apparently some of the tion; DNA Repair; DNA Replication; DNA
pre-mRNAs were being cut and spliced cor- Structure and Function; Genetic Code; Ge-
rectly, but not enough to produce the normal netic Code, Cracking of; Molecular Genetics;
male phenotype. Noncoding RNA Molecules; One Gene-One
The same kinds of mutations as those dis- Enzyme Hypothesis; Protein Structure; Protein
cussed above can lead to cancer, but muta- Synthesis; Pseudohermaphrodites; Repetitive
tions that change the level of transcription of DNA; RNA Isolation; RNA Structure and Func-
proto-oncogenes can also lead to cancer. Proto- tion; RNA World.
oncogenes are normal genes involved in regu-
lating the cell cycle, and when these genes are Further Reading
overexpressed they become oncogenes (cancer- Hampsey, Michael. Molecular Genetics of the
causing genes). Overexpression of proto- RNA Polymerase II General Transcriptional
oncogenes leads to overexpression of other Machinery. Microbiology and Molecular Biol-
genes, because many proto-oncogenes are ogy Reviews 62, no. 2 (1998): 465-503. Over-
transcription factors, signal proteins that inter- view of the role of RNA polymerase II.
act with molecules controlling intracellular Latchman, David S. Transcription-Factor Mu-
growth and growth factors released by cells to tations and Disease. The New England Jour-
stimulate other cells to divide. nal of Medicine 334 (1996): 28-33. A general
686 RNA World
overview of the kinds of diseases caused by The Central Dogma and the Modern
mutations in transcription factor genes. In- Genetic World
cludes an overview of potential treatments. Soon after the discovery of the double-helical
Macfarlane, W. M. Transcription. Journal of structure of DNA in 1953 by James Watson and
Clinical Pathology: Molecular Pathology 53 Francis Crick, Crick proposed an idea regard-
(2000): 1-7. A general introduction with an ing information flow in cells that he called the
emphasis on transcription factors and their central dogma of molecular biology. Crick
role in transcription. correctly predicted that in all cells, informa-
Ptashne, Mark, and Alexander Gann. Genes and tion flows from DNA to RNA to protein. DNA
Signals. Cold Spring Harbor, N.Y.: Cold was known to be the genetic material, the li-
Spring Harbor Laboratory Press, 2002. A brary of genetic information, and it had been
nice overview of transcription and related clear for some time that the enzymes that actu-
topics, readable by advanced high school ally did the work of facilitating chemical reac-
students and undergraduates. tions were invariably protein molecules. The
Shatkin, Aaron J., and James L. Manley. The discovery of three classes of RNA during the
Ends of the Affair: Capping and Polyade- 1960s seemed to provide the link between the
nylation. Nature Structural Biology 7, no. 10 DNA instructions and the protein products.
(2000): 838-842. In the modern genetic world, cells contain
White, Robert J. Gene Transcription: Mechanisms three classes of RNA that act as helpers in the
and Control. Malden, Mass.: Blackwell, 2001. synthesis of proteins from information stored
An in-depth look at all aspects, including in DNA, a process called translation. A messen-
regulation, of transcription. Aimed mostly at ger RNA (mRNA) is transcribed from a seg-
upper undergraduate students, but begins ment of DNA (a gene) that contains informa-
with the basics. tion about how to build a particular protein
and carries that information to the cellular site
of protein synthesis, the ribosome. Ribosomal
RNAs (rRNAs) interacting with many proteins
RNA World make up the ribosome, whose major job is to
coordinate and facilitate the protein-building
Fields of study: Evolutionary biology; procedure. Transfer RNAs (tRNAs) act as de-
Molecular genetics coding molecules, reading the mRNA informa-
Significance: The RNA world is a theoretical time tion and correlating it with a specific amino
in the early evolution of life, during which RNA acid. As the ribosome integrates the functions
molecules played important genetic and enzymatic of all three types of RNA, polypeptides are built
roles that were later taken over by molecules of DNA one amino acid at a time. These polypeptides,
and proteins. Ideas about RNAs ancient func- either singly or in aggregations, can then func-
tions have led to new concepts of the origin of life tion as enzymes, ultimately determining the ca-
and have important implications in the use of pabilities and properties of the cell in which
gene therapy to treat diseases. they act.
While universally accepted, the central
Key term dogma led many scientists to question how this
ribosomal RNA (rRNA): a type of RNA that complex, integrated system came about. It
forms a major part of the structure of the ri- seemed to be a classic chicken and egg di-
bosome lemma: Proteins could not be built without in-
ribosome: an organelle that functions in pro- structions from DNA, but DNA could not rep-
tein synthesis, composed of a large and a licate and maintain itself without help from
small subunit composed of proteins and ri- protein enzymes. The two seemed mutually de-
bosomal RNA molecules pendent upon each other in an inextricable
ribozyme: an RNA molecule that can function way. An understanding of the origins of the
catalytically as an enzyme modern genetic system seemed far away.
RNA World 687
tions (energy in the form of lightning, for ex- without containing any proteins. As proteins
ample), more complex organic molecules began to be synthesized from the information
would be formed. His theory was first tested in in the template RNAs, they slowly began to as-
1953 and was resoundingly confirmed. A mix- sume some of the RNA roles and probably in-
ture of methane, ammonia, water vapor, and corporated themselves into the ribosome to al-
hydrogen gas was energized with high-voltage low it to function more efficiently.
electricity, and the products were impressive: The transition to the modern world would
several amino acids and aldehydes, among not be complete without the introduction of
other organic molecules. Subsequent experi- DNA as the major form of the genetic material.
ments have been able to produce ribonucleo- RNA, while well suited to diverse roles, is actu-
tide bases. It seems reasonable, then, that nu- ally a much less suitable genetic material than
cleotides could have been present on the early DNA for a complex organism (even one only as
Earth and that their random linkage could lead complex as a bacterium). The reason for this is
to the formation of an RNA chain. that the slight chemical differences between
After a while, RNA molecules would have the sugars contained in the nucleotides of RNA
found a way to synthesize proteins, which are and DNA cause the RNA to be more reactive
able to act as more efficient and diverse en- and much less chemically stable; this is good for
zymes than ribozymes by their very nature. Why a ribozyme but clearly bad if the genetic mate-
are proteins better enzymes than ribozymes? rial is to last for any reasonable amount of time.
Since RNA contains only four bases that are Once DNA initially came into existence, there-
fundamentally similar in their chemical prop- fore, it is likely that the relatively complex or-
erties, the range of different configurations ganisms of the time quickly adopted it as their
and functional capabilities is somewhat limited genetic material; shortly thereafter, it became
as opposed to proteins. Proteins are con- double-stranded, which facilitated its replica-
structed of twenty different amino acids whose tion immensely. This left RNA, the originator
functional groups differ widely in terms of of it all, relegated to the status it enjoys today;
their chemical makeup and potential reactivity. molecular fossils exist that uncover its former
It is logical to suppose, therefore, that proteins glory, but it functions mainly as a helper in pro-
eventually took over most of the roles of RNA tein synthesis.
enzymes because they were simply better suited This still leaves the question of how DNA
to doing so. Several of the original or efficient evolved from RNA. At least two protein en-
ribozymes would have been retained, and zymes were probably necessary to allow this
those are the ones that can be observed today. process to begin. The first, ribonucleoside
How could a world composed strictly of diphosphate reductase, converts RNA nucleo-
RNAs, however, be able to begin protein syn- tides to DNA nucleotides by reducing the hy-
thesis? While it seems like a tall order, scientists droxyl group located on the 2 carbon of
have envisioned an early version of the ribo- ribose. Perhaps more important, the enzyme
some that was composed exclusively of RNA. reverse transcriptase would have been neces-
Biologist Harry Noller reported in the early sary to transcribe RNA genomes into corre-
1990s that the activity of the modern ribosome sponding DNA versions. Examples of both of
that is responsible for catalyzing the formation these enzymes exist in the modern world.
of peptide bonds between amino acids is in fact Some concluding observations are in order
carried out by rRNA. This so-called peptidyl- to summarize the evidence that RNA and not
transferase activity had always been attributed DNA was very likely the first living molecule.
to one of the ribosomal proteins, and rRNA No enzymatic activity has ever been attributed
had been envisioned as playing a primarily to DNA; in fact, the 2 hydroxyl group that RNA
structural role. Nollers discovery that the large possesses and DNA lacks is vital to RNAs ability
ribosomal RNA is actually a ribozyme allows to function as a ribozyme. Furthermore, ribose
scientists to picture a ribosome working in is synthesized much more easily than deoxy-
roughly the same way that modern ones do, ribose under laboratory conditions. All mod-
RNA World 689
ern cells synthesize DNA nucleotides from RNA model, another model is now needed to estab-
precursors, and many other players in the cellu- lish the precursor to the RNA world.
lar machinery are RNA-related. Important ex- Apart from origin-of-life concerns, the dis-
amples include adenosine triphosphate (ATP), coveries that led to the RNA world theory are
the universal cellular energy carrier, and a host beginning to have a more practical impact in
of coenzymes such as nicotinamide adenine the fields of industrial genetic engineering and
dinucleotide (NAD), derived from B vitamins medical gene therapy. The unique ability of ri-
and vital in energy metabolism. bozymes to find particular sequences and initi-
ate cutting and pasting at desired locations
Impact and Applications makes them powerful tools. Impressive uses
The discovery of ribozymes and the other in- have already been found for these tools in theo-
teresting classes of RNAs has dramatically al- retical molecular biology and in the genetic en-
tered the understanding of genetic processes at gineering of plants and bacteria. Most impor-
the molecular level and has provided compel- tant to humans, however, are the implications
ling evidence in support of exciting new theo- for curing or treating genetically related dis-
ries regarding the origin of life and cellular evo- ease using this powerful new RNA-based tech-
lution. The RNA world theory, first advanced as nology.
a radical and unsupported hypothesis in the Gene therapy, in general, is based on the
early 1970s, has gained almost universal accep- idea that any faulty, disease-causing gene can
tance by scientists. It is the solution to the evo- theoretically be replaced by a genetically engi-
lutionary paradox that has plagued scientists neered working replacement. While theoreti-
since the discovery and understanding of the cally a somewhat simple idea, in practice it is
central dogma: Which came first, DNA or pro- technically very challenging. Retroviruses may
teins? Since they are inextricably dependent be used to insert DNA into particular target
upon each other in the modern world, the idea cells, but the results are often not as expected;
of the RNA world proposes that, rather than one the new genes are difficult to control or may
giving rise to the other, they are both descended have adverse side effects. Molecular biologist
from RNA, that most ancient of genetic and Bruce Sullenger pioneered a new approach to
catalytic molecules. Unfortunately, the RNA gene therapy, which seeks to correct the ge-
world model is not without its problems. netic defect at the RNA level. A ribozyme can
In the mid- to late 1990s, several studies on be engineered to seek out and replace dam-
the stability of ribose, the sugar portion of aged sequences before they are translated into
ribonucleotides, showed that it breaks down defective proteins. Sullenger has shown that
relatively easily, even in neutral solutions. A this so-called trans-splicing technique can work
study of the decay rate of ribonucleotides at dif- in nonhuman systems and, in 1996, began trials
ferent temperatures also caused some concern to test his procedure in humans.
for the RNA world theory. Most current scenar- Many human diseases could be corrected us-
ios see life arising in relatively hot conditions, ing gene therapy technology of this kind, from
at least near boiling, and the instability of ribo- inherited defects such as sickle-cell disease to
nucleotides at these temperatures would not al- degenerative genetic problems such as cancer.
low for the development of any significant RNA Even pathogen-induced conditions such as ac-
molecules. Ribonucleotides are much more quired immunodeficiency syndrome (AIDS),
stable at 0 degrees Celsius (32 degrees Fahren- caused by the human immunodeficiency virus
heit), but evidence for a low-temperature envi- (HIV), could be amenable to this approach. It
ronment for the origin of life is limited. Conse- is ironic and gratifying that an understanding
quently, some evolutionists are suggesting that of the ancient RNA world holds promise for
the first biological entities might have relied on helping scientists to solve some of the major
something other than RNA, and that the RNA problems in the modern world of DNA-based
world was a later development. Therefore, al- life.
though the RNA world seems like a plausible Matthew M. Schmidt, updated by Bryan Ness
690 RNA World
See also: Ancient DNA; Antisense RNA; left from this historic biological period. Illus-
Chromosome Structure; DNA Isolation; DNA trated (some color).
Repair; DNA Replication; DNA Structure and Hart, Stephen. RNAs Revising Machinery.
Function; Genetic Code; Genetic Code, Crack- Bioscience 46 (May, 1996). A discussion of the
ing of; Molecular Genetics; Noncoding RNA use of ribozymes in gene therapy.
Molecules; One Gene-One Enzyme Hypothe- Horgan, John. The World According to RNA.
sis; Protein Structure; Protein Synthesis; Repet- Scientific American 189 (January, 1996). Sum-
itive DNA; RNA Isolation; RNA Structure and marizes the accumulated evidence that RNA
Function; RNA Transcription and mRNA Pro- molecules once served both as genetic and
cessing. catalytic agents.
Miller, Stanley L. From the Primitive Atmosphere to
Further Reading the Prebiotic Soup to the Pre-RNA World. NASA
De Duve, Christian. The Beginnings of Life on CR-2076334007116722. Washington, D.C.:
Earth. American Scientist 83 (September/ National Aeronautics and Space Administra-
October, 1995). Discusses several scenarios tion, 1996. Miller discusses his famous 1953
regarding RNAs possible involvement in experiment, whereby he produced organic
lifes origins. amino acids from inorganic materials in lab-
Gesteland, Raymond F., Thomas R. Cech, and oratory, igniting a new understanding of
John F. Atkins, eds. The RNA World: The Na- how RNA and DNA work.
ture of Modern RNA Suggests a Prebiotic RNA. Watson, James D., et al. The Molecular Biology of
2d ed. Cold Spring Harbor, N.Y.: Cold the Gene. 5th ed. Menlo Park, Calif.: Ben-
Spring Harbor Laboratory Press, 1999. An jamin Cummings, 2003. Includes a compre-
advanced, detailed look at the theories be- hensive discussion of all aspects of the RNA
hind the RNA world, the evidence for its ex- world.
istence, and the modern fossils that may be
Shotgun Cloning
other samples. A cloned gene can also be in-
Field of study: Genetic engineering and serted into an expression vector where it will
biotechnology produce the genes protein product.
Significance: Shotgun cloning is the random inser- Shotgun cloning begins with the isolation of
tion of a large number of different DNA fragments DNA from the organism of interest. In separate
into cloning vectors. A large number of different re- test tubes, the DNA to be cloned and the cloning
combinant DNA molecules are generated, which vector DNA are digested (cut) with a restriction
are then introduced into host cells, often bacteria, endonuclease that cuts the vector in just one
and amplified. Because a large number of differ- location and the foreign DNA many times. Many
ent recombinant DNAs are generated, there is a restriction endonucleases create single-
high likelihood one of the clones contains a frag- stranded ends that are complementary, so the
ment of DNA of interest. end of any DNA molecule cut with that endo-
nuclease can join to the end of any other DNA
Key terms cut with the same endonuclease. When the di-
cloning vector: a plasmid or virus into which gested vector and foreign DNA are mixed, they
foreign DNA can be inserted to amplify the join randomly and are then sealed using DNA
number of copies of the foreign DNA ligase, an enzyme that seals the small gap be-
marker: a gene that encodes an easily detected tween two pieces of DNA. This creates recombi-
product that is used to indicate that foreign nant DNA molecules composed of a copy of the
DNA is in an organism vector and a random copy of foreign DNA. The
recombinant DNA: a novel DNA molecule recombinant DNA molecules are then intro-
formed by the joining of DNAs from differ- duced into host cells where the cloning vector
ent sources can replicate each time the cell divides, which is
restriction endonuclease: an enzyme that approximately every twenty minutes in the case
recognizes a specific nucleotide sequence in of Escherichia coli. The resulting collection of
a piece of DNA and causes cleavage of the clones, each containing a potentially different
DNA; often simply called a restriction en- fragment of foreign DNA, called a genomic li-
zyme brary. If a large collection of clones is produced,
it is likely that every part of the genome from
Recombinant DNA Cloning and Shotgun which the DNA came will be represented some-
Cloning where in the genomic library.
Before the development of recombinant The presence of the cloning vector in host
DNA cloning, it was very difficult to study DNA cells is determined by selecting for a marker
sequences. Cloning a DNA fragment allows a gene in the cloning vector. Most vectors have
researcher to obtain large amounts of that spe- two marker genes, and often both are different
cific DNA sequence to analyze without inter- antibiotic resistance genes. A common exam-
ference from the presence of other DNA se- ple is the plasmid pBR322, which has a tetracy-
quences. There are many uses for a cloned cline and an ampicillin resistance gene. A re-
DNA fragment. For example, a DNA fragment striction endonuclease cuts once somewhere
can be sequenced to determine the order of in the tetracycline resistance gene, and if a
its nucleotides. This information can be used foreign DNA fragment becomes incorporated,
to determine the location of a gene and the the resulting recombinant plasmid will have a
amino acid sequence of the genes protein nonfunctional tetracycline resistance gene. A
product. Cloned pieces of DNA are also useful bacterial cell transformed with a recombinant
as DNA probes. Because DNA is made of two plasmid will therefore be resistant to ampicil-
strands that are complementary to each other, lin, but will be sensitive to tetracycline. Many
a cloned piece of DNA can be used to probe for plasmids will not incorporate any foreign DNA
copies of the same or similar DNA sequences in and will be nonrecombinant. Cells that are
692 Sickle-Cell Disease
transformed with a nonrecombinant plasmid See also: cDNA Libraries; Cloning; Cloning
will be resistant to both tetracycline and ampi- Vectors; Genomic Libraries; Genomics; Hu-
cillin. After the bacterial cells have been trans- man Genome Project; Restriction Enzymes.
formed, they are grown on a medium with
ampicillin. The only cells that will survive will Further Reading
be those that have received a plasmid vector. To Glick, Bernard R. Molecular Biotechnology: Princi-
determine which cells have received a recombi- ples and Applications of Recombinant DNA.
nant plasmid, the colonies are carefully trans- Washington, D.C.: ASM Press, 2003. Covers
ferred onto a new medium that has both ampi- the scientific principles of biotechnology
cillin and tetracycline. On this medium, only and gives applications. Color illustrations.
cells with nonrecombinant plasmids will sur- Kreuzer, Helen, and Adrianne Massey. Recombi-
vive. Thus, colonies that grew on the first me- nant DNA and Biotechnology: A Guide for Stu-
dia, but not on the second, contain recombi- dents. 2d ed. Washington, D.C.: ASM Press,
nant plasmids. Cells from these colonies are 2001. For high school level. Gives introduc-
collected and grown, each in a separate tube, tory text and activities to learn the basics of
and these constitute a genomic library. molecular biology and biotechnology.
Once a genomic library has been produced, _______. Recombinant DNA and Biotechnology: A
the DNA fragments contained in it can be Guide for Teachers. 2d ed. Washington, D.C.:
screened and analyzed in various ways. Using ASM Press, 2001. For high school and intro-
the right techniques, specific genes can be ductory college level. Presents a guide to
found, which can then be used in future analy- biotechnolgy with history, applications, sim-
ses and experiments. ple protocols, and exercises.
Micklos, David A, Greg A. Freyer, and David A.
Alternatives to Shotgun Cloning Crotty. DNA Science: A First Course. Cold
In shotgun cloning, many different DNA Spring Harbor, N.Y.: Cold Spring Harbor
fragments from an organism are cloned, and Laboratory Press, 2003. Gives an introduc-
then the specific DNA clone of interest is iden- tion to molecular biology techniques for
tified. The number of clones can be reduced, high school or beginning college students.
making the search easier, if the DNA of interest Includes background text and laboratory
is known to be in a restriction endonuclease procedures.
fragment of a specific size. DNA can be size- Watson, James D., et al. Recombinant DNA. New
selected before cloning using gel electrophore- York: Scientific American Books, 1992. Pro-
sis, in which an electric current carries DNA vides a description of shotgun cloning as
fragments through the pores or openings of well as an overview of many other cloning
an agarose gel. DNA migrates through the gel methods. Full-color illustrations, diagrams,
based on DNA fragment size, with the smaller bibliography, index.
fragments traveling more rapidly than the
larger fragments. DNA of a specific size range
can be isolated from the gel and then used for
cloning. Finally, to clone a piece of DNA known
to code for a protein, scientists can use an
enzyme called reverse transcriptase to make
Sickle-Cell Disease
DNA copies (called a complementary DNA or Field of study: Diseases and syndromes
cDNA) of isolated messenger RNA (mRNA). Significance: Sickle-cell disease is a treatable hered-
The cDNA is then cloned, in a similar manner itary blood disease that occurs mainly among peo-
to that already discussed, to produce what is ple of African, Caribbean, and Mediterranean de-
called a cDNA library. One of the advantages of scent, which has led to concerns, particularly in
this approach is that the number of clones is the United States, that it might be used as a surro-
greatly reduced. gate for discrimination against particular racial
Susan J. Karcher, updated by Bryan Ness groups. It is one of the most well documented exam-
Sickle-Cell Disease 693
Key terms
hemoglobin: a molecule made up of
two alpha and two beta amino acid
chains whose precise chemical and
structural properties normally al-
low it to bind with oxygen in the
lungs and transport it to other parts
of the body
heterozygous: having two different Image not available
forms (alleles) of the same gene
(locus), each inherited from a dif-
ferent parent
homozygous: having the same allele
from both parents
hydroxyurea, a chemical thought to stimulate when the red cells of people who are hetero-
the production of fetal hemoglobin. zygous for the sickle-cell gene are invaded by
Attention to and funding for research on the malarial parasite, the red cells adhere to
sickle-cell disease has increased since World blood vessel walls, become deoxygenated, and
War II, although misinformation about the dis- assume the sickled shape, prompting both
ease persists. Many have raised concerns that their destruction and that of their parasitic
carriers of the disease are discriminated against, invader. This provides the heterozygous car-
both by potential employers and insurance com- rier with a natural resistance to malaria and
panies. Several organizations were established explains the relatively high frequency of the
in the United States in the early 1970s to pro- sickle-cell gene in such environments. Sickle-
mote education, treatment, and research for cell disease thus represents a particularly well-
the disease, including Howard Universitys Cen- documented example of a selective process
ter for Sickle-Cell Disease, founded by Ronald known as heterozygote advantage, in which in-
B. Scott in 1972. Today, forty U.S. states, the dividuals heterozygous for a given gene have a
District of Columbia, Puerto Rico, and the Vir- greater probability of surviving or reproducing
gin Islands, were screening newborns for the than either homozygote. This is an important
sickle-cell trait. phenomenon from an evolutionary standpoint
because it provides a mechanism by which ge-
Evolutionary Significance netic diversity in a population may be pre-
In most cases, hereditary diseases with such served.
negative consequences as those associated with David Wijss Rudge
sickle-cell disease are kept at low frequencies in See also: Amniocentesis and Chorionic Vil-
populations by natural selection; that is, indi- lus Sampling; Biopharmaceuticals; Genetic En-
viduals who carry genes for hereditary diseases gineering; Genetic Screening; Genetic Testing;
are less likely to survive and reproduce than Hardy-Weinberg Law; Incomplete Dominance;
those who carry the normal form of the gene. Mutation and Mutagenesis; RFLP Analysis;
The continued presence of defective genes in a Shotgun Cloning.
population therefore reflects the action of
chance mutations. Yet the sickle-cell gene is Further Reading
much more common than one would expect if Allison, Anthony. Sickle Cells and Evolution.
its frequency in a population was caused by mu- Scientific American 202 (August, 1956). An
tation alone. early discussion of sickle-cell disease as an
In some areas that are associated with a high evolutionary phenomenon.
incidence of malaria, such as the equatorial Anionwu, Elizabeth N., and Karl Atkin. The Poli-
belt of Africa, some tribes have been found to tics of Sickle Cell and Thalassaemia. Philadel-
have frequencies of the sickle-cell gene as high phia: Open University Press, 2001. Discus-
as 40 percent. This curious correlation be- sion centers on the experiences of patients
tween high frequencies of the sickle-cell gene and their families. Bibliography, index.
and areas where malaria is common led An- Ingram, Vernon M. How Do Genes Act? Scien-
thony C. Alison to suggest, in 1953, that the tific American 204 (January, 1958). Summa-
sickle-cell gene provides an advantage in such rizes authors research on the amino acid
environments. Malaria is a deadly, mosquito- structure of hemoglobin.
borne disease caused by a microscopic para- Serjeant, Graham R., and Beryl E. Serjeant.
site, Plasmodium vivax, which uses human red Sickle Cell Disease. 3d ed. New York: Oxford
blood cells as hosts for part of its life cycle. University Press, 2001. Discusses the biology
People who have normal hemoglobin are vul- of sickle-cell disease and the diseasess man-
nerable to the disease, and people who are ho- agement. Illustrations, maps, bibliography,
mozygous for the sickle-cell gene in malaria- index.
infested regions die quite early in life because Steinberg, Martin H., et al., eds. Disorders of He-
of anemia and other complications. However, moglobin: Genetics, Pathophysiology, and Clini-
696 Signal Transduction
cal Management. Foreword by H. Franklin ing. The protein products of these genes allow cells
Bunn. New York: Cambridge University to communicate with each other in order to coordi-
Press, 2001. Covers the diseases molecular nate their metabolism, movements, and reproduc-
and genetic bases, their epidemiology and tion. Failure of cells to communicate properly can
genetic selection, and their diagnoses and lead to cancer, defects in embryological develop-
treatments. Illustrations (some color), bibli- ment, and many other disorders.
ography, index.
Tapper, Melbourne. In the Blood: Sickle Cell Ane- Key terms
mia and the Politics of Race. Philadelphia: Uni- cell cycle: the orderly sequence of events by
versity of Pennsylvania Press, 1999. Explores which a cell grows, duplicates its chromo-
anthropological, genetic, medical, and po- somal DNA, and partitions the DNA into two
litical texts, and other discourses on race, to new cells
discuss how the disease has come to be cell signaling: communication between cells
known as a black disease since its medical that occurs most commonly when one cell
identification in 1910. Index. releases a specific signaling molecule that
Wailoo, Keith. Dying in the City of the Blues: Sickle is received by another cell
Cell Anemia and the Politics of Race and Health. receptors: molecules in target cells that bind
Chapel Hill: University of North Carolina specifically to a particular signaling mole-
Press, 2001. Examines medical literature, pa- cule
tient accounts, black newspapers, blues lyr- target cell: the cell that receives and re-
ics, and other popular sources, and discusses sponds to a signaling molecule
how individuals made sense of and lived with
the disease, even before its medical and sci- Signal Transduction Pathways
entific recognition. Illustrations, bibliogra- Signal transduction can occur by a number
phy, index. of different, often complex, sequences of mo-
lecular events called signal transduction path-
Web Sites of Interest ways, which result in several kinds of target cell
Dolan DNA Learning Center, Your Genes Your response, including the turning on of genes,
Health. http://www.ygyh.org. Sponsored by the activation of metabolic pathways, and ef-
the Cold Spring Harbor Laboratory, this fects on the cell cycle. Among the signaling
site, a component of the DNA Interactive molecules found in higher organisms are hor-
Web site, offers information on more than a mones, local mediators that produce local
dozen inherited diseases and syndromes, in- physiological effects, growth factors that act lo-
cluding sickle-cell disease. cally to promote growth, and survival factors
Sickle Cell Information Center. http://www that act locally to repress cell suicide (apopto-
.scinfo.org. This site provides news and re- sis). Growth factors and survival factors are par-
search updates, worldwide resource links, ticularly important during embryological de-
and an interactive link for children. velopment, when they orchestrate the changes
in cell types, positions, and numbers that give
rise to the new organism.
Types of Receptors
Signal Transduction Most signal transduction pathways begin
with the binding of signaling molecules to spe-
Field of study: Molecular genetics cific receptors in target cells. Signaling mole-
Significance: Signal transduction consists of all of cules are often referred to as receptor ligands.
the molecular events that occur between the arrival The binding of the ligand to its receptor initi-
of a signaling molecule at a target cell and its re- ates a signal transduction pathway. A cell can
sponse. A significant proportion of the genome in respond to a particular signaling molecule only
animals consists of genes involved in cell signal- if it possesses a receptor for it.
Signal Transduction 697
Receptors are protein molecules. There are not previously producing. The hormone hy-
two categories of them, based on location in drocortisone, for example, triggers the synthe-
the cell: receptors that are intracellular and re- sis of the enzymes aminotransferase and
ceptors that are anchored in the cells surface tryptophan oxygenase. A single hormone such
membrane. The membrane-anchored recep- as hydrocortisone can turn on synthesis of two
tors can be further divided based on the steps or more proteins if each of the genes for the
of the signal transduction pathway that they ini- proteins contains an HRE. In some cases, when
tiate: receptors that bind to and activate GTP- hormone-receptor complexes bind to an HRE,
binding proteins (G proteins), receptors that they suppress transcription rather than pro-
are enzymes, and receptors that are ion chan- mote it.
nels. Receptors that are channels bind neuro-
transmitters or hormones and increase or de- G Protein-Binding Receptors
crease the flow of specific ions into the cell, Many hormones, growth factors, and other
leading to a physiological response by the cell. signaling molecules bind to membrane recep-
These receptors generally do not have a direct tors that can associate with and activate hetero-
effect on gene expression (although changes trimeric G proteins when a signaling mole-
in a cells calcium ion concentrations can influ- cule is bound to the receptor. Heterotrimeric G
ence gene expression). Each of the other re- proteins are a family of proteins that are pres-
ceptor types stands at the head of a signal ent on the cytoplasmic surface of the cell mem-
transduction pathway that is characteristic for brane. Many cell types in the body contain one
each receptor type and can lead to gene expres- or more of these family members, and differ-
sion. In what follows, some of the more com- ent cell types contain different ones. All hetero-
mon transduction pathways that can lead to trimeric G proteins are made up of three sub-
gene expression are described. units: the alpha, beta, and gamma subunits.
The alpha subunit has a binding site for GTP
Intracellular Receptors or GDP (hence the name G proteins) and is
Intracellular receptors include the recep- the principal part of the protein that differs
tors for lipid-soluble hormones such as steroid from one heterotrimeric G protein family
hormones. Some of these receptors are in the member to another. When the receptor is
cells cytoplasm and some are in the nucleus. empty (no signal molecule attached), these G
Hormone molecules enter the cell by first dif- proteins have GDP bound to the alpha sub-
fusing across the membrane and then binding unit and the G protein is not bound to the re-
to the receptor. Before the hormones enter the ceptor.
cell, the receptors are attached to chaperone However, when a signaling molecule binds
proteins, which hold the receptor in a configu- to the receptor, the cytoplasmic domain of the
ration that allows hormone binding but pre- receptors changes shape so that it now binds
vents it from binding to DNA. Hormone mole- to the G protein. In binding to the receptor,
cules displace these chaperone molecules, the G protein also changes shape, causing GDP
enabling the receptor to bind to DNA. If the re- to leave and GTP to bind instead. Simulta-
ceptor is a cytoplasmic receptor, the hormone- neously, the alpha subunit detaches from the
receptor complex is first transported into the beta-gamma subunit and both the alpha sub-
nucleus, where it binds to a specific DNA nucle- unit and the beta-gamma subunit detach from
otide sequence called a hormone response ele- the receptor. The alpha subunit or the beta-
ment (HRE) that is part of the promoter of cer- gamma subunit (depending upon the particu-
tain genes. In most cases the receptors bind as lar G-protein family member involved and the
dimers; that is, two hormone-receptor com- cell type) then activates (or with some G-protein
plexes bind to the same HRE. The receptor- family members, inhibits) one of several en-
hormone complex functions as a transcription zymes, most commonly adenylate cyclase or
factor, promoting transcription of the gene phospholipase C. Alternatively, they can open
and production of a protein that the cell was or close a membrane ion channel, altering the
698 Signal Transduction
electrical properties of the cell; for example, cytoplasm (the cytoplasmic domain) has cata-
potassium ion channels in heart muscle cells lytic capability. Binding of a signaling molecule
can be opened by G proteins in response to the to the external domain of the receptor acti-
neurotransmitter acetylcholine. vates the catalytic activity of the cytoplasmic do-
In cases where adenylate cyclase or phospho- main. There are several kinds of catalytic recep-
lipase C is activated, these enzymes catalyze re- tors based on the type of reaction they catalyze;
actions that produce molecules called second these include receptor tyrosine phosphatases,
messengers, which, through a series of steps, receptor guanylate cyclases, receptor serine/
activate proteins that lead to a physiological re- threonine kinases, and receptor tyrosine ki-
sponse (such as contraction of smooth mus- nases. Receptor tyrosine kinases (RTKs) are
cle), a biochemical response (such as glycogen the most common of these.
synthesis) or a genetic response (such as acti- RTKs are the receptors for many growth fac-
vating a gene). tors and at least one hormone. For example,
Activation of adenylate cyclase causes it to they are the receptors for fibroblast growth
catalyze the conversion of adenosine triphos- factor (FGF), epidermal growth factor (EGF),
phate (ATP) to the second messenger cyclic platelet-derived growth factor (PDGF), nerve
adenosine monophosphate (cAMP), which in growth factor (NGF), and insulin. RTKs play a
turn activates a protein called protein kinase A role in regulating many fundamental pro-
which, in some cells, moves into the nucleus cesses, such as cell metabolism, the cell cycle,
and phosphorylates and activates transcription cell proliferation, cell migration, and embry-
factors such as CREB (CRE-binding protein). onic development. In most cases, when a ligand
CREB binds to a specific DNA sequence in binds to this type of receptor, a conformational
the promoter of certain genes called the CRE (shape) change occurs in the receptor so that
(cAMP-response element), as well as to other it binds to another identical receptor-ligand
transcription factors, to activate transcription complex to produce a double or dimeric recep-
of the gene. In other cells, protein kinase A acti- tor. The dimeric receptor then catalyzes a cyto-
vates enzymes or other proteins involved in plasmic reaction in which several tyrosine
physiological or metabolic responses. amino acids in the cytoplasmic domain of the
Activation of phospholipase C catalyzes the receptor itself are phosphorylated. The phos-
breakdown of a glycolipid component of the phorylated tyrosines then function as docking
cell membrane called phosphatidylinositol sites for several other proteins, each of which
bisphosphate (PIP2) into two second messen- can initiate one of the many branches of the
gers, inositol triphosphate (IP3) and diacyl- RTK signal transduction pathway, leading to
glycerol (DAG). DAG activates a protein called the various cell responses. One of the major
protein kinase C (PK-C), which in turn acti- branches of the RTK pathway that in many
vates other proteins, leading to various cell re- cases results in gene expression begins with the
sponses, including, in certain cells of the im- binding of the G protein ras (ras is not one of
mune system, activation of transcription factors the trimeric G proteins discussed above) to the
which turn on genes involved in the bodys im- activated RTK receptor via adapter proteins.
mune response to infection. IP3 causes the re- Binding of ras to the adapter proteins activates
lease of calcium ions stored in the endoplasmic it by allowing it to bind GTP instead of GDP. Ac-
reticulum. These ions bind and activate the tivated ras then phosphorylates the enzyme
protein calmodulin, which activates a variety of MEK, which phosphorylates and activates an
proteins, leading in most cases to a physiologi- enzyme of the MAP kinase family. In cases
cal response in the cell. where this enzyme is MAP kinase itself, the en-
zyme dimerizes, moves into the nucleus, and
Catalytic Receptors activates genes, usually many genes, by phos-
Catalytic receptors are receptors that func- phorylating and activating their transcription
tion as enzymes, catalyzing specific reactions in factors
the cell. The part of the receptor that is in the
Signal Transduction 699
Signal Transduction and the Cell Cycle example would be if the gene for pRB that
The biochemical machinery that produces binds to and inhibits the cyclin E transcription
the cell cycle consists of several cyclins whose factor were mutated such that the pRB could
concentrations rise and fall throughout the cell never bind to the transcription factor; then the
cycle. Cyclins activate cyclin-dependent kinases cell would divide continuously. Mutations in
(cdks), which activate the proteins that carry both ras and pRB are in fact known to cause
out the events of each stage of the cell cycle. In cancer in humans.
higher organisms, control of the cell cycle is Robert Chandler
carried out primarily by growth factors. In the See also: Burkitts Lymphoma; Cancer; Cell
absence of growth factors, many cells will stop Cycle, The; Cell Division; DNA Replication;
at a point in the cell cycle known as the G1 Gene Regulation: Bacteria; Model Organism:
checkpoint and cease dividing. The cell cycle is Saccharomyces cerevisiae; Oncogenes; One Gene-
started when the cells are exposed to a growth One Enzyme Hypothesis; Steroid Hormones;
factor. For example, some growth factors start Tumor-Suppressor Genes.
cell division by binding to a membrane recep-
tor and initiating the RTK/MAP kinase signal
transduction pathway. The activated transcrip- Further Reading
tion factor that results from this pathway acti- Alberts, Bray, et al. Molecular Biology of the Cell.
vates a gene called myc. The protein that is pro- New York: Garland, 2002. A condensed ver-
duced from this gene is itself a transcription sion of one of the standard textbooks in the
factor, which activates the cyclin D gene, which field of cell biology. One chapter contains es-
produces cyclin D, an important component of sential, basic information about signal trans-
the cell cycle biochemical machinery. Cyclin D duction.
activates cyclin-dependent kinase 4 (cdk4), Cell 103, no. 2 (October 13, 2000): 181-320. A
which drives the cell into the G1 phase of the special issue of the journal Cell devoted en-
cell cycle. cdk4 also causes an inhibiting mole- tirely to the topic of cell signaling. The cited
cule called pRB to be removed from a tran- pages contain three minireviews and
scription factor for the cyclin E gene. Cyclin E is eleven reviews of the relatively recent pri-
then produced and activates cyclin-dependent mary literature. A good entry into the pri-
kinase 2 (cdk2), which drives the cell into the S mary literature.
phase of the cell cycle, during which chromo- Gomperts, Kramer, et al. Signal Transduction.
somal DNA is replicated, leading to cell divi- San Diego, Calif.: Academic Press, 2002. Pro-
sion by mitosis. vides comprehensive yet readable coverage
of signal transduction; contains excellent
Signal Transduction and Cancer illustrations and citations of other litera-
Cancer is caused primarily by uncontrolled ture.
cell proliferation. Since many signal transduc- Hoch, James A., and Thomas J. Silhavy, eds.
tion pathways lead to cell proliferation, it is Two-Component Signal Transduction. Washing-
not surprising that defects in these pathways ton, D.C.: ASM Press, 1995. Written for mi-
can lead to cancer. For example, as described crobiologists working in the areas of gene
above, many growth factors promote cell prolif- expression, pathogenesis, and bacterial me-
eration by activating the RTK/MAP kinase sig- tabolism, covers the molecular and cellular
nal transduction pathway. In that pathway a se- biology of a wide variety of two-component
ries of proteins is activated (ras, MAP kinase, signal transduction systems in bacteria. Illus-
and so on). If a mutation occurred in the gene trated.
for one of these, ras for example, such that the Lodish, Harvey, et al. Molecular Cell Biology. New
mutant ras protein is always activated rather York: W. H. Freeman, 2000. One of the stan-
than being activated only when it binds to the dard textbooks in the field of cell biology.
receptor, then the cell would always be dividing Chapter 20 provides detailed information
and cancerous growth could result. Another on signal transduction.
700 Smallpox
composed of linear, double-stranded DNA con- pressed. One of the first steps involves the pro-
taining more than two hundred genes. Chem- duction of enzymes that degrade the proteins
ically, the smallpox virion consists of 90 percent of the viral core, which releases the naked viral
protein, 3 percent DNA, and 5 percent lipid. DNA into the cytoplasm. Additional transcrip-
The DNA genome codes for several hundred tion takes place, initially producing structural
polypeptides, including several transcriptases proteins and enzymes, including DNA poly-
responsible for replication of the virus within merase, which promotes the replication of the
the cells of the host. viral DNA. Finally, the late messenger RNA
Replication of smallpox begins when the vi- (mRNA) is transcribed, producing additional
rus attaches to the surface of a host cell. After structural proteins and assembly enzymes that
binding to receptors on the plasma membrane complete virion construction. During viral rep-
of the host cell, the host cell passes the virus lication, most host-cell protein synthesis is
into the cytoplasm by endocytosis. Once inside blocked, because transport of host-cell mRNA
the cell, the virus becomes trapped in a lyso- molecules though the nuclear envelope into
some vesicle in the cytoplasm. The first step in the cytoplasm is prevented.
removing its viral coat probably occurs at this Newly completed virons exit the host cell
stage, as host cell enzymes dissolve the viral en- through microvilli on the cell surface or fuse
velope. The viral core, containing the DNA, with the cell membrane, after which they exit
then exits the lysosome and enters the cyto- the cell by the process of exocytosis. Once in
plasm, where the viral genome can be ex- the tissue, fluids, and bloodstream, the newly
released and highly infectious viral particles rash that begins in the mouth and spreads
can invade and replicate in other host cells. across the face, forearms, trunk, and legs. The
rash is first confined to a reddish or purplish
Transmission swelling of the blood vessels but soon becomes
Smallpox is transmitted from one human to pustular as little round nodules appear on the
another, either by direct contact or via droplets surface of the body. If the patient recovers, the
released into the air during sneezing and pustules crust over and the resultant scabs
coughing fits. The virus does not live long out- eventually split, which causes scarring of the
side the human body and does not reproduce face.
outside the human body. No natural animal Death occurs within a few days following the
carriers of variola other than monkeys, which appearance of the rash, most commonly from
are also susceptible, are known for the small- toxemia caused by variola antigens and various
pox disease. In extremely rare cases smallpox is immune complexes circulating in the blood. In
transmitted by carriers that are themselves im- some cases the disease is followed by encephali-
mune to the disease but can transmit the dis- tis. Smallpox fatalities typically occur because
ease to others. Still, only a few droplets settling of complications such as pneumonia, septice-
on another person are sufficient to transmit mia, and nephritis (kidney failure). Survivors
smallpox. Because of the virulence and mode often suffer from general scarring, ulcers, scar-
of transmission, public health regulations spec- ring of the cornea leading to blindness, and
ify decontamination procedures. Living quar- skin abscesses. Treatment of survivors with che-
ters, bedding, clothes, and other articles of in- motherapy has reduced the severity of many of
fected persons must be thoroughly cleansed by these complications.
heat or with formaldehyde, or destroyed alto- The considerably less virulent form of small-
gether. pox, Variola minor, produces a much less severe
illness characterized by fever, chills, and a
Pathogenesis and Symptoms milder rash. The same conditions are some-
Infection occurs when the variola virus en- times seen in patients who have previously
ters the respiratory mucosa of the nasal or pha- been vaccinated or even as a response to vacci-
ryngeal region of the upper respiratory tract of nations.
humans. Apparently, only a few viral particles
are needed to produce an infection. After a few Treatment and Control
hours or a few days, the virus migrates to and in- Despite decades of research, there is no spe-
vades cells in the lymph nodes of the nasopha- cific treatment for smallpox other than bed rest
ryngeal region, where it enters the cells, follow- and application of antibiotics to prevent sec-
ing which rapid reproduction occurs. After a ondary infections. Therefore, only prevention
few days, it enters the bloodstream, a condition of spread by quarantine of infected persons
called viremia. At this time symptoms of small- prevents epidemics. Immediate recognition of
pox appear. The virus spreads into lymph the disease remains the strongest control mea-
nodes, spleen, and bone marrow, where repro- sure, followed by vaccination of all health care
duction continues rapidly. By the eighth day of personnel and others that may come in contact
infection, the virus is contained in white blood with infected persons.
cells or leukocytes, which transmit it to the Widespread and aggressive inoculation pro-
small blood vessels in the dermis of the skin as grams conducted during the first half of the
well as in the mucosa that lines the mouth and twentieth century eradicated smallpox from
pharynx. most regions of the world, including North
Following an incubation period of about two America, Eurasia, and Oceania, largely as a re-
weeks (the range is between seven and seven- sult of the success of the vaccination process
teen days), symptoms appear, including high originally developed by Edward Jenner. By
fever, headache, nausea, malaise, and often 1967 smallpox was found only in thirty-three
backache. Accompanying these symptoms is a countries and had an annual infection rate of
Smallpox 703
10 million to 15 million cases. In that year the would be classed as an international crime, but
World Health Organization (WHO) initiated a prevention of its use is difficult unless all exist-
campaign to eliminate smallpox completely as ing stocks can be identified and destroyed.
a human disease, concentrating in Africa, In- Smallpox is a potential bioterrorism weapon
dia, and Indonesia. The last case of smallpox in because of its transmissibility, its known lethal-
Asia was reported in Bangladesh in 1975 and ity, and the general lack of immunity of much
the last known smallpox victim was recorded in of the global population. Because of its bioter-
Somalia in October, 1977. Eradication was con- rorism potential, research is now centered on
sidered accomplished by 1979. The cost of the rapid identification methods that enable the
eradication campaign was $150 million. early detection of smallpox as well as aggressive
Most researchers conclude that the effective vaccination programs for individuals most at
eradication of smallpox was made possible for risk, who have been identified as health care
several reasons: (1) smallpox cases could be workers. In addition, smallpox vaccinations
quickly and positively identified, (2) there are were reinstated in 2002 for some U.S. military
no natural carriers that serve as disease reser- personnel and some health care workers, es-
voirs, (3) humans were the only carriers, (4) in- sentially those considered at highest risk. The
dividuals who survived did not continue to har- vaccine is made from live but weakened vac-
bor the virus, and (5) the smallpox vaccine cinia virus that is pricked into the skin. The
proved highly effective. characteristic blister scabs over within three
weeks. During this time it is possible to transmit
Recombinant DNA Technology and the virus to other parts of the body and to other
Vaccinia Viruses people. Reactions to the vaccine range from a
Vaccinia viruses can absorb comparatively mild soreness around the vaccination site to
large amounts of foreign DNA without losing more severe effects that may include brain in-
their ability to replicate, giving rise to the idea flammation and a rare and progressive bacterial
that they may provide a vehicle for providing inflammation called vaccinia that is sometimes
immunity for other viral diseases of humans. fatal. For these reasons, mass vaccinations of
One of several ongoing investigations involves the general public have been discouraged.
insertion of 22-25 kilobase pairs into vaccinia. See also: Anthrax; Bacterial Resistance and
Experiments using this technique have pro- Super Bacteria; Biological Weapons; Emerging
duced vaccinia strains that encode surface pro- Diseases; Gene Regulation: Viruses; Heredi-
teins (antigens) of a number of important vi- tary Diseases; Viral Genetics.
ruses, including influenza, hepatitis B, and Dwight G. Smith
herpesvirus. One possible outcome of these re-
combinant DNA experiments is the produc- Further Reading
tion of vaccinia strains that can serve as vac- Anderson, R. M., and R. M. May. Infectious Dis-
cines for several viral diseases simultaneously. eases of Humans: Dynamics and Control. Ox-
ford, England: Oxford University Press,
Smallpox as a Bioterrorism Weapon 1992. Smallpox and other major diseases of
Since its official eradication in 1979, only humans are described and discussed.
two stocks of smallpox officially remain; one Brooks, G. F., J. S. Butel, and S. A. Morse. Medi-
stock is held at the Centers for Disease Control cal Microbiology. 21st ed. Stamford, Conn.:
in Atlanta, Georgia, and the other is kept at Appleton and Lange, 1998. Includes a sum-
VECTOR, Novosibirsk, in central Russia. How- mary of biological and medical properties of
ever, there remains the possibility that clandes- the virus that causes smallpox.
tine stocks still exist, and these stocks may serve Fenner, F., D. A. Henderson, I. Arita, Z. Jezek,
as potential bioterrorism weapons, either to be and I. D. Ladnyi. Smallpox and Its Eradication.
used against military or civilian populations or Geneva, Switzerland: World Health Organi-
to be mounted as international threats. The zation Report, 1988. The detailed story of
use of smallpox as a bioterrorism weapon the eradication of smallpox as a disease of
704 Sociobiology
When sociobiological concepts were applied When a reproductively mature acorn wood-
to human sociality, many scientists, especially pecker stays with its parents to help raise the
social scientists, feared a return to scientific next generation, the woodpecker is bypassing
theories of racial and gender superiority. They its own reproduction for one or more years.
rebelled vigorously against such ideas. Wilson Should it not leave home and attempt to set up
was vilified by many of these scientists, and its own nest and hatch its own young? Eusocial
some observers assert that the term socio- species, such as honeybees and naked mole
biology generated such negative responses that rats, actually have many members who never re-
scientists who studied in the field began using produce; they work their entire lives to support
other names for it. At least one scientific jour- and protect a single queen, several reproduc-
nal dropped the word sociobiology from its tive males, and their offspring. It would seem
title, perhaps in response to its negative conno- that all these altruistic situations should pro-
tations. However, the study of sociobiological duce a decrease in the number of members of
phenomena existed in the social branches of the next generation carrying altruistic genes in
animal behavior and ethology long before the favor of more members with selfish genes.
term was coined. Despite the criticism, research Sociobiologists have reinterpreted some of
has continued under the name sociobiology these apparently altruistic acts as camouflaged
as well as other names, such as behavioral selfishness. The barking prairie dog, for exam-
ecology. ple, may be notifying the hawk that it sees the
predator, that it is close to its burrow and can-
Sociobiology and the Understanding of not be caught; therefore, the hawk would be
Altruism better off hunting someone else. Perhaps the
Sociobiologists have contributed to the un- young acorn woodpecker learns enough from
derstanding of a number of aspects of social be- the years of helping to make its fewer reproduc-
havior, such as altruism. Illogical in the face of tive years more successful than its total repro-
evolutionary theory, apparently altruistic acts ductive success without the training period.
can be observed in humans and other animal It is difficult, however, to explain the worker
groups. Darwinian evolution holds that the or- honeybee this way. The worker bee never gets
ganism that leaves the largest number of ma- an opportunity to reproduce. Sociobiologists
ture offspring will have the greatest influence explain this and other phenomena by invoking
on the characteristics of the next generation. kin selection. Since the worker bees are closely
Under this assumption, altruism should disap- related to the queen (as sisters or daughters),
pear from the population as each individual to reproductive males, and to other workers
seeks to maximize its own offspring produc- they help feed and protect, they share a large
tion. If an individual assists another, it uses en- number of genes with them. If they help raise
ergy, time, and material it might have used for enough brothers and sisters (especially males
its own survival and reproduction and simulta- and queens) to more than make up for the off-
neously contributes energy, time, and material spring they do not produce themselves, they
to the survival and reproductive effort of the re- will actually increase the proportion of individ-
cipient. As a result, more members of the next uals similar to themselves more than if they
generation should be like the assisted organ- selfishly reproduced.
ism than like the altruistic one. Should this The prairie dogs behavior might be ex-
continue generation after generation, altruism plained this way as well. The organisms the
would decrease in the population and selfish- prairie dog is warning are primarily relatives.
ness would increase. Yet biologists have cata- By warning them, the prairie dog helps pre-
loged a number of altruistic behaviors. serve copies of its own genes in its relatives. If
When a prairie dog barks, thus warning the cost of the behavior (an occasional barking
others of the presence of a hawk, the prairie prairie dog being captured by a hawk because
dog draws the hawks attention. Should it not the warning call drew the hawks attention) is
just slip into its burrow, out of the hawks reach? more than compensated for by the number of
706 Sociobiology
Edward O. Wilsons studies of insect behavior influenced his controversial theories of sociobiology. (AP/Wide World Photos)
relatives saved from the hawk by the warning, argument over the relative importance of he-
kin selection will preserve the behavior. The redity or environment (nature or nurture) in
helper acorn woodpeckers behavior may be determining individual success had been more
explained in similar ways, not as an altruistic or less decided in favor of the environment, at
act but as a selfish act to favor copies of the least by social scientists. Poor people were not
helpers genes in its relatives. Another explana- poor because they were inherently inferior but
tion of altruism set forth by sociobiologists is because the environment they lived in did not
reciprocity or reciprocal altruism: If the prairie give them an equal chance. Black, Hispanic,
dog is sometimes warned by others and returns and other minority people were not inordi-
the favor by calling out a warning when it sees a nately represented among the poor because
predator, the prairie dog town will be safer for they were genetically inferior but because their
all prairie dogs. environment kept them from using their ge-
netic capabilities.
Opposition to the Application of Sociobiologists entered the fray squarely on
Sociobiology to Humans the side of an appreciable contribution from
Wilsons new synthesis attempted to incor- genetic and evolutionary factors. Few, if any,
porate biology, genetics, population biology, said that the environment was unimportant in
and evolution into the study and explanation the molding of racial, gender, and individual
of social behavior. When the analyses turned to characteristics; rather, sociobiologists claimed
human sociality, critics feared that they would that the genetic and evolutionary history of hu-
lead back to the sexist, racist, and determinist man individuals and groups played an impor-
viewpoints of the early twentieth century. The tant role in determining their capabilities, just
Sociobiology 707
as they do in other animals. Few, if any, claimed University Press, 1999. Argues that human
that this meant that one race, gender, or group behavior and cultural production, such as
was superior to another. However, many (if not habits and the making of songs, ideas, and
all) sociobiologists were accused of promoting objects, are memetic. That is, they replicate
racist, sexist, and determinist ideas with their in the form of memes, as do genes, within
application of sociobiological concepts to hu- and between populations. Also argues that
mans. memes serve as the foundation of culture.
Extremists on both sides of the question Bibliography, index.
have confused the issues. Such extremists range Cartwright, John. Evolution and Human Behav-
from opponents of sociobiological ideas who ior: Darwinian Perspectives on Human Nature.
minimize genetic or evolutionary influence on Cambridge, Mass.: MIT Press, 2000. Offers
the human cultural condition to sociobiolo- an overview of the key theoretical principles
gists who minimize the role of environmental of human sociobiology and evolutionary
influences. In at least some minds, extremists psychology and shows how they illuminate
in the sociobiological camp have done as much the ways humans think and behave. Argues
damage to sociobiology as its most ardent op- that humans think, feel, and act in ways that
ponents. Sociobiology (by that or another once enhanced the reproductive success of
name) will continue to contribute to the un- our ancestors.
derstanding of the social systems of animals Cronk, Lee. That Complex Whole: Culture and the
and humans. The biological, genetic, and evo- Evolution of Human Behavior. Boulder, Colo.:
lutionary bases of human social systems must Westview Press, 1999. Discusses the links be-
be studied. The knowledge obtained may prove tween behavioral and social scientists, who
to be as enlightening as has sociobiologys con- do not have a basic understanding of the im-
tribution to the understanding of social sys- port of culture on human behavior, and an-
tems in other animals. thropologists, who in turn lack a complete
Carl W. Hoagstrom understanding of evolutionary biology. Bib-
See also: Aggression; Alcoholism; Altruism; liography, index.
Behavior; Biological Clocks; Biological Deter- Cziko, Gary. The Things We Do: Using the Lessons
minism; Criminality; Developmental Genetics; of Bernard and Darwin to Understand the What,
Eugenics; Gender Identity; Genetic Engi- How, and Why of Our Behavior. Cambridge:
neering: Medical Applications; Genetic Engi- MIT Press, 2000. Contrary to the Newton-
neering: Social and Ethical Issues; Genetic inspired idea that humans react to the envi-
Screening; Genetic Testing; Genetic Testing: ronment, Cziko argues that humans are less
Ethical and Economic Issues; Heredity and En- passive and reactive and more active beings,
vironment; Homosexuality; Human Genetics; acting on their environments in order to
Inbreeding and Assortative Mating; Intelli- shape their perceptions of the world. Illus-
gence; Klinefelter Syndrome; Knockout Genet- trations, bibliography, index.
ics and Knockout Mice; Miscegenation and Segerstrle, Ullica. Defenders of the Truth: The
Antimiscegenation Laws; Natural Selection; Battle for Science in the Sociobiology Debate and
Twin Studies; XYY Syndrome. Beyond. New York: Oxford University Press,
2000. Addresses Wilsons Sociobiology and the
Further Reading ensuing debates on determinism versus free
Alcock, John. The Triumph of Sociobiology. Re- will, nature versus nurture, adaptationism
print. New York: Oxford University Press, versus environmentalism, and others. Bibli-
2003. Reviews the history of the controver- ography, index.
sies and debates surrounding Wilsons ideas Van der Dennen, Johan M. G., David Smillie,
on sociobiology. Illustrations, bibliography, and Daniel R. Wilson, eds. The Darwinian
index. Heritage and Sociobiology. Westport, Conn.:
Blackmore, Susan J. The Meme Machine. Fore- Praeger, 1999. Interdisciplinary approach to
word by Richard Dawkins. New York: Oxford Darwins influence on sociobiology, and dis-
708 Speciation
Multipotent cells are specialized stem cells ca- Behavior in Cell Culture
pable of giving rise to one class of cells. During the 1980s researchers first estab-
A fertilized egg, or zygote, is totipotent. The lished in vitro culture conditions that allowed
zygote first divides into two cells about one day embryonic stem cells to divide without differ-
after fertilization and becomes an embryo. The entiating. Embryonic stem cells are relatively
embryonic cells remain totipotent for about easy to grow in culture but appear to be geneti-
four days after fertilization. At that point, the cally unstable; mice cloned from embryonic
embryo consists of about eight cells. As the cells stem cells by nuclear transfer suffered many ge-
of the embryo continue to divide, they form a netic defects as a result of the genetic instability
hollow sphere. The approximately fifty to one of the embryonic stem cells. As embryonic
hundred cells on the inner side of the sphere stem cells divide in culture, they lose the tags
are pluripotent and will continue developing that tell an imprinted gene to be either turned
to form the embryo, while the cells on the on or turned off during development. Re-
outer surface will give rise to the extraembry- searchers have found that even clones made
onic tissues, such as the placenta and the um- from sister stem cells show differences in their
bilical cord. gene expression. However, these genetic
Multipotent stem cells are found in a variety changes, while having defined roles in fetal de-
of tissues in adult mammals and are sometimes velopment, may have little significance in ther-
referred to as adult stem cells. They are special- apeutic uses, because the genes involved do not
ized stem cells that are committed to giving rise serve a critical role in adult differentiated cells.
to cells that have a particular function.
Identities of some multipotent stem
cells have been confirmed. Hemato-
poietic stem cells give rise to all the
types of blood cells. Mesenchymal stem
cells in the bone marrow give rise to a
variety of cell types: bone cells, carti-
lage cells, fat cells, and other kinds of
connective tissue cells such as those in
tendons. Neural stem cells in the brain
give rise to its three major cell types:
nerve cells (neurons) and two catego-
ries of nonneuronal cells, astrocytes
and oligodendrocytes. Skin stem cells
occur in the basal layer of the epider- Image not available
mis and at the base of hair follicles.
The epidermal stem cells give rise to
keratinocytes, which migrate to the
surface of the skin and form a protec-
tive layer. The follicular stem cells can
give rise to both the hair follicle and
the epidermis.
Stem cells in adult mammalian tis-
sues are rare and difficult to isolate.
There is considerable debate concern-
ing the plasticity of stem cells in adults.
Plasticity is the ability of multipotent
cells to exhibit pluripotency, such as
the capacity of hematopoietic stem Embryonic stem cells in laboratory bottles, 2001. (AP/Wide World
cells to differentiate into neurons. Photos)
712 Stem Cells
Paraplegic protesters in Washington, D.C., staged this mock hanging in the balance in April, 2002, to dramatize the need for em-
bryonic stem cell research and to urge Congress to allow it. Embryonic stem cell research was subsequently limited to an existing num-
ber of cell lines already being investigated. (AP/Wide World Photos)
Unlike embryonic stem cells, adult stem cells other major research thrust has been for thera-
do not divide prolifically in culture. When these peutic uses. Stem cell therapy has been limited
stem cells do divide in culture, their division is almost exclusively to multipotent stem cells ob-
unlike that of most cells. Generally, when a cell tained from umbilical cord blood, bone mar-
divides in culture, the two daughter cells pro- row, or peripheral blood. These stem cells are
duced are identical in appearance as well as in most commonly used to assist in hematopoietic
patterns of gene expression. However, when (blood) and immune system recovery follow-
stem cells divide in culture, at least one of the ing high-dose chemotherapy or radiation ther-
daughter cells retains its stem cell culture while apy for malignant and nonmalignant diseases
the other daughter cell is frequently a transit such as leukemia and certain immune and ge-
cell destined to produce a terminally differenti- netic disorders. For stem cell transplants to suc-
ated lineage. The genes expressed in a stem ceed, the donated stem cells must repopulate
cell and a transit cell are significantly different. or engraft the recipients bone marrow, where
Therefore a culture of adult stem cells may be- they will provide a new source of essential
come heterogeneous in a short time. blood and immune system cells.
In addition to the uses of stem cells in cancer
Potential Therapeutic Issues treatment, the isolation and characterization of
Although stem cells have significant use as stem cells and in-depth study of their molecular
models for early embryonic development, an- and cellular biology may help scientists under-
Stem Cells 713
stand why cancer cells, which have certain prop- missing or necessary protein is introduced into
erties of stem cells, survive despite very aggres- an organ for a therapeutic effect. One of the
sive treatments. Once the cancer cells ability to most difficult problems in gene therapy studies
renew itself is understood, scientists can develop has been the loss of expression (or insufficient
strategies for circumventing this property. expression) following introduction of the gene
Research efforts are under way to improve into more differentiated cells. Introduction of
and expand the use of stem cells in treating and the gene into stem cells to achieve sufficient
potentially curing human diseases. Possible long-term expression would be a major ad-
therapeutic uses of stem cells include treat- vance. In addition, the stem cell is clearly a
ment of autoimmune diseases such as muscular more versatile target cell for gene therapy,
dystrophy, multiple sclerosis, and rheumatoid since it can be manipulated to become theoret-
arthritis; repair of tissues damaged during ically any tissue. A single gene transfer into a
stroke, spinal cord injury, or myocardial infarc- pluripotent stem cell could enable scientists to
tion; treatment of neurodegenerative diseases generate stem cells for blood, skin, liver, or
such as amyotrophic lateral sclerosis (ALS, com- even brain targets.
monly called Lou Gehrigs disease) and numer-
ous neurological conditions such as Parkin- Ethical Issues Concerning Use
sons, Huntingtons, and Alzheimers diseases; Stem cell research, particularly embryonic
and replacement of insulin-secreting cells in di- stem cell research, has unleashed a storm of
abetics. controversy. One primary controversy sur-
Stem cells may also find use in the field of rounding the use of embryonic stem cells is
gene therapy, where a gene that provides a based on the belief by opponents that a fertil-
A group of pro-life demonstrators urge a ban on embryonic stem cell research, seeing such investigations as tantamount to baby
killing. (AP/Wide World Photos)
714 Stem Cells
ized egg is fundamentally a human being with A number of states already have laws that ban
rights and interests that need to be protected. human cloning for reproductive purposes,
Those who oppose stem cell research do not while a small number of states forbid cloning of
want fetuses and fertilized eggs used for re- embryos for stem cells as well.
search purposes. Others accept the special sta- Lisa M. Sardinia
tus of an embryo as a potential human being See also: Aging; Alzheimers Disease; Auto-
yet argue that the respect due to the embryo in- immune Disorders; Biochemical Mutations;
creases as it develops and that this respect, in Bioethics; Cancer; Cell Culture: Animal Cells;
the early stages in particular, may properly be Cell Culture: Plant Cells; Cell Cycle, The; Cell
weighed against the potential benefits arising Division; Cloning; Cloning: Ethical Issues;
from the proposed research. Cloning Vectors; Cystic Fibrosis; Developmen-
Another ethical issue concerns the method tal Genetics; Eugenics; Eugenics: Nazi Ger-
by which embryonic stem cells are obtained. many; Gene Therapy; Gene Therapy: Ethical
Embryonic stem cells are isolated from two and Economic Issues; Genetic Engineering:
sources: surplus embryos produced by in vitro Medical Applications; Huntingtons Disease;
fertilization and embryos produced by somatic In Vitro Fertilization and Embryo Transfer; In-
cell nuclear transfer (SCNT), often referred to fertility; Knockout Genetics and Knockout
as therapeutic cloning. In SCNT, genetic mate- Mice; Model Organism: Mus musculus; Organ
rial from a cell in an adults body is fused with Transplants and HLA Genes; Totipotency;
an enucleated egg cell. With the right condi- Transgenic Organisms.
tions, this new cell can then develop into an
embryo from which stem cells could be har- Further Reading
vested. Opponents argue that therapeutic Holland, Suzanne, Karen Lebacqz, and Laurie
cloning is the first step on the slippery slope to Zoloth, eds. The Human Embryonic Stem Cell
reproductive cloning, the use of SCNT to cre- Debate: Science, Ethics, and Public Policy (Basic
ate a new adult organism. Proponents maintain Bioethics). Cambridge, Mass.: MIT Press,
that producing stem cells by SCNT using ge- 2001. A collection of twenty essays organized
netic material from the patient will eliminate into four sections: basic science and history
the possibility of rejection when the resulting of stem cell research, ethics, religious per-
stem cells are returned to the patient. spectives, and public policy.
Kaji, Eugene H., and Jeffrey M. Leiden. Gene
Legal Status and Stem Cell Therapies. Journal of the Amer-
On August 9, 2001, President George W. ican Medical Association 285, no. 5 (2001):
Bush announced that federal funds could be 545-550. An overview of stem cells from a
used to support research using the sixty human clinical viewpoint. Includes discussion of the
embryonic stem cell lines that had been de- feasibility of stem cell therapy, future re-
rived before that date. However, there were no search, and ethical issues.
restrictions placed on the types of research that Kiessling, Ann, and Scott C. Anderson. Human
could be conducted on mouse embryonic stem Embryonic Stem Cells: An Introduction to the Sci-
cell lines and no federal law or policy prohibit- ence and Therapeutic Potential. Boston: Jones
ing the private sector from isolating stem cells and Bartlett, 2003. In the context of the so-
from human embryos. Several states have in- cial debate and public policy of the George
troduced legislation to encourage research on W. Bush administration, addresses the vari-
stem cells taken from human embryos. ous stem cell research from the perspectives
As of March, 2003, neither reproductive of many disciplines, from cell biology, em-
cloning nor therapeutic cloning was forbidden bryology, and endocrinology to transplanta-
by law in the United States. Congress was debat- tion medicine.
ing competing legislation; one bill proposed to Marshak, Daniel R., Richard L. Gardner, and
ban both types of cloning, while an alternative David Gottlieb, eds. Stem Cell Biology. Cold
proposal would ban only reproductive cloning. Spring Harbor, N.Y.: Cold Spring Harbor
Sterilization Laws 715
In 1927, the U.S. Supreme Court, in its Buck v. Bell decision, supported the eugenic principle that states could use involuntary ster-
ilization to eliminate genetic defects from the population. The result was the sterilization of more than sixty thousand mainly young
people deemed to be weak, feebleminded, or otherwise genetically inferior. Two sterilized residents of Lynchburg, Virginia, where
many such sterilizations occurred, observe a historical marker that commemorates the tragic decision. (AP/Wide World Photos)
forced, twenty-two states currently have steril- generate offspring for crime, or to let them
ization laws on the books. starve for their imbecility, society can prevent
The U.S. Supreme Court, in its 1927 Buck v. those who are manifestly unfit from continuing
Bill decision, supported the eugenic principle their kind. The principle that sustains compul-
sory vaccination is broad enough to cover cut-
that states could use involuntary sterilization to
ting the Fallopian tubes.
eliminate genetic defects from the population.
The vote of the Court was eight to one. The Ironically, the sterilization laws of the United
courts reasoning went as follows: States and Canada served as models for the eu-
genics movement in Nazi Germany in its pro-
We have seen more than once that the public
gram to ensure so-called racial purity and supe-
welfare may call upon the best citizens for their
lives. It would be strange if it could not call upon
riority.
those who already sap the strength of the state
for these lesser sacrifices, often not felt to be such Impact and Applications
by those concerned, in order to prevent our be- Two problems associated with eugenics are
ing swamped with incompetence. It is better for the subjective nature of deciding which traits
all the world, if instead of waiting to execute de- are desirable and determining who should de-
Steroid Hormones 717
cide. These concerns aside, the question of and stereotypes they faced from the medical
whether there is a sound scientific basis for the profession, which often deemed steriliza-
desire to manipulate the human gene pool re- tion pathological. Bibliography, index.
mains. Does the sterilization of individuals who Gallagher, Nancy L. Breeding Better Vermonters:
are mentally retarded or who have some other The Eugenics Program in the Green Mountain
mental or physical defect improve the human State. Hanover, N.H.: University Press of New
genetic composition? Involuntary sterilization England, 2000. A biologist looks at the sci-
of affected individuals would quickly reduce ence of eugenics and the social, ethnic, and
the incidence of dominant genetic traits. Indi- religious tensions brought about by the Eu-
viduals who were homozygous for recessive genics Survey of Vermont, an organization
traits would also be eliminated. However, most in existence from 1925 to 1936.
harmful recessive genes are carried by individ- Kevles, Daniel J. In the Name of Eugenics: Genetics
uals who appear normal and, therefore, would and the Uses of Human Heredity. Cambridge,
not be obvious for sterilization purposes. Mass.: Harvard University Press, 1995. A
These normal people would continue to pass comprehensive introduction to the history
the bad gene on to the next generation, and a of the eugenics movement and the develop-
certain number of affected people would again ment of sterilization laws. Discusses genetics
be born. It would take an extraordinary num- both as a science and as a social and political
ber of generations to significantly reduce the perspective, and how the two often collide to
frequency of harmful genes. muddy the boundaries of science and opin-
Although the number of involuntary steril- ion.
izations in the United States is now minimal,
the impact sterilization laws had on the popula- Web Sites of Interest
tion through 1960 was far-reaching, as nearly Cold Spring Harbor Laboratory, Image Archive
sixty thousand people were sterilized. Other on the American Eugenics Movemement.
countries also had laws that allowed forced ster- http://www.eugenicsarchive.org/eugenics.
ilizations, with many programs continuing into Comprehensive and extensively illustrated
the 1970s. The province of Alberta, Canada, site that covers the eugenics movement in
sterilized three thousand people before its law the United States, including sterilization
was repealed. Another sixty thousand were ster- laws.
ilized in Sweden. The story of sterilization and University of Vermont, Vermont Eugenics: A
euthanasia in Germany needs no retelling. Documentary History. http://www.uvm.edu/
With the ability to decipher the human ge- ~eugenics/sterilizationdl.html. A listing of
nome and implement improved genetic testing original documents related to sterilization
procedures, a danger exists that new programs and eugenics in the United States, including
of eugenics and involuntary sterilization might a statement from the American Eugenics So-
once again emerge. ciety (1926) and related newspaper articles.
Donald J. Nash
See also: Criminality; Eugenics; Eugenics:
Nazi Germany; Hardy-Weinberg Law; Miscege-
nation and Antimiscegenation Laws; Prion Dis-
eases: Kuru and Creutzfeldt-Jakob Syndrome;
Race.
Steroid Hormones
Fields of study: Developmental genetics;
Further Reading Molecular genetics
Campbell, Annily. Childfree and Sterilized: Significance: Steroid hormoneshormones con-
Womens Decisions and Medical Responses. New taining a steroid ring derived from cholesterol
York: Cassell, 1999. Explores the lives of are important for many processes that control sex
twenty-three women who chose sterilization determination, reproduction, behavior, and me-
over bearing children and the prejudices tabolism. Mutations in the genes that produce or
718 Steroid Hormones
regulate the action of specific steroid hormones genes at specific nucleotide sequences termed
may lead to infertility, sterility, sex determination, hormone-responsive elements. The binding of
osteoporosis, autoimmune diseases, heart abnor- the hormone-receptor complex to hormone-
malities, and breast, uterine, and prostate cancer. responsive elements causes the increased pro-
duction of transcription and protein produc-
Key terms tion in most cases. In some instances, binding
anabolic steroids: drugs derived from an- to a specific hormone-responsive element will
drogens and used to enhance performance stop the production of proteins that are usually
in sports made in the absence of the hormone.
androgens: steroid hormones that cause mas- There are two types (sex steroid and adrenal
culinization steroid) and five classes of steroid hormones.
estrogens: steroid hormones that produce fe- The sex steroid hormones include the andro-
male characteristics gens, estrogens, and progestins and are pro-
glucocorticoids: steroid hormones that re- duced by the male testes (androgens) and
spond to stress and maintain sugar, salt, and female ovaries. Adrenal steroid hormones in-
body fluid levels clude glucocorticoids and mineralocorticoids
hormones: chemical messengers produced by and are produced by the adrenal glands.
endocrine glands and secreted into the
blood Sex Steroid Hormones
mineralocorticoids: a group of steroid hor- Sex steroid hormone genes are responsible
mones important for maintenance of salt for determining the sex and development of
and water balance males and females. Androgens are a group of
progestins: steroid hormones important for steroid hormones that cause masculinization.
pregnancy and breast development The principal androgen is testosterone, which
testosterone: the principal androgen, pro- is produced by the testes and is responsible for
duced by the testes and responsible for male male secondary sexual characteristics (growth
secondary sexual characteristics of facial and pubic hair, deepening of voice,
sperm production). Estrogens are sex steroid
Steroid Hormone Characteristics and hormones produced in the ovaries and cause
Function femininization. In addition, estrogens control
Steroid hormones represent a group of hor- calcium content in the bones, modulate other
mones that all contain a characteristic steroid hormones produced in the ovary, modify sex-
ring structure. This steroid ring is derived from ual behavior, regulate growth of secondary sex
cholesterol, and cholesterol is the starting ma- characteristics (menstrual periods, breast de-
terial for the production of different steroid velopment, pubic hair) and are essential for
hormones. Steroid hormones, like other types pregnancy to occur. The most potent estrogen
of hormones, are secreted by endocrine glands is 17-beta estradiol. Progestins, including pro-
into the bloodstream and travel throughout gesterone, are also sex steroid hormones. Pro-
the body before having an effect. All steroid gesterone is important for proper breast devel-
hormones, although specific for the regulation opment and normal and healthy pregnancies;
of certain genes, function in a similar manner. it functions in the mother to alter endometrial
Because steroid hormones are derived from cells so the embryo can implant. The loss of
cholesterol, they have the unique ability to dif- progesterone at the end of a pregnancy aids in
fuse through a cells outer plasma membrane. the beginning of uterine contractions.
Inside the cell, the steroid hormone binds to Anabolic steroids are drugs derived from the
its specific receptor in the cytoplasm. Upon male steroid hormone testosterone and were
binding, the newly formed hormone-receptor developed in the late 1930s to treat hypogo-
complex relocates to the nucleus. In the nu- nadism in men, a condition that results in insuf-
cleus, the hormone-receptor complex binds to ficient testosterone production by the testes.
the DNA in the promoter region of certain During this same period, scientists discovered
Steroid Hormones 719
that anabolic steroids also increased the muscle have also been linked to bone loss (osteoporo-
mass in animals. These findings led to the use sis) and infertility, whereas excessive levels are
of anabolic steroids by bodybuilders, weight- associated with an increased risk of breast and
lifters, and other athletes to increase muscle uterine cancer. Similarly, genetic mutations in
mass and enhance performance. Anabolic ste- the progesterone production pathway or the
roid use can seriously affect the long-term progesterone receptor are associated with in-
health of an individual and in women results in fertility. In addition, bone loss is one of the
masculinization. most serious results of progesterone deficiency,
made worse by inappropriate diet and lack of
Adrenal Steroid Hormones exercise.
Adrenal steroid hormones are secreted
from the adrenal cortex and are important for Genetic Defects Affecting Adrenal Steroid
many bodily functions, including response to Hormones
stress, maintenance of blood sugar levels, fluid Genetic abnormalities in adrenal steroid
balance, and electrolytes. The glucocorticoids hormone biosynthesis are known to cause hy-
represent one class of adrenal steroid hormone. pertension in some cases of congenital adrenal
The most important, cortisol, performs criti- hyperplasia (CAH). In people with this condi-
cally important functions; it helps to maintain tion, hypertension usually accompanies a char-
blood pressure and can decrease the response acteristic phenotype with abnormal sexual dif-
of the bodys immune system. Cortisol can also ferentiation. CAH is a family of autosomal
elevate blood sugar levels and helps to control recessive disorders of adrenal steroidogenesis.
the amount of water in the body. Elevated corti- Each disorder has a specific pattern of hor-
sol helps the body respond to stress. The gluco- monal abnormalities resulting from a deficiency
corticoids cortisone and hydrocortisone are of one of the enzymes necessary for cortisol
used as anti-inflammatory drugs to control itch- synthesis. The most common form of CAH is
ing, swelling, pain, and other inflammatory 21-hydroxylase deficiency; however, in all forms,
reactions. Prednisone and prednisolone, also cortisol production is impaired, which results
members of the glucocorticoid class of hor- in an increase in adrenocorticotropin and the
mones, are the broadest anti-inflammatory and overproduction of androgen steroids.
immunosuppressive medications available. There are two major forms of 21-hydroxylase
The second class of adrenal steroid hor- deficiency. Classic CAH deficiency results in
mones is the mineralocorticoids, including al- masculinized girls that are born with genital
dosterone, which helps maintain salt and water ambiguity and may possess both female and
balance and increases blood pressure. Aldoste- male genitalia. Nonclassic 21-hydroxylase defi-
rone is crucial for retaining sodium in the kid- ciency does not produce ambiguous genitalia
ney, salivary glands, sweat glands, and colon. in female infants but may result in premature
puberty, short stature, menstrual irregularities
Genetic Defects Affecting Sex Steroid or lack of a menstrual cycle, and infertility. Fa-
Hormones milial glucocorticoid deficiency (FGD) is an ex-
Defects in the genes involved in the produc- tremely rare, genetic autosomal recessive con-
tion of sex steroid hormones can have serious dition in which a part of the adrenal glands are
consequences. Mutations in the androgen re- destroyed. These changes result in very low lev-
ceptor, the receptor for testosterone, result in els of cortisol. Although this disease is easily
testicular feminization syndrome. In this syn- treatable if recognized, when left untreated it
drome, the individual has the genes of a male is often fatal or can lead to severe mental dis-
(XY) but develops, behaves, and appears fe- ability.
male. Other gene defects in androgen biosyn- Recently, the genetic basis of four forms of
thesis often result in sterility. Genetic defects severe hypertension transmitted on an auto-
in estrogen receptors or estradiol biosynthesis somal basis has been determined. All of these
lead to infertility. Reduced levels of estradiol conditions are characterized by salt-sensitive
720 Swine Flu
increases in blood pressure, indicating an in- phorylation, and hormonal and antihor-
creased mineralocorticoid effect. The four dis- monal ligands.
ordersaldosteronism, mineralocorticoid ex- National Institutes of Health. Steroid Abuse and
cess syndrome, activating mutation of the Addiction. NIH 00-3721. Bethesda, Md.: Au-
mineralocorticoid receptor, and Liddle syn- thor, 2000. This pamphlet outines the dan-
dromeare a consequence of either abnormal gers of steroid use for unapproved purposes
biosynthesis, abnormal metabolism, or abnor- such as bodybuilding.
mal action of steroid hormones and the devel- Tilly, J., J. F. Strauss III, and M. Tenniswood,
opment of hypertension. Adrenal insufficiency eds. Cell Death in Reproductive Physiology. New
is known as Addisons disease and causes death York: Springer, 1997. Describes the selective
within two weeks unless treated. Classical Addi- death of steroid-producing tissues.
sons disease results from a loss of both cortisol Wynn, Ralph M., and W. Jollie, eds. Biology of the
and aldosterone secretion as a result of the Uterus. 2d rev. ed. Boston: Kluwer Academic,
near total or total destruction of both adrenal 1989. Reviews the basic biology of pregnancy
glands. and the role of sex steroid hormones in
Thomas L. Brown pregancy.
See also: Aggression; Allergies; Autoim-
mune Disorders; Behavior; Cancer; Gender
Identity; Heart Disease; Hermaphrodites; Hu-
man Genetics; Metafemales; Pseudohermaph- Swine Flu
rodites; Testicular Feminization Syndrome; X
Chromosome Inactivation; XYY Syndrome. Fields of study: Diseases and syndromes;
Viral genetics
Further Reading Significance: The swine flu outbreak of 1918 was
Ethier, Stephen P., ed. Endocrine Oncology. the most lethal worldwide epidemic known to hu-
Humana Press, 2000. Experts provide chap- mankind. Constant genetic changes in the influ-
ters on cancers of the breast, prostate, enza virus that caused the disease keep alive the po-
endometrium, and ovary from cellular and tential for such another pandemic to occur in the
molecular perspectives, including the way future.
that steroid hormones function in both nor-
mal processes and pathogenesis. Key terms
Freedman, Leonard P., and M. Karin, eds. Mo- antigenic drift: minor changes in the H and
lecular Biology of Steroid and Nuclear Hormone N proteins of the influenza virus
Receptors. Boston: Birkhauser, 1999. A molec- antigenic shift: the acquisition by a strain of
ular perspective on steroid functions in both influenza virus of a different H and/or N
normal and cancerous cells. protein
Khan, Sohaib A., and George M. Stancel, eds. hemagluttinin (H): a protein necessary for
Protooncogenes and Growth Factors in Steroid entry of the influenza virus into a host cell
Hormone Induced Growth and Differentiation. neuraminidase (N): a protein necessary for
Boca Raton, Fla.: CRC Press, 1994. Experts exit of the influenza virus from an infected
from cancer centers discuss the roles of ste- cell
roid hormones in cancer from the perspec- pandemic: a worldwide outbreak of a particu-
tives of biochemistry, physiology, develop- lar disease
ment, genetics, endocrinology, and other
disciplines. Virus Structure and Replication
Moudgil, V. K., ed. Steroid Hormone Receptors: Ba- Swine flu is a respiratory disease of humans
sic and Clinical Aspects. Boston: Birkhauser, caused by the H1N1 subtype of influenza A vi-
1994. A scientific researcher examines the rus. Various types of influenza A virus can be
structural and functional alterations in ste- found in humans, birds, swine, and other ani-
roid hormone receptors induced by phos- mals. Human disease is spread most commonly
Swine Flu 721
person to person and, rarely, from animal to brane and the RNA is released. Inside the host
person. Although some antiviral drugs are cell viral RNA is replicated and new proteins
available, treatment involves mainly supportive are synthesized. Newly assembled virus parti-
therapy. Vaccination prevents disease, but the cles bud through the host cell membrane to ac-
genetic nature of the virus requires that vacci- quire their envelopes. Neuraminidase keeps
nations must be given annually to be effective. the new virus particles from sticking to the dy-
Advances in genetic technology are helping sci- ing host cell so they are free to infect surround-
entists to understand why the swine flu virus ing cells. The cycle continues until either the
caused such a devastating epidemic in 1918 host is dead or the hosts immune system stops
and to develop treatment and prevention strat- the spread of the virus. The majority of the
egies that will be effective against future poten- hosts immune response to infection is di-
tial epidemics of swine flu. rected against the H and N proteins.
The swine flu virus is composed of eight seg- Type A influenza viruses are continuously
ments of RNA surrounded by a lipid envelope. changing in the amino acid sequence of their
Embedded in the envelope are two proteins es- H and N proteins by a process called antigenic
sential for viral replication, known as hema- drift. These changes occur because mistakes
gluttinin (H) and neuraminidase (N). The in- are made during the replication of the viral
fectious cycle begins when hemagluttinin RNA that codes for these proteins. Changes
binds to the surface of the host cell. Next, the that result in H and N proteins that are no lon-
viral envelope fuses with the host cell mem- ger recognized by the hosts immune system al-
Victims of the 1918 influenza pandemic line an emergency hospital facility at Fort Riley, Kansas, near where the virus is thought to
have originated. The pandemic caused at least 20 million deaths worldwide. (AP/Wide World Photos)
722 Swine Flu
ruses. Scientific American 280, no. 1 (1999): known as active immunization. Active immuni-
78-87. Describes the viral replication cycle, zation was the first form of antibody therapy to
vaccine strategies, and virulence theories. Il- be developed and is used to prevent diseases
lustrated by helpful diagrams. such as measles and polio.
Taubenberger, J. K., et al. Initial Genetic Char- The oldest method of producing therapeu-
acterization of the 1918 Spanish Influenza tic antibodies outside the human body is
Virus. Science 275 (1997): 1793-1796. De- known as passive immunization. This process
scribes the historic use of genetic technology involves exposing an animal to an antigen so
to sequence the virus from the RNA of a vic- that it develops antibodies to it. The antibodies
tim of the 1918 pandemic. are separated from the animals blood and ad-
ministered to a patient. Passive immunization
Web Site of Interest is used to treat diseases such as rabies and diph-
National Center for Infectious Diseases. http:// theria. A disadvantage of antibodies derived
www.cdc.gov/ncidod/diseases/flu/fluvirus from animal blood is the possibility that the pa-
.htm. This page on influenza provides basic tient may develop an allergic reaction. Because
information on the various forms of the vi- the animals antibodies are foreign substances,
rus, its effects, and treatments. the patients own antibodies may treat them as
antigens, leading to fever, rash, itching, joint
pain, swollen tissues, and other symptoms.
Antibodies derived from human blood are
Synthetic Antibodies much less likely to cause allergic reactions than
antibodies from the blood of other animals.
Field of study: Immunogenetics This led researchers to seek a way to develop
Significance: Synthetic antibodies are artificially synthetic human antibodies.
produced replacements for natural human anti- A major breakthrough in the search for syn-
bodies. They are used to treat a variety of illnesses thetic antibodies was made in 1975 by Cesar
and promise to be an important part of medical Milstein and Georges Khler. They developed
technology in the future. a technique that allowed them to produce a
specific antibody outside the body of a living
Key terms animal. This method involved exposing an ani-
antibody: a protein molecule that binds to a mal to an antigen, causing it to produce anti-
substance in order to remove, destroy, or de- bodies. Instead of obtaining the antibodies
activate it from the animals blood, they obtained B cells
antigen: the substance to which an antibody from the animals spleen. These cells are then
binds combined with abnormal B cells known as
B cells: white blood cells that produce anti- myeloma cells. Unlike normal B cells, myeloma
bodies cells can reproduce identical copies of them-
monoclonal antibodies: identical antibod- selves an unlimited number of times. The nor-
ies produced by identical B cells mal B cells and the myeloma cells fuse to form
cells known as hybridoma cells. Hybridoma
The Development of Antibody Therapy cells are able to reproduce an unlimited num-
Natural antibodies are protein molecules ber of times and are able to produce the same
produced by white blood cells known as B cells antibodies as the B cells. Those hybridoma cells
in response to the presence of foreign sub- that produce the desired antibody are sepa-
stances. A specific antibody binds to a specific rated from the others and allowed to repro-
substance, known as an antigen, in a way that duce. The antibodies produced this way are
renders it harmless or allows it to be removed known as monoclonal antibodies.
from the body or destroyed. A person will pro- Because human B cells do not normally
duce antibodies naturally upon exposure to form stable hybridoma cells with myeloma
harmless versions of an antigen, a process cells, B cells from mice are usually used. Be-
724 Synthetic Antibodies
tic shock, a syndrome caused by toxic sub- tion in diseased humans, animals, and plants by
stances released by certain bacteria. replacing defective natural genes with appropri-
The most active area of research involving ately modified synthetic genes.
synthetic antibodies in the 1990s was in the
treatment of cancer. On November 26, 1997, Key terms
the U.S. Food and Drug Administration ap- restriction enzyme: an enzyme that cleaves,
proved a synthetic antibody for use in non- or cuts, DNA at specific sites with sequences
Hodgkins lymphoma, a cancer of the white recognized by the enzyme; also called re-
blood cells. It was the first synthetic antibody striction endonucleases
approved for use in cancer therapy. reverse transcription: the synthesis of DNA
Rose Secrest from RNA
See also: Allergies; Anthrax; Antibodies;
Autoimmune Disorders; Biopharmaceuticals; A Brief History
Blotting: Southern, Northern, and Western; In 1871, Swiss physician Johann Friedrich
Burkitts Lymphoma; Cancer; Central Dogma Miescher reported that the chief constituent of
of Molecular Biology; Cloning; Diabetes; Diph- the cell nucleus was nucleoprotein, or nuclein.
theria; Genetic Engineering: Historical De- Later it was established that the nuclei of bacte-
velopment; Genetic Engineering: Industrial ria contained little or no protein, so the heredi-
Applications; Hybridomas and Monoclonal tary material was named nucleic acid. At the
Antibodies; Immunogenetics; Molecular Ge- end of the nineteenth century, German bio-
netics; Multiple Alleles; Oncogenes; Organ chemist Albrecht Kossel identified the four ni-
Transplants and HLA Genes; Prion Diseases: trogenous bases: the purines adenine (A) and
Kuru and Creutzfeldt-Jakob Syndrome; Trans- guanine (G) and the pyrimidines cytosine (C)
genic Organisms. and uracil (U). In the 1920s, Phoebus A.
Levene and others indicated the existence of
Further Reading two kinds of nucleic acid: ribonucleic acid
Coghlan, Andy. A Second Chance for Anti- (RNA) and deoxyribonucleic acid (DNA); the
bodies. New Scientist 129 (February 9, 1991). latter contains thymine (T) instead of uracil.
An early discussion of the history and future The chemical identity of genes began to un-
of antibody therapy. fold in 1928, when Frederick Griffith discov-
Kontermann, Roland, and Stefan Dbel, eds. ered the phenomenon of genetic transforma-
Antibody Engineering. New York: Springer, tion. Oswald Avery, Colin MacLeod, and Maclyn
2001. A detailed look at basic methods, pro- McCarty (in 1944) and Alfred Hershey and
tocols for analysis, and recent and develop- Martha Chase (in 1952) demonstrated that
ing technologies. Illustrations, bibliography, DNA was the hereditary material. Following
index. the elucidation of the structure of DNA in 1953
Mayforth, Ruth D. Designing Antibodies. San by James Watson and Francis Crick, pioneering
Diego: Academic Press, 1993. Methods of efforts by several scientists led to the eventual
synthetic antibody production are described synthesis of a gene. The successful enzymatic
in detail. Illustrations, bibliography, index. synthesis of DNA in vitro (in the test tube) in
1956, by Arthur Kornberg and colleagues, and
that of RNA by Marianne Grunberg-Manago
and Severo Ochoa also contributed to the de-
Synthetic Genes velopment of synthetic genes. In 1961, Marshall
Nirenberg and Heinrich Matthaei synthesized
Field of study: Genetic engineering and polyphenylalanine chains using a synthetic
biotechnology messenger RNA (mRNA). In 1965, Robert W.
Significance: Synthetic genes have been shown to Holley and colleagues determined the com-
function in biological organisms. Scientists hope plete sequence of alanine transfer RNA (tRNA)
that it will prove possible to restore normal func- isolated from yeast. The interpretation of the
726 Synthetic Genes
genetic code by several groups of scientists enzyme used in cheese making) in calves can
throughout the 1960s was also clearly impor- be synthesized from its known nucleotide se-
tant. quence instead of isolating it from calf DNA
In 1970, Har Gobind Khorana, along with using restriction enzymes. Alternatively, chy-
twelve associates, synthesized the first gene: the mosin mRNA can be obtained from calf stom-
gene for an alanine tRNA in yeast. There were ach cells, which can be transformed into DNA
no automatic DNA synthesizers available then. through reverse transcription.
In 1976, Khoranas group synthesized the tyro- New or modified genes may be manufac-
sine suppressor tRNA gene of Escherichia coli (E. tured to obtain a desired product. Gene synthe-
coli). The lac operator gene (twenty-one nucle- sis, coupled with automated rapid sequencing
otides long) was also synthesized, introduced and protein analysis, has yielded remarkable
into E. coli, and demonstrated to be functional. dividends in medicine and agriculture. Ge-
It took ten years to synthesize the first gene; by netic engineers are designing new proteins
the mid-1990s, gene machines could synthe- from scratch to learn more about protein func-
size a gene in hours. tion and architecture. With synthetic genes,
the process of mutagenesis can be explored in
Gene Synthesis greater depth. It is possible to produce various
Protein engineering is possible by making alterations at will in the nucleotide sequence of
targeted changes in a DNA sequence to pro- a gene and observe their effects on protein
duce a different product (protein) polypeptide function. Such studies carry the potential to
with different properties, such as stress toler- unravel many biochemical and genetic path-
ance. The process of targeting a specific change ways that could be the key to a better under-
in the nucleotide sequence (site-directed mu- standing of health and disease.
tagenesis) allows the correlation of gene struc- Manjit S. Kang
ture with protein function. Rapid sequencing See also: Biopharmaceuticals; Cell Culture:
with modern capillary DNA sequencers facili- Plant Cells; Cloning; Cloning Vectors; DNA Se-
tates determination of the order of nucleotides quencing Technology; Gene Therapy; Genetic
that make up a gene in a matter of hours. Engineering; Protein Synthesis; Restriction En-
Once the sequence of a gene is known, it can zymes; Reverse Transcriptase; Synthetic Anti-
be synthesized from nucleotides using gene bodies.
machines. A gene machine is simply a chemical
synthesizer made up of tubes, valves, and Further Reading
pumps that bonds nucleotides together in the Aldridge, Susan. The Thread of Life: The Story of
right order under the direction of a computer. Genes and Genetic Engineering. New York:
An intelligent person with a minimum of train- Cambridge University Press, 1996. Provides
ing can produce synthetic genes. A gene may a guide to DNA and genetic engineering.
be isolated from an organism using restriction Henry, Robert J. Practical Applications of Plant
enzymes (any of the several enzymes found in Molecular Biology. New York: Chapman &
bacteria that serve to chop up the DNA of in- Hall, 1997. Gives protocols for important
vading viruses), or it may be made on a gene plant molecular biology techniques. Illustra-
machine. For example, the chymosin gene (an tions, bibliography, index.
Tay-Sachs Disease ous symptoms appear. The child may show
Field of study: Diseases and syndromes poor head control and an involuntary back-
Significance: Tay-Sachs disease (TSD) is a lethal and-forth movement of the eyes. Also distinc-
disease inherited as an autosomal recessive disor- tive of TSD is a cherry red spot on the retina
der. Affected children are normal at birth, and of the eye, first described by Tay, that usually ap-
symptoms are usually noticed by six months of age, pears after one year of age as atrophy of the op-
after which they progressively worsen; the child tic nerve head occurs. The symptoms are pro-
usually dies at or before four years of age. There is gressive, and the child loses all the motor and
no cure for this severe disorder of the nervous sys- mental skills developed to that point. Convul-
tem, but an understanding of the genetic nature of sions, increased motor tone, and blindness de-
the disorder has led to effective population screen- velop as the disease progresses. The buildup of
ing, prenatal diagnosis, and genetic counseling. storage material in the brain causes the head to
enlarge, and brain weight may be 50 percent
Key terms greater than normal at the time of death. There
genetic screening: the testing of individuals is no cure for TSD, and death usually occurs be-
for a disease-causing gene tween two and four years of age, with the most
hexosaminidase A (Hex A): a lysosomal en- common cause of death being pneumonia.
zyme, the absence of which leads to Tay- There are several forms of Tay-Sachs disease
Sachs disease in addition to the classical, or infant, form al-
lysosome: an organelle or structure in the cy- ready described. There is a juvenile form in
toplasm of a cell that contains enzymes in- which similar symptoms appear between two
volved in the breakdown of metabolic prod- and five years of age, with death occurring
ucts around age fifteen. A chronic form of TSD has
prenatal diagnosis: the identification of a symptoms beginning at age five that are far
gene or disease in an embryo or fetus milder than those of the infant and juvenile
forms. Late-onset Tay-Sachs disease (LOTS) is
Symptoms of Tay-Sachs Disease a rare form in which there is some residual Hex
Tay-Sachs disease (TSD) is an inherited A activity so that symptoms appear later in life
birth defect that is named after Warren Tay, an and the disease progresses much more slowly.
English ophthalmologist, and Bernard Sachs,
an American neurologist, who first described Genetics of Tay-Sachs Disease
the disorder. TSD is one of the lysosomal stor- All forms of TSD are inherited as autosomal
age disorders, as are Hurlers syndrome, Hun- recessive disorders. One of the interesting fea-
ters syndrome, Gaucher disease, and Fabry tures of TSD, as is true of some other genetic
disease. Lysosomes are organelles found in the disorders, is its variation across ethnic groups.
cytoplasm of cells and contain many enzymes The Ashkenazi Jewish population, ancestors of
that digest the cells food and waste. TSD is most of the Jewish people in the United States,
caused by the lack of the enzyme hexosamin- is a group of Jews of Eastern European descent.
idase A (Hex A), which facilitates the break- This group has a high incidence of TSD, about
down of fatty substances and gangliosides in 1 in 3,600. Approximately one in thirty Ashke-
the brain and nerve cells. When Hex A is suffi- nazi Jews is a heterozygote (a person who car-
ciently lacking, as in TSD, gangliosides accu- ries one copy of the gene but does not show
mulate in the body and eventually lead to the symptoms), compared to a figure of perhaps
destruction of the nervous system. one in three hundred for the rest of the worlds
Children with TSD appear normal at birth population. It is possible to screen the popula-
and up to six months of age. During this time, tion and identify heterozygous individuals by
they may show an exaggerated startle response means of a blood plasma assay that detects
to sound. Shortly after six months, more obvi- differences in Hex A activity. If two people are
728 Telomeres
carriers of the gene, they have a one-quarter Internet Age. San Diego: Icon Press, 2002.
chance of having a child with TSD. If one or Topics include the essentials on Tay-Sachs
both individuals are not carriers, they can be disease, parents rights, and insurance.
reassured that their child will not have TSD. If Zallen, Doris Teichler. Does It Run in the Family?
both people are carriers, once pregnancy en- A Consumers Guide to DNA Testing for Genetic
sues, prenatal diagnosis can determine whether Disorders. New Brunswick, N.J.: Rutgers Uni-
the developing fetus is affected. In cases of a versity Press, 1997. Covers the applications
positive diagnosis, couples can be counseled re- and social implications of testing for genetic
garding therapeutic pregnancy termination. disorders. Bibliography, index.
Telomerase activity can be lost in certain higher eukaryotes as well as with other human
strains of simple eukaryotes, such as protozoa. cell types. In contrast, the process of telomere
When this happens to a given cell line, each cell shortening does not happen when germ-cell
division leads to the additional shortening of its lineswhich in the whole organism produce
telomeres. This process continues for a fixed sperm and ovaare grown in tissue culture.
number of cell divisions; it then ends with the This suggests a basis for differences in longevity
death of the telomerase-deficient cell line. of the germ cells and the somatic cells that
A related observation has been made in hu- make up other human tissues.
mans. It has been shown that when human
fibroblasts are grown in tissue culture, telomere Impact and Applications
length is longest when cells are obtained from The discovery and study of telomeres and
young individuals. They are shorter in cells telomerases produced new insights into DNA
taken from the middle-aged, and very short in synthesis, the number of times a cell can repro-
cells taken from the aged. Similar observations duce, and the aging process. The circular DNA
have been made with the fibroblasts from other of bacteria (which are prokaryotes) allows them
Dolly the sheep, the first mammal to be cloned from that the type of cell used in the cloning process may
adult cells, was born on July 5, 1996. While Dolly ush- be an important factor. In 2002, Norikazu Miyashita
ered in a new era of mammalian cloning, her tenure and colleagues reported that cows cloned from
as the cloning communitys lovable mascot was, quite mammary gland cells (like Dolly) had shorter-than-
literally, short-lived. Dolly was euthanized on Febru- normal telomeres, clones obtained from skin fibro-
ary 14, 2003, after being diagnosed with a progres- blasts (connective tissue precursors, those used by
sive lung disease; she had already been suffering Lanza) had longer-than-normal telomeres, and
from debilitating arthritis. While Dollys health clones obtained from muscle cells showed no signifi-
problems could have resulted from natural causes, cant differences in telomere length.
both ailments are more characteristic of much older The telomere length of clones may also be species-
sheep. Sheep normally live to an age of about twelve, specific. Teruhiko Wakayama and colleagues cloned
Dolly was only half that. mice sequentially for six generations but saw no dif-
Dollys early demise was actually foreshadowed in ference in telomere length in any of the clones pro-
1999, when the group which cloned her reported duced. Mice, however, are known to have extremely
that Dollys telomeres were shorter than expected long telomeres to begin with; also, unlike the so-
for a sheep of her age. Dollys telomeres were about matic cells of cows or sheep, many of the somatic
the length one would expect if her cells had been six cells of mice are known to express the telomerase en-
years old on the day she was born (Dolly was cloned zyme.
from a six-year-old ewe). Since telomere length acts More research is necessary to understand exactly
as a molecular clock that determines the age of a why certain animal clones are produced with short-
cell, researchers had hoped that this clock would ened telomeres and others are not. Currently, our
somehow be reset upon transfer of an adult nu- lack of knowledge on the subject remains one of the
cleus to a host ovum. more compelling reasons not to attempt to clone a
While clearly not the case for Dolly, this resetting human at this time. A human clone produced with
of telomere length has been demonstrated in cloned unusually short telomeres may, like Dolly, meet with
cows. In 2000, Robert Lanza and colleagues reported an untimely death. In fact, patients with a human ge-
that cloned cows had longer-than-normal telomeres. netic disease called Hutchinson-Gilford progeria
Will these super cows be able to live appreciably have skin fibroblasts with greatly reduced telomere
longer than normal cows? Only time will tell, since lengths; persons affected with this disease live to an
cows have a normal life span of about twenty years. average age of about thirteen years.
What accounts for the difference between Dolly and James S. Godde
these cloned cows? Subsequent research has shown
Testicular Feminization Syndrome 731
to undergo many more cycles of reproduction Cold Spring Harbor Laboratory Press, 1995.
than the somatic cells of the eukaryotes. The Covers the discovery, synthesis, and poten-
linear eukar yote chromosome may have tial effects of telomeres on normal life, ag-
evolved because such DNA molecules were too ing, neoplasms, and other pathologies. Illus-
large to survive as circular molecules given trations, bibliography, index.
their rigidity and fragility. In addition, the ob- Double, John A., and Michael J. Thompson,
servation of telomere shortening in simple and eds. Telomeres and Telomerase: Methods and Pro-
complex eukaryotes raises the fascinating pos- tocols. Totowa, N.J.: Humana Press, 2002. A
sibility that the life spans of organisms may be laboratory guide for exploring the world of
related to the conservation of telomeres associ- the telomerase. Illustrations, bibliography,
ated with the replication of these structures by index.
telomerases. Kipling, David, ed. The Telomere. New York: Ox-
The role of telomere length in longevity is ford University Press, 1995. Describes telo-
uncertain, but apparently significant. Cells meres, telomerases, relationships to cancer,
grown in cell culture typically divide only a pre- and other aspects of potential telomere ac-
dictable number of times, and once this limit is tion.
reached they can no longer divide. At the same Krupp, Guido, and Reza Parwaresch, eds.
time, telomere length shortens with each divi- Telomerases, Telomeres, and Cancer. New York:
sion. Sometimes cells in culture will go through Kluwer Academic/Plenum, 2003. Considers
what is called a crisis, after which they be- the way telomeres function in cancer. Illus-
come immortalized and are able to divide an trations, bibliography, index.
indefinite number of times. Immortal cells also Lewis, Ricki. Telomere Tales. Bioscience 48,
actively express telomerases and maintain con- no. 12 (December, 1998). An overview of
stant telomere lengths. Cancer cells typically some of the molecular research that sup-
exhibit these same characteristics. A better un- ports the telomere shortening model of cel-
derstanding of telomeres and telomerase ex- lular aging.
pression might provide insights into aging and
cancer, leading to a potential cure for cancer
and age-related diseases.
Sanford S. Singer
See also: Aging; Animal Cloning; Chromo- Testicular Feminization
some Mutation; Chromosome Structure; Clon- Syndrome
ing Vectors; DNA Replication; Molecular Ge-
netics; Reverse Transcriptase. Field of study: Diseases and syndromes
Significance: The sex of a baby is usually deter-
Further Reading mined at conception by the sex chromosomes, but
Abstracts of Papers Presented at the 2001 Meeting on other genetic events can alter the outcome. One
Telomeres and Telomerase. Arranged by Eliza- such condition is testicular feminization syn-
beth H. Blackburn, Titia De Lange, and Car- drome, which causes a child with male chromo-
ol Grieder. Cold Spring Harbor, N.Y.: Cold somes to be born with feminized genitals. Informa-
Spring Harbor Laboratory Press, 2001. Syn- tion gained from the study of this and similar
opses of research and studies on telomeres conditions is being used to challenge the validity of
and telomerase. Bibliography, index. sex-determination tests for athletes.
Blackburn, Elizabeth H. Telomeres, Telomer-
ase, and Cancer. Scientific American, Feb- Key terms
ruary, 1996. Provides background on telo- androgen receptors: molecules in the cyto-
meres, telomerases, and their potential plasm of cells that join with circulating male
importance in carcinogenesis. hormones
Blackburn, Elizabeth H., and Carol W. Greider, androgens: hormones that promote male
eds. Telomeres. Cold Spring Harbor, N.Y.: body characteristics
732 Testicular Feminization Syndrome
differentiation: the process of changing they are part of a male animal. The androgens
from an unspecialized condition to a final produced by the testes are capable of entering
specialized one a cell through the cell membrane. Inside the
phenotype: the expressed characteristics, cell, the androgens attach to specific protein
both physical and physiological, of an indi- receptor molecules (androgen receptors). At-
vidual tachment causes the receptors to move from
sex determination: events that cause an em- the cytoplasm into the nucleus of the cell. Once
bryo to become male or female in the nucleus, the receptor-steroid complexes
bind to DNA near genes that are designed to re-
Development of Testicular Feminization spond to the presence of these hormones. The
Syndrome binding event is part of the process that turns
Introductory biology courses teach that a on specific genesin this case, the genes that
fertilized egg that receives two X chromosomes direct the process of building male genitals
at conception will be a girl, whereas a fertilized from the unisex embryonic structures as well
egg that receives an X and a Y chromosome will as those that suppress the embryonic female
become a boy. However, other factors can also uterus and tubes present in the embryos ab-
affect the development of a persons gender. domen.
Gender development in mammals begins at In cases of testicular feminization, androgen
conception with the establishment of chromo- receptors are missing from male cells. This is
somal sex (the presence of XX or XY chromo- the result of a recessive allele located on the X
somes). Even twelve weeks into development, chromosome. Because normal males have only
male and female embryos have the same exter- one X, the presence of a recessive allele on that
nal appearance. Internal structures for both X will result in no production of the androgen
sexes are also similar. However, the machinery receptor in that individual. The developing
has been set in motion to cause the external embryo is producing androgen in the testes;
genitals to become male or female, with corre- without the receptor molecules, however, the
sponding internal structures of the appropri- cells of the genitals are unable to sense the an-
ate sex. The baby is usually born with the drogen and respond to it. For this reason, the
proper phenotype to match its chromosomal disorder is sometimes known by an alternate
sex. However, development of the sex organs name: androgen-insensitivity syndrome. The
is controlled by several genes. This leaves a cells of the genitals are still capable of respond-
great deal of room for developmental errors to ing to estrogen from the testes. As a result, the
occur. genitals become feminized: labia and clitoris
The primary gene involved in sex determi- instead of a scrotum and penis, and a short,
nation is carried on the Y chromosome. It is re- blind vagina. To the obstetrician and parents,
sponsible for converting the early unisex go- the baby appears to be a perfect little girl. An
nads into testes. Once formed, the testes then internal examination would show the presence
produce the balance of androgen and estrogen of testes rather than ovaries and the lack of a
that pushes development in the direction of uterus and Fallopian tubes, but there would
the male phenotype. In the absence of this normally be no reason for such an examina-
gene, the undetermined gonads become ova- tion.
ries, and the female phenotype emerges.
Therefore, the main cause of sex determina- Impact and Applications
tion is not XX or XY chromosomes, but rather Several events may lead to the diagnosis of
the presence or absence of the gene that pro- this condition. The attempted descent of the
motes testis differentiation. testes into a nonexistent scrotum will cause
In order for the male hormones to have an pain that may be mistaken for the pain of a her-
influence on the development of the internal nia; the presence of testes in the apparent girl
and external reproductive structures, the cells will be discovered when the child undergoes re-
of those structures must receive a signal that pair surgery. In other cases, the child may seek
Thalidomide and Other Teratogens 733
medical help in the mid-teen years because she Time 139 (February 24, 1992). The syndrome
does not menstruate. Exploratory surgery and its relationship to athletes and athletic
would then reveal the presence of testes and performance.
the absence of a uterus. As a general rule, the Mange, Elaine Johansen, and Arthur P. Mange.
testes are left in the abdomen until after pu- Basic Human Genetics. 2d ed. Sunderland,
berty because they are needed as a source of es- Mass.: Sinauer Associates, 1999. Provides a
trogen to promote the secondary sex charac- detailed discussion of testicular feminization
teristics, such as breast development. Without syndrome. Illustrations (some color), maps,
this estrogen, the girl would remain childlike in laser optical disc, bibliography, index.
body form. After puberty, the testes are usually
removed because they have a tendency to be- Web Sites of Interest
come cancerous. Intersex Society of North America. http://www
As a result of its phenotypic sex, an infant .isna.org. The society is a public awareness,
with testicular feminization is normally raised education, and advocacy organization which
as a girl whose only problem is an inability to works to create a world free of shame, se-
bear children. If the girl has athletic ability, crecy, and unwanted surgery for intersex
however, other problems may arise. Since 1966, people (individuals born with anatomy or
female Olympic athletes have had to submit to physiology which differs from cultural ideals
a test for the presence of the correct chromo- of male and female). Includes links to infor-
somal sex. In the past, this has meant micro- mation on such conditions as clitoromegaly,
scopic examination of cheek cells to count X micropenis, hypospadias, ambiguous geni-
chromosomes. In 1992, this technique was re- tals, early genital surgery, adrenal hyperpla-
placed by a test for the Y chromosome. Individ- sia, Klinefelter syndrome, androgen insensi-
uals who fail the sex test, including those with tivity, and testicular feminization.
testicular feminization syndrome, cannot com- Johns Hopkins University, Division of Pediatric
pete against other women. Proponents argue Endocrinology, Syndromes of Abnormal
that androgens aid muscle development, and Sex Differentiation. http://www.hopkins
the extra testosterone produced by the testes of medicine.org/pediatricendocrinology. Site
a normal male would provide an unfair physi- provides a guide to the science and genetics
cal advantage. However, because people with of sex differentiation, including a glossary.
testicular feminization syndrome are lacking Click on patient resources.
androgen receptors, their muscle development
would be unaffected by the extra androgen
produced by the testes, and thus they would not
be any stronger than well-conditioned women. Thalidomide and Other
Nancy N. Shontz Teratogens
See also: Fragile X Syndrome; Gender
Identity; Hereditary Diseases; Hermaphro- Field of study: Diseases and syndromes
dites; Klinefelter Syndrome; Metafemales; Significance: Teratogenesis is the development of
Pseudohermaphrodites; Steroid Hormones; defects in the embryo or fetus caused by exposure to
XYY Syndrome. chemicals, radiation, or other environmental con-
ditions. Thalidomide, a sedative whose ingestion
Further Reading by pregnant women led to the birth of abnormal
Goodall, J. Helping a Child to Understand babies in the late 1950s and early 1960s, is one
Her Own Testicular Feminisation. Lancet of the more publicized examples of a chemical
337 (January 5, 1991). Discusses how com- teratogen.
municating with children in stages about
their testicular feminization helps them Key terms
cope emotionally. congenital defect: a defect or disorder that
Lemonick, Michael. Genetic Tests Under Fire. occurs during prenatal development
734 Thalidomide and Other Teratogens
gans such as kidneys, bladders, testicles, ovaries, seven thousand births were affected by the in-
thyroids, and lungs. Other genetic teratogenic gestion of thalidomide.
malformations include anencephaly (absence The thalidomide incident made all scientists
of brain at birth), microcephaly (small-size more skeptical about the final approval of any
head), hydrocephaly (large-size head caused by type of medicine, especially those likely to be
accumulation of large amounts of fluids), spina used during pregnancy. The trend intensified
bifida (failure of the spine to close over the spi- the fight against any chemicals that might af-
nal cord), cleft palate (lack of fusion in the ven- fect the fetus during the first trimester, when it
tral laminae), and hermaphrodism (presence is particularly vulnerable to teratogens. Alco-
of both male and female sexual organs). hol and tobacco drew many headlines in the
media in the 1990s. Both have been shown to
Thalidomide and Its Impact create congenital problems in mental develop-
Thalidomide resembles glutethimide in its ment and learning abilities. At the same time,
sedative action. Laboratory studies of the late regulation of new FDA-approved medicine be-
1950s and early 1960s had shown thalidomide came much stricter, and efforts to study the
to be a safe sedative for pregnant women. As long-term effects of various pharmaceuticals
early as 1958, the West German government increased. Surprisingly, thalidomide itself has
made the medicine available without prescrip- been used successfully in leprosy cases and, in
tion. Other Western European countries fol- conjunction with cyclosporine, to treat cases of
lowed, with the medicine available only upon the immune reaction that appears in many
physicians prescription. It took several years bone-marrow transplant patients. There is also
for the human population to provide the evi- a movement to use thalidomide in the treat-
dence that laboratory animals could not. Ger- ment of acquired immunodeficiency syn-
man physician Widukind Lenz established the drome (AIDS).
role of thalidomide in a series of congenital de- In addition to drugs, many other agents can
fects. He proved that administration of the affect fetal development. Essentially, any factor
drug during the first twelve weeks of the with the potential to cause DNA mutations has
mothers pregnancy led to the development a high probability of being teratogenic. Conse-
of phocomelia, a condition characterized by quently, early in pregnancy, women are advised
peromelia (the congenital absence or malfor- to limit their exposure to a variety of potential
mation of the extremities caused by the abnor- teratogens, such as excess radiation, toxic chem-
mal formation and development of the limb icals, tobacco, alcohol, and other drugs. Pre-
bud from about the fourth to the eighth week vention might even include work reassignment
after conception), absence or malformation of to limit or eliminate the womans normal expo-
the external ear, fusion defects of the eye, and sure to teratogens. Unfortunately, teratogen-
absence of the normal openings of the gastro- esis can occur early in the pregnancy, before
intestinal system of the body. the woman is even aware that she is pregnant.
The United States escaped the thalidomide Prevention by avoidance is therefore essential.
tragedy to a great extent because of the efforts Soraya Ghayourmanesh, updated by Bryan Ness
of Frances O. Kelsey, M.D., of the U.S. Food See also: Congenital Defects; Prenatal Di-
and Drug Administration (FDA). She had seri- agnosis.
ous doubts about the drugs safety and was in-
strumental in banning the approval of thalido- Further Reading
mide for marketing in the United States. Other Holmes, L. B. Teratogen-Induced Limb De-
scientists such as Helen Brooke Taussig, a pio- fects. American Journal of Medical Genetics 112
neer of pediatric cardiology and one of the (October 15, 2002). Discusses limb defects, a
physicians who outlined the surgery on babies common effect of human teratogens.
with the Fallot (blue baby) syndrome, played a Stephens, Trent D., and Rock Brynner. Dark
key role in preventing the approval of thalido- Remedy: The Impact of Thalidomide and Its Re-
mide by the FDA. It is estimated that about vival as a Vital Medicine. Cambridge, Mass.:
736 Totipotency
Perseus, 2001. Surveys the history of the sion, the cells begin to differentiate. Once dif-
birth defects epidemic from the 1960s ferentiated, these specialized cells still possess
through today, and discusses the search for all the genetic materials inherited from the zy-
an alternative to thalidomide that retains its gote. Differentiated cells express or use some
curative effects. Bibliography, index. of their genes (not all) to produce their own
specific proteins. For example, epidermal cells
Web Site of Interest in human beings produce fibrous proteins
Teratology Society. http://www.teratology.org. called keratin to protect the skin, and red
The Teratology Society is a multidisciplinary blood cells produce hemoglobin to help trans-
scientific society founded in 1960, the mem- port oxygen. Due to the differences in gene ex-
bers of which study the causes and biological pression, differentiated cells have their own
processes leading to abnormal development distinct structures and functions, and some dif-
and birth defects at the fundamental and ferentiated cells are totipotent.
clinical level, and appropriate measures for A whole organism can be asexually repro-
prevention. duced from a single egg without the sperm by a
process called parthenogenesis. This occurs
naturally in some insects, snakes, lizards, and
amphibians, as well as in some plants. In this
Totipotency type of reproduction, the haploid chromo-
somes within an unfertilized egg duplicate, and
Field of study: Cellular biology the embryo develops as if the egg had been fer-
Significance: Totipotency is the ability of a living tilized. The pseudo-fertilized eggs are totipo-
cell to express all of its genes to regenerate a whole tent and generate all female individuals. The
new individual. Totipotent cells from plants have females can reproduce under favorable envi-
been used in tissue-culture techniques to produce ronmental conditions without waiting for a
improved plant materials that are pathogen-free mate. Like in vitro fertilization, parthenogene-
and disease-resistant. Totipotent cells from ani- sis is used as a technique to create an embryo in
mals are now being used to clone mammals, al- the laboratory. Chromosomal duplication is in-
though ethical questions remain over whether clon- duced in the egg cell to reproduce female indi-
ing a human should be done. viduals. However, no parthenogenic mammals
had been developed.
Key terms It may become possible to produce males
multipotent cell: a stem cell capable of through a process called androgenesis. In the
forming multiple differentiated tissues laboratory, the haploid chromosomes from
parthenogenesis: asexual reproduction from one sperm may be induced to duplicate. As in
a single egg without fertilization by sperm animal cloning, the duplicated chromosomes,
pluripotent cell: a stem cell that forms all which are diploid, can be implanted into an
types of differentiated tissues enucleated egg cell (a cell from which the nu-
unipotent cell: a stem cell that forms only cleus has been removed). Although androgen-
one differentiated tissue esis holds some promise, so far it has not pro-
duced normal embryos.
Egg and Sperm Cells
In plants and animals, a whole organism is Cell Differentiation
sexually reproduced from a zygote, a product Cell differentiation is a process whereby ge-
of fusion between egg and sperm. Zygotes are netically identical cells become different or
totipotent. A zygote in the seed of a plant or in specialized for their specific functions. During
the uterus of a mammal divides by mitosis and differentiation, enzymes and other polypep-
has the potential to produce more cells, called tides, including other large molecules, are syn-
embryonic cells, before developing into an thesized. Ribosomes and other cell structures
adult individual. During embryonic cell divi- are assembled. Differentiated cells express only
Totipotency 737
DNA is removed by pipette suction from a mammalian egg cell to prepare an enucleated egg cell for androgenesis. (AP/Wide World
Photos)
some of their genes to make enzymes and other of unspecialized and loosely arranged cells,
proteins. called a callus, is formed. Each cell from the
Tissue differentiation is usually triggered by callus begins to divide and differentiate, form-
mitosis, followed by cytokinesis. Then differen- ing a multicellular embryoid. One test tube can
tiation occurs in the daughter cells. Often the accommodate thousands of cells, and each
two daughter cells have different structures embryoid has the potential to become a com-
and functions, but both retain the same genes. plete plantlet. Plantlets can be transplanted
For example, the epidermal cell mitotically di- into the soil to develop into adult plants.
vides to produce one large and one small cell The phloem tissues from the roots of carrots
on the root surface; the large one maintains (Daucus species) also exhibit totipotency. Cells
the role of epidermal cell as a root covering, in pollen grains of tobacco are totipotent, and
whereas the small one becomes the root hair. they produce haploid plants. Using meristem
tissues of shoot and root tips, the cells regener-
Totipotent Cells in Plant-Tissue Culture ate new plants that are free of viruses, bacteria,
Cuttings of plants and tissue-culture tech- and fungi. Pathogen elimination is possible be-
niques have proven that many plant cells are cause vascular tissues (xylem and phloem), in
totipotent. Tissue culture, however, helps to which viruses move, do not reach the root or
identify what specific type of cell is totipotent, shoot apex. The protoplasts (cells without cell
because the technique uses a very small piece walls) from mesophyll cells of the leaf regener-
of known tissue. For example, if pith tissues ate new plants.
from tobacco (Nicotiana tobaccum), soybean
(Glycine max), and other dicot stems are cut off Plant Hormones
and cultured aseptically on an agar medium Totipotency of plant cells is enhanced by the
with proper nutrients and hormones, a clump presence of hormones, such as auxins and
738 Totipotency
cytokinins, in the culture media. Addition of Cloning of Dolly the sheep (Ovis species)
auxins influences the expression of genes and used the mammary cell of a six-year-old ewe as
causes physiological and morphological the donor cell. It was injected into the enucle-
changes in plants. Addition of cytokinins pro- ated sheeps egg cell. Cloning a mammal re-
motes cell division, cytokinesis, and organ for- quires a surrogate mother. The blastula stage of
mation. If these are present in the proper ratio, embryo was developed in vitro and was im-
callus from many plant species can be made to planted into a surrogate mother. After five
develop into an entire new plant. If the months, a lamb was born. The lamb was geneti-
cytokinin-to-auxin ratio is high, cells in the cal- cally identical to the sheep from which the
lus divide and give rise to the development of mammary cell was taken. Today, cloning has
buds, stems, and leaves. If the cytokinin-to- been done by scientists to produce other ani-
auxin ratio is low, root formation is favored. To- mals, including cattle, pigs, monkeys, cats, and
tipotency of some plant cells is promoted by the dogs. Cloning a human seems possible, but
addition of coconut water to the culture me- there are so many ethical and moral questions
diaan indication that coconut water has the whether it should be done or not.
right proportion of cytokinin and auxin to re-
generate an entire plant. Stem Cells in Animal Cloning
Stem cells exhibit totipotency because they
Importance of Totipotency in Plants can generate new types of tissues. Some sources
Clonal propagation of plants using tissue of stem cells are the blastocyst (the immature
culturing is used commercially to mass-pro- embryo), the fetus, the placenta, bone marrow,
duce numerous ornamentals, vegetables, and blood, skeletal muscle, and brain. Because
forest trees. A major use of pathogen-free there is no proof yet whether a single embry-
plants is for the storage of germ plasm and for onic stem cell has the ability to regenerate into
transport of plant materials into different a complete individual, stem cells are generally
countries. It is also posssible to generate plants only partially totipotent. A unipotent stem cell
with desirable traits, such as resistance to herbi- can form only one differentiated tissue. A
cides and environmental stressors or tolerance multipotent stem cell can form multiple differ-
of soil salinity, soil acidity, and heavy-metal tox- entiated tissues. For example, stem cells from
icity. It is easier to select resistant or tolerant blood can form platelets, white blood cells, or
plants from a thousand cells than from a thou- red blood cells. The stem cells from skeletal
sand plants. muscle can form smooth muscle, cardiac mus-
cle, bone, or cartilage. A pluripotent stem cell
Somatic Cells in Animal Cloning from embryo, brain, or bone marrow has the
Animals are more difficult to reproduce ability to develop all types of differentiated tis-
asexually than plants are. Somatic cells of ani- sues of the body. For example, brain stem cells
mals become totitopotent when used as donor can be turned into all tissue types, including
cells in cloning. The first successful animal brain, muscles, blood cells, and nerves.
cloned was a frog, Xenopus laevis. This cloning Domingo M. Jariel
involved the use of a nucleus from the intesti- See also: Cell Culture: Plant Cells; Stem
nal epithelial cells of a tadpole and an egg cell Cells.
from a mature frog. In the laboratory, the nu-
cleus from the egg cell was removed (enucle- Further Reading
ated) by micropipette. The tadpoles nucleus Prentice, David A. Stem Cells and Cloning. New
(the donor cell) was inserted into the enucle- York: Benjamin Cummings, 2003. Discusses
ated frogs egg cell. The nuclei-injected egg cell partial totipotency and differentiation of
underwent a series of embryonic developmen- stem cells, including illustrations showing
tal stages, including the blastula stage, develop- the sources of stem cells and how embryos
ing into tadpoles that later died before becom- can be developed by cloning techniques.
ing adults. Russell, Peter J. Genetics. San Francisco, Calif.:
Transgenic Organisms 739
Benjamin Cummings, 2002. Discusses toti- In the late 1970s and early 1980s, molecu-
potency of some plants and animals. In- lar biologists learned how to surpass the limita-
cludes illustrations on how cells from plants tions of selective breeding. They invented pro-
are used in tissue-culture techniques and cedures for combining the DNA of species as
how cells from animals are used in animal distantly related as plants and animals. Organ-
cloning. isms produced by such means are termed trans-
Smith, Roberta H. Plant Tissue Culture Tech- genic. This branch of genetic engineering made
niques and Experiments. New York: Academic it possible to design novel organisms for ge-
Press, 2000. Discusses the totipotency of dif- netic and biochemical research and for medi-
ferent types of cells in regenerating new cal, agricultural, and ecological innovations.
plants in vitro using culture growth media. Commercial use of transgenic organisms also
Includes an illustration of explant prepara- created worldwide controversy because of their
tion and discusses media preparation and potential threat to human health and the envi-
transplantation of regenerated plants. ronment.
Transgenesis is much like gene therapy in
that both transform cells for a specific purpose.
However, whereas gene therapy targets only
Transgenic Organisms certain cells in order to cure a defect in them,
transgenesis seeks to produce an entirely modi-
Field of study: Genetic engineering and fied organism by incorporating the transgene
biotechnology into all the cells of the mature organism and
Significance: Implanting genes from one organism changing the genome. This is done by trans-
into the genome of another enables scientists to forming not only the somatic (body) cells of
study basic genetic mechanisms and inherited dis- the host organism but also the germ cells, so
eases and to create plants and animals with traits that when the organism reproduces, the trans-
that are beneficial to humans. gene will pass to the next generation. Trans-
genes perform their alterations by blocking the
Key terms function of a host gene, by replacing the host
genome: the complete genetic material carried gene with one that codes for a variant protein,
by an individual or by introducing an additional gene.
plasmid: a circular piece of bacterial DNA that
is often used as a vector Transgenic Animals
transformation: integration of foreign DNA In 1978, yeast cells were the first to be trans-
into a cell formed by insertion of foreign DNA, followed
transgene: the foreign gene incorporated into by mouse cells in 1979. Mouse embryos were
a cells DNA during transformation transformed in 1980, which later led to the de-
vector: a carrier molecule that introduces for- velopment of a supermouse that grew much
eign genetic materials into a cell larger than ordinary mice because it had re-
ceived the gene for human growth hormone.
Engineering Organisms Most of these transformations came after mi-
Domestication and selective breeding of ani- croinjection of DNA directly into cells. Later,
mals and plants began before recorded history. scientists were able to deliver foreign genes
In fact, historians propose, the shaping of or- into hosts by several other methods: incorpo-
ganisms to fit human needs contributed to the rating them into retroviruses and then infect-
rise of settled, complex culture. Until late in ing target cells; electroinfusion, whereby an
the twentieth century, farmers and scientists electric current passed the foreign DNA
could breed novel strains only from closely re- through the relatively flimsy animal cell wall;
lated species or subspecies because the DNA biolistics, a means of mechanically shooting a
had to be compatible in order to produce off- DNA bullet into cells; and conveying the DNA
spring that in turn were fertile. into an ovum aboard sperm. Two methods, de-
740 Transgenic Organisms
veloped at first for mice, are particularly suc- munodeficiency disorder (SCID). In 2001 the
cessful in growing genetically modified animals first transgenic primate, a rhesus monkey, was
after transformation. The first entails inject- born, potentially supplying a research model
ing transformed embryonic stem cells into a genetically much more similar to humans than
blastocyst (an early spherical form of an em- mice are.
bryo). In the second, the DNA is inserted into Beginning in the late 1990s, transgenic ani-
the pronucleus of a freshly fertilized egg. The mals were developed for production of pro-
blastocyst or egg is then implanted into a foster teins that can be used in pharmaceutical drugs
mother for gestation. to treat human disease. Accordingly, they have
The first complex transgenic animals were become known as pharm animals. Lactating
intended for genetic research. After disabling a transgenic mice make tissue plasminogen acti-
specific gene, scientists could study its effect on vator in their milk. Similarly, transgenic sheep
the appearance, metabolic processes, and supply blood coagulation factor IX and alpha1-
health of the mature animal. By 2003 thou- antitrypsin, transgenic pigs produce human
sands of genes had been tested. Also, research hemoglobin, and transgenic cows make hu-
with mice transformed with human DNA en- man lactoferrin. Scientists have also developed
abled scientists to identify genes associated transgenic pigs that may supply tissue and or-
with breast and prostate cancers, cystic fibrosis, gans for transplantation into humans without
Alzheimers disease, and severe combined im- tissue rejection.
Transgenic Plants
Plant cells present greater difficulties for
transformation because their cells walls are
sturdier than animal cell walls. Microinjection
and biolistics are possible but tricky and slow. A
breakthrough for plant transgenesis came in
1983, when three separate teams of scientists
used plasmids as vectors (carrier molecules) to
infect plants with foreign DNA. The achieve-
ment came about because of research into
plant tumors caused by crown gall disease. The
pathogen, the soil bacterium Agrobacterium
tumefaciens, caused the disease by ferrying bits
of its own DNA into the genome of plants via
Image not available plasmids, circular bits of extranuclear DNA.
Scientists found that they could take the same
plasmid, cut out bits of its DNA with enzymes
and insert transgenes, and then use the altered
plasmids as vectors to transform plants. Subse-
quently, scientists discovered that liposomes
can be vectors. A liposome is a tiny ball of
lipids that binds readily to a cell wall, opens a
passage, and delivers any DNA that has been
put inside it.
A great variety of transgenic plants have
been designed for agriculture to produce ge-
netically modified (GM) foods. The first to be
marketed was a strain of tomato that ripened
These two rhesus monkeys were born from cloned embryos in slowly so that it gained flavor by staying longer
1996. (AP/Wide World Photos) on the vine and remained ripe longer on super-
Transgenic Organisms 741
market shelves. This Flavr Savr tomato was not are concerned with specific dangers that trans-
a commercial success, however. Corn, cotton, genic organism may pose. Many consumers,
soybeans, potatoes, and papayas received a gene most noticeably those in Europe, worry that
from the bacterium Bacillus thuringiensis (Bt) GM foods contain hidden health risks. After
that enables them to make a caterpillar-killing transgenes were found to escape from crops
toxin; these are frequently referred to a Bt crops. and become part of wild plants, environmen-
Other crops have been made resistant to herbi- talists proposed that there could be unforeseen
cides so that weeds can be easily killed without and harmful ecological consequences, espe-
harming the food plants. Similarly, some trans- cially in the destruction of natural species and
genic crops tolerate salty or aluminum-rich soil, reduction of biodiversity.
have less impact on the land because they re- Even those who welcome the creation of
quire less water or tillage, or produce a high transgenic animals and plants are concerned
yield. about the legal and social effects. Principally,
Like transgenic animals, some transgenic because biotechnology corporations can pat-
crops promise to deliver pharmaceuticals at ent transgenic organisms, they potentially have
lower costs and more conveniently than fac- great influence on agribusiness, perhaps to the
tory-made drugs. GM bananas and potatoes detriment of small farmers and consumers.
contain vaccines for protection against diar- Roger Smith
rheal diseases, such as cholera, and hepatitis B. See also: Antibodies; Biopesticides; Bio-
In 2000, scientists reported invention of rice pharmaceuticals; Genetic Engineering; Ge-
and wheat strains that produce anti-cancer anti- netic Engineering: Agricultural Applications;
bodies. Golden rice, a transgenic strain that Genetic Engineering: Medical Applications;
contains vitamin A, was developed to ward off Genetic Engineering: Risks; Genetic Engi-
blindness from vitamin A deficiency, which is a neering: Social and Ethical Issues; Genetically
problem in countries that subsist largely on Modified (GM) Foods; Genomics; Human
rice. Another strain has elevated iron levels to Growth Hormone; Hybridization and Intro-
combat anemia. In a bid to reduce the health gression; Knockout Genetics and Knockout
risk from smoking, a tobacco company devel- Mice; Lateral Gene Transfer; Model Organism:
oped a strain free of nicotine. Drosophila melanogaster; Model Organism: Mus
musculus; Model Organism: Xenopus laevis; Mo-
The Debate over Transgenesis lecular Genetics; Viroids and Virusoids.
Transgenic organisms offer great benefits to
humankind: deeper understanding of the ge- Further Reading
netic component in disease and aids in diagno- Brown, Kathryn, Karen Hopkin, and Sasha
sis; new, cheaper, more easily produced drugs; Nemecek. GM Foods: Are They Safe? Scien-
and crops that could help alleviate the growing tific American 284, no. 4 (2001): 52-57. De-
hunger in the world. Yet during the 1990s pro- scribes the risks and benefits in growing
tests against transgenesis began that are as con- genetically modified foods and human con-
tentious as any since the controversy over the sumption of them. Accompanied by graph-
pesticide DDT during the 1960s. ics and tables that summarize and clarify
Some opponents object to the very fact that technical matters.
organisms are modified strictly for human ben- Lurquin, Paul F. The Green Phoenix: A History of
efit. They find such manipulations of lifes es- Genetically Modified Plants. New York: Colum-
sential code blasphemous and arrogant, or at bia University Press, 2001. Written by a pio-
the very least unethical and reckless. Further- neer in the field of transgenic plants, this
more, animal rights groups regard the produc- technically detailed but readable book re-
tion of transgenic pharm and research animals quires a basic familiarity with microbiology
cruel and in violation of the natural rights of and genetics. The author discusses the eco-
other species. logical and ethical controversies with insight
The greater portion of opponents, however, and balance.
742 Transposable Elements
Nicholl, Desmond S. T. An Introduction to Ge- tamc. A professional Web site for researchers
netic Engineering. 2d ed. New York: Cam- seeking a host animal to test transgenes.
bridge University Press, 2002. A thorough, However, it contains much useful general
lucidly structured survey of the techniques information about transgenics (especially
and applications of genetic engineering. transgenic rats), vectors, and laboratory pro-
One chapter is devoted to transgenic plants cedures. With links and a photo gallery.
and animals.
Velander, William, et al. Transgenic Livestock
as Drug Factories. Scientific American 276
(January, 1997). Explains how genetic engi- Transposable Elements
neering methods have resulted in the pro-
duction of pharm animals whose milk con- Fields of study: Bacterial genetics;
tains large amounts of medicinal proteins. Molecular genetics
Winston, Mark L. Travels in the Genetically Mod- Significance: Transposable elements are discrete
ified Zone. Cambridge, Mass.: Harvard Uni- DNA sequences that have evolved the means to
versity Press, 2002. A popular account of the move (transpose) within the chromosomes. Trans-
agribusiness, government oversight, and sci- position results in mutation and potentially
ence of genetically modified plants and ani- large-scale genome rearrangements. Transposable
mals. The science is explained cursorily for elements contribute to the problem of multiple anti-
general readers. biotic resistance by mobilizing the genes of patho-
genic bacteria for antibiotic resistance.
Web Sites of Interest
Oak Ridge National Laboratory. Transgenic Key terms
and Targeted Mutant Animal Database. composite transposon: a transposable ele-
http://www.ornl.gov/TechResources/ ment that contains genes other than those
Trans/hmepg.html. A searchable profes- required for transposition
sional database about lines of genetically resistance plasmid (R plasmid): a small, cir-
modified animals, methods used to create cular DNA molecule that replicates inde-
them and descriptions of the modified DNA, pendently of the bacterial host chromosome
the expression of transgenes, and how trans- and encodes a gene for antibiotic resistance
genes are named. selfish DNA: a DNA sequence that has no ap-
TBASE: The Transgenic/Targeted Mutation parent purpose for the host that spreads by
Database, Jackson Laboratory, Bar Harbor, forming additional copies of itself within the
Maine. http://tbase.jax.org. Database of genome
information about transgenic animals gen- transposase: an enzyme encoded by a
erated worldwide, searchable by species, transposable element that initiates transpo-
technique, DNA construct, phenotype, labo- sition by cutting specifically at the ends of
ratory. Features the Knockout Model of the the element and randomly at the site of in-
Montha discussion of new animal mod- sertion
elsand a glossary.
Transgenic Crops: An Introduction and Re- Jumping Genes
source Guide http://www.colostate.edu/ Transposable elements are DNA sequences
programs/lifesciences/transgeniccrops. that are capable of moving from one chromo-
This richly illustrated site provides informa- somal location to another in the same cell. In
tion about the history of plant breeding, the some senses, transposable elements have been
making of transgenic plants, government likened to intracellular viruses. The first ge-
regulations, and risks and concerns. Also netic evidence for transposable elements was
available in Spanish. described by Barbara McClintock in the 1940s.
University of Michigan. Transgenic Animal She was studying the genetics of the pigmenta-
Model Core. http://www.med.umich.edu/ tion of maize (corn) kernels and realized that
Transposable Elements 743
Barbara McClintock
Though best known for her research on mobile ge- chromosomes to elucidate many aspects of genetic
netic elements (for which she won the first unshared control. Her first major contribution was the identi-
Nobel Prize in Physiology or Medicine awarded to a fication and naming of the maize chromosomes.
woman), Barbara McClintocks contributions to the Shortly after, using cytological markers on the chro-
field of genetics were many. McClintocks career in mosomes, McClintock and graduate student Har-
genetics spanned the development of the field itself. riet Creighton demonstrated the correlation be-
While an undergraduate at Cornell University (from tween patterns of inheritance and chromosomal
which she earned her bachelor of science degree in crossoverthe exchange of material between chro-
1923), she was invited to participate in a graduate mosomes. Breeding experiments focusing on link-
course in genetics, then a fledgling discipline. She age groups allowed McClintock to associate each of
continued at Cornell as a graduate student (earning corns ten chromosomes with the genes they carry.
her Ph.D. in 1927), combining her interests in the At that point, Lewis Stadler, who was studying the
microscopic internal structure of the cell (cytology) mutagenic effects of X rays, sent some irradiated
with the transmission of heritable traits (genetics). corn to McClintock. McClintock demonstrated that
McClintocks keen observational skills and her the resultant broken chromosomes can fuse into a
holistic approach to science allowed her to make sig- ring, and she then hypothesized the existence of the
nificant advancements. It had only recently been es- telomere, a protective stabilizing structure at the end
tablished that the chromosomes (visible under the of the chromosome. At the University of Missouri,
microscope) were the carriers of Gregor Mendels McClintock observed the ability of such broken
factors, or genes. McClintock used information chromosomes to go through a series of breakages
gleaned from characteristics of the corn plant, Zea and fusions (the breakage-fusion-bridge cycle) and
mays (maize), in conjunction with changes in its identified concomitant chromosomal inversions
and deletions. She ultimately discovered that cer-
tain genes could transfer from cell to cell and be-
tween chromosomes, thereby influencing the
color patterns in the leaves and kernels of corn.
In 1941, McClintock moved to Cold Spring Har-
bor, New York, where she would remain. Doing
much of her work before the discovery of the dou-
ble helical structure of DNA, she rejected the sim-
plistic one-way flow from DNA to RNA to protein
outlined in the central dogma of molecular biol-
ogy, seeking instead an explanation for the spatial
and temporal variation in gene expression needed
to link genetics to developmental and evolutionary
change. Her own work showed that both the loca-
tion and direction of genetic material, as well as the
presence of other controlling elements, had im-
portant effects on the expression of the gene.
In addition to this better-known work, McClin-
tock identified the chromosomes of the bread
mold Neurospora and described its meiotic cycle.
She also headed a study aimed at conserving indig-
enous corn varieties in the Americas. In recogni-
tion of her place as one of the most distinguished
scientists of the twentieth century, The Barbara Mc-
Clintock Papers are available through the National
Library of Medicine through its Profiles in Sci-
ence Web site.
Barbara McClintock. ( The Nobel Foundation) Lee Anne Martnez
744 Transposable Elements
the patterns of inheritance were not following sons that transposons are likened to viruses. Vi-
Mendelian laws. Furthermore, she surmised ruses can be thought of as transposons that
that insertion and excision of genetic material gained the genes for a protein coat and thus
were responsible for the genetic patterns she the ability to leave one cell and infect others;
observed. McClintock was recognized for this conversely, transposons can be thought of as
pioneering work with a Nobel Prize in Physiol- intracellular viruses.
ogy or Medicine in 1983. It was not until the
1960s that the jumping genes that McClintock Genetic Change and Selfish DNA
postulated were isolated and characterized. Transposition is a significant cause of muta-
The first transposable elements to be well char- tion for many organisms. When McClintock
acterized were found in the bacteria Escherichia studied the genetic patterns of maize kernel
coli but have subsequently been found in the pigmentation, she saw the results of insertion
cells of many bacteria, plants, and animals. and excision of transposable elements into and
Transposable elements are discrete DNA se- out of the pigment genes. Subsequently, it has
quences that encode a transposase, an enzyme been well established that mutations in many
that catalyzes transposition. Transposition re- organisms are the result of insertion of
fers to the movement within a genome. The transposable elements into and around genes.
borders of the transposable element are de- Transposition sometimes results in deletion
fined by specific DNA sequences; often the se- mutations as well. Occasionally the transposase
quences at either end of the transposable ele- will cut at one end of the transposable element
ment are inverted repeats of one another. The but skip the other end, cutting the DNA further
transposase enzyme cuts the DNA sequences at downstream. This can result in a deletion of the
the ends of the transposable element to initiate DNA between the end of the transposable ele-
transposition and cuts the DNA at the insertion ment and the cut site.
site. The site for insertion of the transposable In addition to these direct results, it is be-
element is not specific. Therefore, transposi- lieved that transposable elements may be re-
tion results in random insertion into chromo- sponsible for large-scale rearrangements of
somes and often results in mutation and ge- chromosomes. Genetic recombination, the ex-
nome rearrangement. In many organisms, change of genetic information resulting in new
transposition accounts for a significant fraction combinations of DNA sequences, depends upon
of all mutation. Although the details of the DNA sequence homology. Normally, recombi-
mechanism may vary, there are two basic mech- nation does not occur between nonhomolo-
anisms of transposition: conser vative and gous chromosomes or between two parts of the
replicative. In conservative transposition, the same chromosome. However, transposition can
transposable element is excised from its origi- create small regions of homology (the trans-
nal site and inserted at another. In replicative posable element itself) spread throughout the
transposition, a copy of the transposable ele- chromosomes. Recombination occurring be-
ment is made and is inserted in a new location. tween homologous transposable elements can
The original transposable element remains at create deletions, inversions, and other large-
its initial site. scale rearrangements of chromosomes.
A subset of the replicative transposable ele- Scientists often take advantage of transpos-
ments includes the retrotransposons. These el- able elements to construct mutant organisms
ements transpose through an RNA intermedi- for study. The random nature of insertion en-
ate. Interestingly, their DNA sequence and sures that many different genes can be mu-
organization are similar to those of retrovi- tated, the relatively large insertion makes it
ruses. It is likely that either retroviruses evolved likely that there will be a complete loss of gene
from retrotransposons by gaining the genes to function, and the site of insertion is easy to lo-
produce the proteins for a viral coat or retro- cate to identify the mutated region.
transposons evolved from retroviruses that lost Biologists often think of natural selection as
the genes for a viral coat. This is one of the rea- working at the level of the organism. DNA se-
Transposable Elements 745
quences that confer a selective advantage to the Resistance to antibiotics is a growing public
organism are increased in number as a result of health problem that threatens to undo much of
the increased reproductive success of the or- the progress that the antibiotic revolution
ganisms that possess those sequences. It has made against infectious disease. Transposition
been said that organisms are simply DNAs of composite transposons is part of the prob-
means of producing more DNA. In 1980, how- lem. Transposition can occur between any two
ever, W. Ford Doolittle, Carmen Sapienza, sites within the same cell, including between
Leslie Orgel, and Francis Crick elaborated on the chromosome and plasmid DNA. Plasmids
another kind of selection that occurs among are small, circular DNA molecules that repli-
DNA sequences within a cell. In this selection, cate independently of the bacterial host chro-
DNA sequences are competing with each other mosome. Resistance plasmids (R plasmids) are
to be replicated. DNA sequences that spread by created when composite transposons carrying
forming additional copies of themselves will in- an antibiotic resistance gene insert into a plas-
crease relative to other DNA sequences. There mid. What makes this particularly serious is
is selection for discrete DNA sequences to that some plasmids encode fertility factors
evolve the means to propagate themselves. (genes that promote the transfer of the plas-
One of the key points is that this selection does mid from one bacteria to another). This pro-
not work at the level of the organisms pheno- vides a mechanism for rapid and widespread
type. There may be no advantage for the organ- antibiotic resistance whenever antibiotics are
ism to have these DNA sequences. In fact, it used. The great selective pressure exerted by
may be that there is a slight disadvantage to hav- antibiotic use results in the spread of R plas-
ing many of these DNA sequences. For this rea- mids throughout the bacterial population.
son, DNA sequences that are selected because This, in turn, increases the opportunities for
of their tendency to make additional copies of composite transposon insertion into R plas-
themselves are referred to as selfish DNA. mids to create multiple drug-resistant R plas-
Transposable elements are often cited as exam- mids. The first report of multiple antibiotic re-
ples of selfish DNA. sistance caused by R plasmids was in Japan in
1957 when strains of Shigella dysenteriae, which
Composite Transposons and Antibiotic causes dysentery, became resistant to four com-
Resistance mon antibiotics all at once. Some R plasmids
Some transposable elements have genes un- encode resistance for up to eight different anti-
related to the transposition process located biotics, which often makes treatment of bacte-
between the inverted, repeat DNA sequences rial infection difficult. Furthermore, some
that define the ends of the element. These plasmids are able to cause genetic transfer be-
are referred to as composite transposons. Very tween bacterial species, limiting the usefulness
frequently, bacterial composite transposons of many antibiotics.
contain a gene that encodes resistance to anti- Craig S. Laufer
biotics. The consequence is that the antibiotic See also: Antisense RNA; Archaea; Bacte-
resistance gene is mobilized: It will jump along rial Resistance and Super Bacteria; Immuno-
with the rest of the transposable element to genetics; Lateral Gene Transfer; Model Or-
new DNA sites. Composite transposons may be ganism: Escherichia coli; Molecular Genetics;
generated when two of the same type of Mutation and Mutagenesis; Plasmids; Repeti-
transposable elements end up near each other tive DNA.
and flanking an antibiotic resistance gene. If
mutations occurred to change the sequences at Further Reading
the inside ends of the transposable elements, Capy, Pierre, et al. Dynamics and Evolution of
the transposase would then only recognize and Transposable Elements. New York: Chapman &
cut at the two outside end sequences to cause Hall, 1998. Addresses the structure of the
everything in between to be part of a new com- transposable elements, heterochromatin,
posite transposon. host phylogenies, the origin and coevolu-
746 Tumor-Suppressor Genes
tion of retroviruses, evolutionary links be- mal form of an oncogene, called a proto-
tween telomeres and transposable elements, oncogene, is involved in regulating the cell
population genetics models of transposable cycle
elements, and more. Illustrations, maps, bib- p53 gene: a tumor-suppressor gene, implicated
liography. in many types of cancer
Keller, Evelyn Fox. A Feeling for the Organism: The
Life and Work of Barbara McClintock. 10th an- Discovery of Tumor-Suppressor Genes
niversary ed. New York: W. H. Freeman, The existence of genes that play critical roles
1993. A now-classic look at McClintock and in cell cycle regulation by inhibiting cell divi-
her pathbreaking work. sion was predicted by several lines of evidence.
McClintock, Barbara. The Discovery and Charac- In vitro studies involving the fusion of normal
terization of Transposable Elements: The Collected and cancer cell lines were often observed to re-
Papers of Barbara McClintock. New York: Gar- sult in suppression of the malignant pheno-
land, 1987. Presents the papers on trans- type, suggesting that normal cells contained in-
posable elements that McClintock wrote hibitors that could reprogram the abnormal
between 1938 and 1984. Illustrations, bibli- growth behavior in the cancer cell lines. In ad-
ography. dition, studies by Alfred Knudsen on inherited
McDonald, John F., ed. Transposable Elements and noninherited forms of retinoblastoma, a
and Genome Evolution. London: Kluwer Aca- childhood cancer associated with tumor for-
demic, 2000. Includes the seminal papers mation in the eye, suggested that the inactiva-
presented in 1992 at the University of Geor- tion of recessive genes as a consequence of mu-
gia during a meeting of molecular, popula- tation could result in the loss of function of
tion, and evolutionary geneticists to discuss inhibitory gene products critical to cell division
the relevance of their research to the role control. With the advent of molecular methods
played by transposable elements in evolu- of genetic analysis, the gene whose inactivation
tion. Illustrations, bibliography, index. is responsible for retinoblastoma was identified
and designated Rb.
Additional tumor-suppressor genes were
identified by studies of DNA tumor viruses
Tumor-Suppressor Genes whose cancer-causing properties were found to
result, in part, from the ability of specific viral
Field of study: Molecular genetics gene products to inactivate host cell inhibitory
Significance: Molecular analysis of tumor-sup- gene products involved in cell cycle regulation.
pressor genes has provided important information By inactivating these host cell proteins, the tu-
on mechanisms of cell cycle regulation and pat- mor virus removes the constraints on viral and
terns of growth control in normal dividing cells cellular proliferation. The most important cel-
and cancer cells. Tumor-suppressor genes repre- lular gene product to be identified in this way is
sent cell cycle control genes that inhibit cell divi- the p53 protein, named after its molecular
sion and initiate cell death processes in abnormal weight. Genetic studies of human malignancies
cells. Mutations in these genes have been identified have implicated mutations in the p53 gene in
in many types of human cancer and play a critical up to 75 percent of tumors of diverse tissue ori-
role in the genetic destabilization and loss of gin, including an inherited disorder called Li-
growth control characteristic of malignancy. Fraumeni syndrome, associated with many
types of cancer. In addition, studies of other
Key terms rare inherited malignancies have led to the
cell cycle: a highly regulated series of events identification of many other recessive genes
critical to the initiation of cell division pro- whose inactivation contributes to oncogenic or
cesses cancer-causing mechanisms. Included in this
oncogenes: a mutated or improperly ex- list are the BRCA1 and BRCA2 genes in breast
pressed gene that can cause cancer; the nor- cancer, the NF1 gene in neurofibromatosis, the
Tumor-Suppressor Genes 747
p16 gene in melanoma, and the APC gene in cer cells. Taken together, research on the pat-
colorectal carcinoma. Each of these genes has terns of oncogene activation and the loss of tu-
also been implicated in nonhereditary cancers. mor-suppressor gene function in many types of
human malignancy suggest a general model of
The Properties of Tumor-Suppressor oncogenesis. Molecular analyses of many tu-
Genes mors show multiple genetic alterations involv-
Molecular analyses of the genetic and bio- ing both oncogenes and tumor-suppressor
chemical properties of tumor-suppressor genes genes, suggesting that oncogenesis (develop-
have suggested that these gene products play ment of cancer) requires unregulated stimula-
critical but distinct roles in regulating pro- tion of cellular proliferation pathways along
cesses involved in cellular proliferation. The Rb with a loss of inhibitory activities that operate at
gene product represents a prototype tumor- cell cycle checkpoints.
suppressor gene that blocks progression of the With respect to clinical applications, restora-
cell cycle and cell division by binding to tran- tion of p53 tumor-suppressor gene function by
scription factors in its active form. In order for gene therapy appears to result in tumor regres-
cell division to occur in response to growth fac- sion in some experimental systems; however,
tor stimulation, elements of the signal cascade much more work needs to be done in this area
inactivate Rb-mediated inhibition by a mecha- to achieve clinical relevance. More important,
nism involving the addition of phosphate to research on the mechanism of action of stan-
the molecule, a reaction called phosphoryla- dard chemotherapeutic drugs suggests that
tion. Loss of Rb function as a consequence of cytotoxicity may be caused by p53-induced cell
mutation removes the brakes on this form of in- death; the absence of functional p53 in many
hibitory control; the cell division machinery tumors may account for their resistance to che-
proceeds regardless of appropriate initiation motherapy. Promising research suggests that it
by growth factors or other stimuli. may be possible to elicit cell death in tumor
The p53 tumor-suppressor gene product is a cells lacking functional p53 gene product in re-
DNA-binding protein that regulates the ex- sponse to chemotherapy. The clinical signifi-
pression of specific genes in response to ge- cance of activating these p53-independent cell
netic damage or other abnormal events that death mechanisms may be extraordinary.
may occur during cell cycle progression. In re- Sarah Crawford Martinelli
sponse to p53 activation, the cell may arrest the See also: Aging; Breast Cancer; Cancer;
process of cell division (by indirectly blocking Cell Cycle, The; Cell Division; DNA Repair; Hu-
Rb inactivation) to repair genetic damage be- man Genetics; Human Genome Project; Model
fore proceeding further along the cell cycle; al- Organism: Mus musculus; Oncogenes.
ternatively, if the damage is too great, the p53
gene product may initiate a process of cell Further Reading
death called apoptosis. The loss of p53 activity Ehrlich, Melanie, ed. DNA Alterations in Cancer:
in the cell as a consequence of mutation results Genetic and Epigenetic Changes. Natick, Mass.:
in genetic destabilization and the failure of cell Eaton, 2000. A comprehensive overview of
death mechanisms to eliminate damaged cells the numerous and varied genetic alterations
from the body; both events appear to be critical leading to the development and progression
to late-stage oncogenic mechanisms. of cancer. Topics include oncogenes, tumor-
suppressor genes, cancer predisposition,
Impact and Applications DNA repair, and epigenetic alteration such
The discovery of tumor-suppressor genes as methylation.
has revealed the existence of inhibitory mecha- Fisher, David E., ed. Tumor Suppressor Genes in
nisms critical to the regulation of cellular pro- Human Cancer. Totowa, N.J.: Humana Press,
liferation. Mutations that destroy the func- 2001. Covers models used in suppressor
tional activities of these gene products cause gene studies, cancer drugs, and gene de-
the loss of growth control characteristic of can- scriptions. Illustrated (some color).
748 Turner Syndrome
tic of Turner syndrome. The incidence of short fertilization (fertilizing a womans egg with
stature among women with Turner syndrome is sperm outside the body) and embryo transfer
virtually 100 percent. Women who have this (moving the fertilized egg into a womans
condition are, on average, 4 feet 8 inches (1.4 uterus). Individuals with Turner syndrome can
meters) tall. The cause of the failure to grow is be healthy, happy, and productive members of
unclear. However, growth-promoting therapy society.
with growth hormones has become standard. Nevertheless, because of its relative rarity, a
Most women with the syndrome also experi- woman with Turner syndrome may never meet
ence ovarian failure. Since the ovaries normally another individual with this condition and may
produce estrogen, women with Turner syn- suffer from self-consciousness, embarrass-
drome lack this essential hormone. This deficit ment, and poor self-esteem. The attitudes of
results in infertility and incomplete sexual de- parents, siblings, and relatives are important in
velopment. Cardiovascular disorders are the helping develop a strong sense of identity and
single source of increased mortality in women self-worth. The Turner Syndrome Society of
with this condition. High blood pressure is the United States is a key source of information
common. and support groups. Advances in chromo-
Other physical features often associated with somal analysis have proved helpful in the diag-
Turner syndrome include puffy hands and feet nosis and management of Turner syndrome. In
at birth, a webbed neck, prominent ears, a addition, new developments in hormonal ther-
small jaw, short fingers, a low hairline at the apy for short stature and ovarian failure, com-
back of the neck, and soft fingernails that turn bined with advances in in vitro fertilization,
up at the ends. Some women with Turner syn- have significantly improved the potential for
drome have a tendency to become overweight. growth, sexual development, and fertility for
Many women will exhibit only a few of these dis- afflicted individuals.
tinctive features, and some may not show any of Fred Buchstein
them. This condition does not affect general See also: Amniocentesis and Chorionic Vil-
intelligence. Girls with Turner syndrome fol- lus Sampling; Dwarfism; Hereditary Diseases;
low a typical female developmental pattern Infertility; Klinefelter Syndrome; Mutation
with unambiguous female gender identifica- and Mutagenesis; Nondisjunction and Aneu-
tion. However, another possible symptom is ploidy; X Chromosome Inactivation; XYY Syn-
poor spatial perception abilities. For example, drome.
women with this condition may have difficulty
driving, recognizing subtle social clues, and Further Reading
solving nonverbal mathematics problems; they Albertsson-Wikland, Kerstin, and Michael B.
may also suffer from clumsiness and attention- Ranke, eds. Turner Syndrome in a Life Span Per-
deficit disorder. spective: Research and Clinical Aspects. New
York: Elsevier, 1995. Focuses on molecular
Treatments and Therapies genetic evaluation, prenatal diagnosis,
No treatment is available to correct the chro- growth, medical and psychosocial manage-
mosome abnormality that causes this condi- ment, pediatric and adult care, estrogen sub-
tion. However, injections of human growth stitution therapy, bone mineralization, hear-
hormone can restore most of the growth defi- ing, and more. Illustrations, bibliography,
cit. Unless they undergo hormone replace- index.
ment therapy, girls with Turner syndrome will Broman, Sarah H., and Jordan Grafman, eds.
not menstruate or develop breasts and pubic Atypical Cognitive Deficits in Developmental Dis-
hair. In addition to estrogen replacement ther- orders: Implications for Brain Function.
apy, women with Turner syndrome are often Hillsdale, N.J.: Lawrence Erlbaum, 1994. In-
advised to take calcium and exercise regularly. cludes multidisciplinary research about
Although infertility cannot be altered, preg- Turner syndrome. Illustrations, bibliogra-
nancy may be made possible through in vitro phy, index.
750 Twin Studies
be called identical twins. These thirty-five pairs their physical traits to their children by means
reported that people often had difficulty tell- of genes in chromosomes. Each chromosome
ing them apart. Using questionnaires and in- carries two genes (called alleles) for every he-
terviews, Galton compared the thirty-five iden- reditary trait. One allele comes from the father
tical pairs with the other twins. He found that and one comes from the mother. Any set of full
the identical twins were much more similar to brothers and sisters will share many of the same
one another in habits, interests, and personali- alleles, since all of their genes come from the
ties, as well as in appearance. They were even same parents. However, brothers and sisters
much more alike in physical health and suscep- usually also differ substantially; each zygote
tibility to illness. The one area in which all indi- (ovum, or egg, fertilized by a sperm cell) will
viduals seemed to differ markedly was in hand- combine alleles from the father and the
writing. mother in a unique manner, so different zy-
gotes will develop into unique individuals.
Modern Twin Studies Even when two fertilized eggs are present at the
Since Galtons time, researchers have discov- same time, as in the case of dizygotic or frater-
ered how biological inheritance occurs, and nal twins, the two will have different combina-
this has made possible an understanding of tions of genes from the mother and the father.
why twins are similar. It has also enabled re- Identical twins are an exception to the rule
searchers to make more sophisticated use of of unique combinations of genes. Identical
twins in studies that address various aspects of twins develop from a single zygote, a cell cre-
the nature vs. nurture problem. Parents pass ated by one union of egg and sperm. There-
In the background, the co-director of the Twins Reared Apart project, Nancy Segal, with twins Mark Newman and Gerald Levey,
separated at birth. (AP/Wide World Photos)
752 Twin Studies
fore, monozygotic twins (from one zygote) will assume that monozygotic twins are biologically
normally have the same genetic makeup. Dif- identical, some critics have claimed that there
ferences between genetic twins, researchers ar- are reasons to question this assumption. Even
gue, must therefore be produced by environ- though these twins tend to show greater unifor-
mental factors following birth. mity than other people, developmental differ-
The ideal way to conduct twin studies is to ences may emerge even in the womb after the
compare monozygotic twins who have been splitting of the zygote.
reared apart from each other in vastly different Twins who show a great physical similarity
types of families or environments. This is rarely may also be subject to environmental similari-
possible, however, because the number of twins ties so that traits believed to be caused by genet-
separated at birth and adopted is relatively ics may, in fact, be a result of upbringing. Some
small. For this reason, researchers in most twin parents, for example, dress twins in matching
studies use fraternal twins as a comparison clothing. Even when twins grow up in separate
group, since the major difference between homes without being in contact with each
monozygotic and dizygotic twins is that the for- other, their appearances and mannerisms may
mer are genetically identical. Statistical similar- evoke the same kinds of responses from others.
ities among monozygotic twins that are not Physical attractiveness, height, and other char-
found among dizygotic twins are therefore be- acteristics often affect how individuals are
lieved to be caused by genetic inheritance. treated by others so that the biologically based
Researchers use several types of data on resemblances of twins can lead to common ex-
twins to estimate the extent to which human periences.
characteristics are the consequence of genet- Finally, critics of twin studies point out that
ics. One of the main sources for twin studies is twins constitute a special group of people and
the Minnesota Twin Registry. In the 1990s, this that it may be difficult to apply findings from
registry consisted of about 10,500 twins in Min- twin studies to the population at large. Some
nesota. They were found in Minnesota birth re- studies have indicated that intelligence quo-
cords from the years 1936 through 1955, and tient (IQ) scores of twins, on average, are about
they were located and recruited by mail be- five points below IQ scores in the general popu-
tween 1985 and 1990. A second major source of lation, and twins may differ from the general
twin studies is the Virginia Twin Registry. This population in other respects. It is conceivable
is a register of twins constructed from a system- that genetics plays a more prominent role in
atic review of public birth records in the Com- twins than in most other people.
monwealth of Virginia. A few other states also
maintain records of twins. Some other organi- Impact and Applications
zations, such as the American Association of Twin studies have provided evidence that a
Retired Persons (AARP), keep records of twins substantial amount of human character and
who volunteer to participate and make these behavior may be genetically determined. In
records available to researchers. 1976, psychologists John C. Loehlin and Rob-
Zygosity, or degree of genetic similarity be- ert C. Nichols published their analyses of the
tween twins, is usually measured by survey ques- backgrounds and performances of 850 sets of
tions about physical similarity and by how often twins who took the 1962 National Merit Schol-
other people mistake one twin for the other. In arship test. Results showed that identical twins
some cases, zygosity may be determined more showed greater similarities than fraternal twins
rigorously through analysis of DNA samples. in abilities, personalities, opinions, and ambi-
tions. A careful examination of backgrounds
Problems with Twin Studies indicated that these similarities could not be
Although twin studies are one of the best explained by the similar treatment received by
available means for studying genetic influences identical twins during upbringing.
in human beings, there are a number of prob- Later twin studies continued to provide evi-
lems with this approach. Although twin studies dence that genes shape many areas of human
Twin Studies 753
life. Monozygotic twins tend to resemble each Press, 1976. One of the most influential
other in probabilities of developing mental ill- books on modern twin studies. Graphs, bib-
nesses, such as schizophrenia and depression, liography, index.
suggesting that these psychological problems Piontelli, Alessandra. Twins: From Fetus to Child.
are partly genetic in origin. A 1996 study pub- New York: Routledge, 2002. A longitudinal
lished in the Journal of Personality and Social Psy- study of the everyday lives of thirty pairs of
chology used a sample from the Minnesota Twin twins, from life in the womb to age three. Il-
Registry to establish that identical twins are lustrations, bibliography, index.
similar in probabilities of divorce. A 1997 study Spector, Tim D., Harold Snieder, and Alex J.
in the American Journal of Psychiatry indicated MacGregor, eds. Advances in Twin and Sib-
that there is even a great resemblance between Pair Analysis. New York: Oxford University
twins in intensity of religious faith. Twin studies Press, 2000. Discusses background and con-
have offered evidence that homosexual or het- text of twin and sib-pairs analysis, and epide-
erosexual orientation may be partly a genetic miological and biostatistical perspectives on
matter, although researcher Scott L. Hersh- the study of complex diseases. Illustrations,
berger has found that the genetic inheritance bibliography, index.
of sexual orientation may be greater among Steen, R. Grant. DNA and Destiny: Nurture and
women than among men. Nature in Human Behavior. New York: Plenum,
Carl L. Bankston III 1996. A medical researcher and popular sci-
See also: Aging; Animal Cloning; Behavior; ence writer summarizes evidence regarding
Cloning: Ethical Issues; Diabetes; DNA Finger- the relative contributions of genetics and en-
printing; Gender Identity; Genetic Testing; Ge- vironment in shaping human personalities.
netics in Television and Films; Heredity and Bibliography, index.
Environment; Homosexuality; Intelligence; Wright, Lawrence. Twins: And What They Tell Us
Prenatal Diagnosis; Quantitative Inheritance. About Who We Are. New York: John Wiley &
Sons, 1997. An overview of the use of twin
Further Reading studies in behavioral genetics, written for
Hershberger, Scott L. A Twin Registry Study of general readers. Bibliography, index.
Male and Female Sexual Orientation. Jour-
nal of Sex Research 34, no. 2 (1997). Discusses Web Site of Interest
the results of a Minnesota study of twins, ho- Minnesota Twin Family Study. http://www
mosexual orientation, sibling environment, .psych.umn.edu/psylabs/mtfs. Site of an on-
and the genetic influence on sexuality. going research study into the genetic and
Loehlin, John C., and Robert C. Nichols. Hered- environmental factors of psychological de-
ity, Environment, and Personality: A Study of velopment. Includes the discussion, Whats
850 Sets of Twins. Austin: University of Texas Special About Twins to Science?
Viral Genetics themselves do not grow or undergo division.
Field of study: Viral genetics Virus particles are produced from the assem-
Significance: The composition and structures of vi- bling of pre-formed components, whereas
rus genomes are more varied than any identified other agents actually grow from an increase in
in the entire bacterial, botanical, or animal king- the integrated sum of their components and re-
doms. Unlike the genomes of all other cells, which produce by division. The reason is that viruses
are composed of DNA, virus genomes may contain lack the genetic information that encodes the
their genetic information encoded in either DNA or apparatus necessary for the generation of met-
RNA. Viruses cannot replicate on their own but abolic energy or for protein synthesis (ribo-
must instead use the reproductive machinery of somes). The most critical interaction between a
host cells to reproduce themselves. virus and a host cell is the need of the virus for
the hosts cellular apparatus for nucleic acid
Key terms and for the synthesis of proteins. No known vi-
capsid: the protective protein coating of a vi- rus has the biochemical or genetic potential to
rus particle generate the energy necessary for producing
ribosome: a cytoplasmic organelle that serves all biological processes. Viruses depend totally
as the site for amino acid incorporation dur- on a host cell for this function.
ing the synthesis of protein Viruses are therefore not living in the tradi-
virions: mature infectious virus particles tional sense, but they nevertheless function as
living things; they do replicate their own genes.
What Is a Virus? Inside a host cell, viruses are alive, whereas
Viruses are submicroscopic, obligate intra- outside the host they are merely a complex as-
cellular parasites. This definition differentiates semblage of metabolically inert chemicals
viruses from all other groups of living organ- basically a protein shell. Therefore, while vi-
isms. There exists more biological diversity ruses have no inner metabolism and cannot re-
within viruses than in all other known life- produce on their own, they carry with them the
forms combined. This is the result of viruses means necessary to get into other cells and
successfully parasitizing all known groups of liv- then use those cells own reproductive machin-
ing organisms. Viruses have evolved in parallel ery to make copies of themselves. Viruses thrive
with other species by capturing and using genes at the host cells expense.
from infected host cells for functions that they
require to produce their progeny, to enhance Replication
their escape for their hosts cells and immune The sole goal of a virus is to replicate its ge-
system, and to survive the intracellular and netic information. The type of host cell in-
extracellular environment. At the molecular fected by a virus has a direct effect on the pro-
level, the composition and structures of virus cess of replication. For viruses of prokaryotes
genomes are more varied than any others iden- (bacteria, primarily), reproduction reflects the
tified in the entire bacterial, botanical, or ani- physical simplicity of the host cell. For viruses
mal kingdoms. Unlike the genomes of all other with eukaryotic host cells (plants and animals),
cells composed of DNA, virus genomes may reproduction is more complex. The coding ca-
contain their genetic information encoded in pacity of the genome forces the virus to choose
either DNA or RNA. The nucleic acid compris- a reproductive strategy. The strategy might in-
ing a virus genome may be single-stranded or volve near-total reliance on the host cell, result-
double-stranded and may occur in a linear, cir- ing in a compact genome encoded for only a
cular, or segmented configuration. few essential proteins (+), or could involve a
large, complex virus genome encoded with
The Need for a Host nearly all the information necessary for repli-
It must be understood that virus particles cation, relying on the host cell only for energy
Viral Genetics 755
and ribosomes. Those viruses with an RNA ge- plete or partial removal of the virus capsid and
nome plus messenger RNAs (mRNAs) have no the exposure of the virus genome as a nucleo-
need to enter the nucleus of their host cell, protein complex. This protein complex can be
although during replication many often do. a simple RNA genome or can be highly com-
DNA genome viruses mostly replicate in the plex, as in the case of a retrovirus containing a
host cells nucleus, where host DNA is repli- diploid RNA genome responsible for convert-
cated and the biochemical apparatus required ing a virus RNA genome into a DNA provirus.
for this process is located. Some DNA viruses How a virus replicates and the resulting ex-
(poxviruses) have evolved to contain the bio- pression of its genes depends on the nature of
chemical capacity to replicate in their hosts cy- its genetic materials. Control of gene expres-
toplasm, with a minimal need for the host cells sion is a vital element of virus replication. Vi-
other functions. ruses use the biochemical apparatus of their
Virus replication involves
several stages carried out by all
types of viruses, including the
Virus Replication
onset of infection, replication,
and release of mature virions
from an infected host cell. The
stages can be defined in eight A. Attachment and penetration:
basic steps: attachment, pene- The virus punctures the
tration, uncoating, replica- bacteriums cell wall and
tion, gene expression, assem- injects its DNA.
bly, maturation, and release.
The first stage, attachment,
occurs when a virus interacts
with a host cell and attaches it- B. Uncoating: Removal of the
selfbinds with a virus-attach- virus capsid and exposure
ment protein (anitreceptor) of the viral genome.
to a cellular receptor molecule
in the cell membrane. The re-
ceptor may be a protein or a
carbohydrate residue. Some
complex viruses, such as her-
pesviruses, use more than one C. Replication and assembly.
receptor and therefore have al-
ternate routes of cellular inva-
sion.
Shortly after attachment the
target cell is penetrated. Cell
penetration is usually an energy- D. Release: The cell wall bursts,
dependent process, and the and new copies of the virus
cell must be metabolically ac- are released.
tive for penetration to occur.
The virus bound to the cellular
receptor molecule is translo-
cated across the cell membrane
by the receptor and is engulfed
by the cells cytoplasm.
Uncoating occurs after pen-
etration and results in the com- (Electronic Illustrators Group)
756 Viroids and Virusoids
infected host cells to express their genetic in- Domingo, Esteban, Robert Webster, and John
formation as proteins and do this by using Holland, eds. Origin and Evolution of Viruses.
the appropriate biochemical language recog- New York: Academic Press, 1999. An inter-
nized by the host cell. Viruses include double- disciplinary reference book consisting of
stranded DNA viruses such as papoviruses, pox- chapters authored by leading researchers in
viruses, and herpesviruses; single-stranded the fields of RNA and DNA viruses; deals
sense DNA viruses such as parvoviruses; double- with the simplest, as well as the most com-
stranded RNA reoviruses; single-stranded sense plex, viral genomes known.
RNA viruses such as flaviviruses, togaviruses, Holland, J. J., ed. Current Topics in Microbiology
and claiciviruses; single-stranded antisense RNA and Immunology: Genetic Diversity of RNA Vi-
such as filoviruses and bunyaviruses; single- ruses. New York: Springer-Verlag, 1992. De-
stranded sense RNA with DNA intermediate tailed collection of papers concerning the
retroviruses; and double-stranded DNA with genetic and biological variabilities of RNA
RNA intermediate-like hepadnaviruses. viruses, replicase error frequencies, the
During assembly, the basic structure of the role of environmental selection pressures in
virus particle is formed. Virus proteins anchor the evolution of RNA populations, and
themselves to the cellular membrane, and, as the emergence of drug resistant virus ge-
virus proteins and genome molecules reach a nomes.
critical concentration, assembly begins. The re- Zimmer, Carl. Parasite Rex: Inside the Bizarre
sult is that a genome is stuffed into a completed World of Natures Most Dangerous Creatures.
protein shell. The process of maturation pre- New York: Free Press, 2000. A fascinating,
pares the virus particle for infecting subse- general publication on parasites and their
quent cells and usually involves the cleavage of effects on their host organisms, with many
proteins to form matured products or confor- references to the historical ramifications of
mational structural changes. viruses on biological evolution and the de-
For most viruses, release is a simple matter of velopment of human culture.
breaking open the infected cell and exiting.
The breakage normally occurs through a physi-
cal interaction of proteins against the inner
surface of the host cell membrane. A virus may
also exit a cell by budding. Budding involves Viroids and Virusoids
the creation of a lipoprotein envelope around
the virion prior to the virions being extruded Field of study: Viral genetics
out through the cell membrane. Significance: Viroids are naked strands of RNA,
Randall L. Milstein 270 to 380 nucleotides long, that are circular and
See also: DNA Structure and Function; do not code for any proteins. However, some viroids
Gene Regulation: Viruses; Genetic Engi- are catalytic RNAs (ribozymes), able to cleave and
neering; Hybridomas and Monoclonal Anti- ligate themselves. In spite of their simplicity, they
bodies; Oncogenes; Organ Transplants and are able to cause disease in susceptible plants,
HLA Genes; RNA Structure and Function; Vir- many of them economically important. Virusoids
oids and Virusoids. are similar to viroids, except that they require a
helper virus to infect a plant and reproduce.
Further Reading
Becker, Yechiel, and Gholamreza Darai, eds. Key terms
Molecular Evolution of Viruses: Past and Present. RNA polymerase: an enzyme that catalyzes the
Boston: Kluwer Academic, 2000. Detailed joining of ribonucleotides to make RNA us-
research of the evolution of viruses by ac- ing DNA or another RNA strand as a tem-
quisition of cellular RNA and DNA, and plate
how virus genes evade the host immune re- RNase: an enzyme that catalyzes the cutting of
sponses. an RNA molecule
Viroids and Virusoids 757
General Characteristics of Viroids and fold dilutions of the filtrate retain the ability to
Virusoids cause infection, suggesting that it is being repli-
Viroids, and some virusoids, are circular, cated. RNase destroys infectivity, suggesting that
single-stranded RNA molecules, which nor- the genetic material (RNA) is exposed to the
mally appear as rods but when denatured by medium, unlike viruses, which have a protec-
heating appear as closed circles. The rod- tive protein coat. When isolated from other cell
shaped structure is formed by extensive base components, an absorbance spectrum shows
pairing within the RNA molecule, and the sec- that viroids are pure nucleic acid, lacking a pro-
ondary structure is divided into five structural tein coat.
domains. One domain is called the pathoge- Although viroids are structurally simple and
nicity (P) domain, because differences among do not code for any proteins, they still cause dis-
variant strains of the same species of viroid ease. Although the molecular mechanisms of
seem to correlate with differences in pathoge- viroid pathogenesis are unknown, it is clear
nicity. Virusoids may also comprise linear RNA that the pathogenesis domain (P domain) is
or, rarely, double-stranded circular RNA. primarily responsible.
The difference between viroids and virusoids Changes in the sequence of nucleotides in
is in their mode of transmission. Viroids have the P domain have been correlated with patho-
no protective covering of any kind and are no genicity. Some research suggests that the patho-
more than the RNA that makes up their genetic genicity of a viroid strain is related to the resis-
material. They depend on breaks in a plants tance of the P domain to heat denaturation,
epidermis or can travel with pollen or ovules to with stability of this region being inversely re-
gain entry. Virusoids, also known as satellite lated to severity. However, some evidence sug-
RNAs, are packaged in the protein coat of gests that this may not be entirely true. In a se-
other plant viruses, referred to as helpers, and ries of nucleotide substitutions introduced by
are therefore dependent on the other virus. researchers into the P region of an intermedi-
Viroids are typically divided into two groups ate strain (that is, intermediate in pathogenic-
based on the nature of their RNA molecule. ity) of potato spindle tuber viroid (PSTVd),
Group A is the smallest group, and their RNA four showed viroid infectivity and pathoge-
has the ability to self-cleave. These include the nicity that were the same as those of a pre-
avocado sunblotch and peach latent mosaic vi- viously reported severe strain of PSTVd. Al-
roids. Group B contains all the other viroids, together, eight different mutant strains were
and their RNA is not capable of self-cleavage. analyzed, and resistance to denaturation and
Species in group B include the potato spindle PSTVd pathogenicity were not correlated in all
tuber, coconut cadang, tomato plant macho, cases.
and citrus bent leaf viroids. Research is under way to understand how
Virusoids are less well studied than viroids viroids move from cell to cell and traverse the
and, although more diverse, are most similar to cytoplasm to the nucleus, where many viroids
group B viroids in that they cannot self-cleave. replicate. There is evidence that a possible in-
Examples include the tomato black ring virus teraction might involve viroid RNA activating
viroid, the peanut stunt virus viroid, and the to- an RNA-activated protein kinase in response to
bacco ringspot virus viroid. Because so little is a nucleotide sequence similar to that of the
known about virusoids, the remainder of this normal RNA activator. Protein kinases are inte-
article will focus on viroids. gral to intracellular signaling pathways that
control many aspects of cell metabolism. Once
Viroid Pathogenesis researchers understand the signals that viroids
If infected leaves are homogenized in a use to get around, it may be possible to devise
blender and passed through an ultrafilter treatments against them. A better understand-
fine enough to exclude bacteria, the infection ing of the process may also shed light on nor-
is easily transmitted to another plant by paint- mal biochemical communication pathways in
ing some of the filtrate on a leaf. Even billion- plant cells.
758 Viroids and Virusoids
It is equally important that there not be known as the Barr body. However, the process
more than two X chromosomes present during of methylation alone cannot entirely account
this early development. Females possessing for inactivation.
three X chromosomes, and therefore two Barr A region on the X chromosome called the X
bodies, are sometimes called superfemales or inactivation center (XIC) is considered the
metafemales because of a tendency to be taller control center for X inactivation. In this region
than average. These females are also two to ten is a gene called the X inactivation specific tran-
times more likely to suffer from mild to moder- scripts (XIST) gene. At the time of its discov-
ate mental retardation. ery, this gene was the only gene known to be
The same phenomenon has been observed functional in an inactivated chromosome. It
in males who possess Barr bodies. Barr bodies produces an RNA that remains inside the nu-
are not normally present in males because they cleus.
have only one X chromosome. The presence Evidence in humans supports the hypothesis
of Barr bodies indicates the existence of an ex- that the XIST gene is turned on and begins to
tra X chromosome that has become inactive. make its RNA when the egg is fertilized. Studies
Just as in females, extra X chromosomes are with mice have shown that RNA is produced, at
also expressed in early development, and ab- first, in low levels and from both X chromo-
normal amounts of gene products result in somes. It has been shown in mice, but not hu-
abnormal physical characteristics and mental mans, that prior to inactivation, Xist (lower-
retardation. Males with Klinefelter syndrome cased when referring to mouse genes) RNA is
have two X chromosomes and a Y chromo- localized at the XIC site only, thus suggesting a
some. In cases in which males have more than potential role prior to actual inactivation of the
two X chromosomes, the effects are even more chromosome. At this point, one X chromo-
remarkable. some will begin to increase its production of
XIST RNA; shortly thereafter, XIST RNA tran-
Mechanism of X Inactivation scription from the other X chromosome
While it has been apparent since the 1960s ceases. It is not clear how XIST RNA initiates
that X inactivation is required for normal fe- the process of inactivation and condensing of
male development, the mechanism has been the inactive chromosome, but XIST RNA binds
elusive. Only with the development of tech- along the entire length of the inactive X chro-
niques to study the molecular events of the cell mosome in females. These results suggest that
and its chromosomes has progress been made inactivation spreads from the XIC region to-
in understanding the process of inactivation. ward the end of the chromosome and that
One process involved in turning off a gene XIST RNA is required to maintain an inactive
(thus shutting down the process of transcrip- state. If a mouses Xist gene is mutated and can-
tion) is the alteration of one of the molecules of not produce its RNA, inactivation of that X
DNA known as cytosine. By adding a methyl chromosome is blocked. Other studies have
group to the cytosine, the gene cannot pro- suggested that a product from a nonsex chro-
duce the RNA necessary to make a protein. It is mosome may interact with the XIC region,
thought that this methyl group blocks the pro- causing it to remain active. As expected, but
teins that normally bind to the DNA so that not explained, the XIST gene is repressed, or
transcription cannot occur. When methyl expresses XIST RNA at only very low levels, in
groups are removed from cytosines, the block is males with only one X chromosome.
removed and transcription begins. This is a No difference has been detected between
common means of regulating transcription of maternally and paternally expressed XIST
genes. Methylation is significantly higher in the genes in humans. This has led scientists to sus-
inactivated X chromosome than in the acti- pect that XIST gene RNA may not be responsi-
vated X chromosome. As the genes on the ble for determining which X chromosome be-
chromosome become inactive, the chromo- comes inactivated. It is also not clear how the
some condenses into the tightly packed mass cell knows how many X chromosomes are pres-
Xenotransplants 761
A human ear grows on the body of a mouse, engineered in Shanghai, China, in 1997. Human cells were used to grow the ear and
then were inserted into the mouse body. (AP/Wide World Photos)
tions; the donor usually can donate bone mar- boon heart into a newborn human infant who
row or one kidney and still survive. Neverthe- otherwise had no chance for survival. The in-
less, for most organs the dilemma remains. fant survived for several days before succumb-
Researchers then suggested that organs ing to complications. Researchers quickly
could be harvested from compatible animals, learned that primates were not ideal candi-
eliminating both the need to wait for a compat- dates for organ donation; their organs were
ible human donor and the shortage of usable small in comparison to those of humans. Chim-
organs. This is one form of xenotransplant, panzee kidneys, for example, are too small to
and it could eliminate the shortage of donor perform adequately in an adult human.
organs. Researchers then turned their attention to
Early research focused on potential donor pigs as possible donors. Swine make ideal do-
animals that were similar to humans, that is, nor candidates because they are physically
primates such as baboons and chimpanzees. large enough to have organs that can sustain
Perhaps the most publicized example of such a humans, have a short gestation cycle, produce
xenotransplant was the 1984 Baby Fay case, in large litters of offspring, and, because they are
which doctors in California transplanted a ba- routinely raised for meat production, are
Xenotransplants 763
viewed as expendable by the general public. By sult from using organs or other tissue from ei-
using a combination of selective breeding and ther swine or primates. While many researchers
genetic manipulation, researchers hope to de- are confident that careful screening of donor
velop swine whose organs will be less suscepti- animals would eliminate or minimize such risks,
ble to rejection by the human body. Pig heart critics remain convinced that it is possible a vi-
valves are already routinely used in humans, rus could lie dormant and undetected in ani-
with an estimated sixty thousand implanted an- mals, causing problems only after the trans-
nually. The use of larger organs has been less plants occurred. Baboons, for example, carry a
successful; transplant recipients experienced virus that has the potential to cause cancer in
hyper-acute rejection. That is, their bodies im- humans.
mediately reacted to the foreign tissue by shut- In addition to the medical issues raised, many
ting off the flow of blood to it. bioethicists question the morality of using ani-
mals as a source of spare parts for humans.
Ethical and Medical Concerns They are particularly troubled by the idea of
Xenotransplantation presents a number of possibly genetically altering a species such as
ethical and medical dilemmas. One major con- swine in order to make their organs more com-
cern is the possibility that a virus, harmless to patible with human hosts. Proponents of xeno-
the donor animal, is transmitted to the human transplants counter these arguments by noting
host and then proves fatal. Scientists worry that that humans have selectively bred animals for
a potentially deadly disease epidemic could re- various purposes for thousands of years to elim-
inate certain characteristics while en-
hancing others. In addition, animals such
as swine are already routinely slaughtered
for human consumption.
Finally, there is the problem of human
perceptions. While many people support
the idea of xenotransplants on the ge-
netic or cellular level, they are less enthu-
siastic about possible organ transplants.
That is, while a majority of people sur-
veyed said they would have no problem
accepting a xenotransplant if it were part
of gene therapy, far fewer were interested
in possibly receiving a pigs heart if the
Image not available need arose. If researchers do achieve suc-
cessful xenotransplants using such or-
gans, however, public perceptions could
change. It is easy to question a medical
procedure when it is still theoretical; it be-
comes much more difficult to do so after
it becomes a reality.
Nancy Farm Mnnikk
See also: Animal Cloning; Cancer;
Cloning; Cloning: Ethical Issues; Gene
Therapy: Ethical and Economic Issues;
Genetic Engineering: Historical Develop-
ment; Heart Disease; Immunogenetics;
Animal rights advocates and other activists protest the use of animals In Vitro Fertilization and Embryo Trans-
as spare parts factories for human organs in this demonstration in fer; Model Organism: Mus musculus; Model
Munich, Germany, in November, 2000. (AP/Wide World Photos) Organism: Xenopus laevis; Organ Trans-
764 XYY Syndrome
egg production is known as nondisjunction, those with sex chromosomal abnormalities. Be-
which is the improper division of chromosomes cause the parents of XYY boys were told of their
between the daughter cells. Nondisjunction in childrens genetic makeup and the possibility
the production of either gamete can result, at of lower intelligence and bad behavior, critics
fertilization, in embryos without the normal claimed that the researchers had biased the
forty-six chromosomes. XYY syndrome is one of parents against their sons, causing the parents
several of these aneuploid conditions that in- to treat the children differently. The environ-
volve the sex chromosome pair. While Klinefel- ment would thus play a greater role than genet-
ter syndrome (an XXY male) and Turner syn- ics in their behavior. Subsequent research has
drome (an X female) are more widely studied shown that the original hypothesis is at least
and recognized genetic diseases, the XYY male partially accurate. There is a disproportion-
occurs with a frequency of 1 in 1,000 male ately large number of XYY males in prison pop-
births in the United States. Caused by a YY- ulations, and they are usually of subaverage in-
bearing sperm fertilizing a normal X-bearing telligence compared to other prisoners. It must
egg, the XYY embryo develops along a seem- be emphasized, however, that the majority of
ingly normal route and, unlike most other sex XYY males show neither low intelligence nor
chromosome diseases, is not apparent at birth. criminal behavior.
In fact, identification of this disorder requires Scientists, doctors, geneticists, and psychol-
genetic testing or screening and is often discov- ogists now agree that the extra Y chromosome
ered accidentally as a consequence of results does cause above normal height, reading and
from another genetic test. The only physical math difficulties, and, in some cases, severe
clue is unusually tall stature; otherwise, an af- acne, but the explanation of the high preva-
fected male will be normal in appearance. The lence of XYY men in prison populations has
XYY male is also fertile, unlike those with aneu- changed its focus from genes to environment.
ploidies involving other combinations of sex Large body size during childhood, adoles-
chromosomes, which usually result in sterility. cence, and early adulthood will no doubt cause
people to treat these individuals differently,
Behavioral and Research Implications and they may in turn have learned to use their
Interest in the association between aggres- size defensively. Aggressive behavior, coupled
sion and the Y chromosome began in the years with academic difficulties, may lead to further
following World War II. Both psychologists and problems. Clearly, however, the majority of XYY
geneticists began intensive scrutiny of the genes males do well. The issue would be much easier
that were located on the male sex chromo- to resolve if a YY or Y male existed, but because
some. Men with multiple copies of the Y chro- lack of an X chromosome results in spontane-
mosome thus became the subjects of much of ous miscarriage, no YY or Y male embryo could
this research. Genetic links to violent, aggres- ever survive.
sive, and even criminal behavior were found, al- Connie Rizzo
though many argued that below-average intelli- See also: Aggression; Behavior; Criminal-
gence played a greater role. Many males with ity; Intelligence; Klinefelter Syndrome; Metafe-
XYY syndrome do perform lower than average males; Nondisjunction and Aneuploidy; Steroid
on standard intelligence tests and have a greater Hormones; Testicular Feminization Syndrome;
incidence of behavioral problems. The major- X Chromosome Inactivation.
ity, however, lead normal lives and are indistin-
guishable from XY males. Further Reading
The controversy surrounding this research Mader, Sylvia S. Human Reproductive Biology. 3d
began with a study at Harvard University that ed. New York: McGraw-Hill, 2000. Provides
began in the early 1960s and ended in 1973 be- an excellent introduction to cell division, ge-
cause of pressure from both public and scien- netics, and sex from fertilization through
tific communities. The researchers screened birth. Illustrations, bibliography, index.
all boys born at a Boston hospital, identifying Tamarin, Robert H. Principles of Genetics. Bos-
766 XYY Syndrome
ton: McGraw-Hill, 2002. A well-written refer- physiology which differs from cultural ideals
ence text on genetics with complete discus- of male and female). Includes links to infor-
sions on aneuploidy, the sex chromosomes, mation on such conditions as clitoromegaly,
genes, and abnormalities; it also includes a micropenis, hypospadias, ambiguous geni-
thorough reading list. Illustrations, maps tals, early genital surgery, adrenal hyperpla-
(some color), bibliography, index. sia, Klinefelter syndrome, androgen insensi-
tivity, and testicular feminization.
Web Sites of Interest Johns Hopkins University, Division of Pediatric
Intersex Society of North America. http://www Endocrinology, Syndromes of Abnormal
.isna.org. The society is a public awareness, Sex Differentiation. http://www.hopkins
education, and advocacy organization which medicine.org/pediatricendocrinology. Site
works to create a world free of shame, se- provides a guide to the science and genetics
crecy, and unwanted surgery for intersex of sex differentiation, including a glossary.
people (individuals born with anatomy or Click on patient resources.
Biographical Dictionary of Important Geneticists
Altman, Sidney (1939- ): Won the 1989 No- monia in the elderly. In 1944, he reported
bel Prize in Chemistry, with Thomas R. that the genetic information in these bacte-
Cech. Working independently Altman and ria is DNA.
Cech discovered that RNA, like proteins, can Bailey, Catherine (1921- ): By applying
act as a catalyst; moreover, they found that methods of selective breeding, developed
when ribosomal RNA participates in transla- new varieties of fruits.
tion of messenger RNA (mRNA) and the Baltimore, David (1938- ): Along with
synthesis of polypeptides, it acts as a catalyst Howard Temin, Baltimore isolated the en-
in some steps. zyme RNA-directed DNA polymerase (re-
Anfinsen, Christian B. (1916-1995): Won the verse transcriptase), demonstrating the
1972 Nobel Prize in Chemistry. Anfinsen, mechanism by which RNA tumor viruses can
studying the three-dimensional structure of integrate their genetic material into the cell
the enzyme ribonuclease, proved that its chromosome. Baltimore was awarded the
conformation was determined by the se- 1975 Nobel Prize in Physiology or Medicine.
quence of its amino acids and that to con- Barr, Murray Llewellyn (1908-1995): Canadian
struct a complete enzyme molecule no sepa- geneticist who discovered the existence of
rate structural information was passed on the Barr (Barrs) body, an inactive X chro-
from the DNA in the cells nucleus. mosome found in cells from a female. The
Arber, Werner (1929- ): First to isolate en- existence or absence of the body has been
zymes that modify DNA and enzymes that used in determining the sex of the individ-
cut DNA at specific sites. Such restriction en- ual from whom the cell originated.
zymes were critical in the developing field Bateson, William (1861-1926): Plant and ani-
of molecular biology. Arber was awarded mal geneticist who popularized the earlier
the 1978 Nobel Prize in Physiology or Medi- work of Gregor Mendel. In his classic Men-
cine. dels Principles of Heredity (1909), Bateson in-
Aristotle (384-322 b.c.e.): Greek philosopher troduced much of the modern terminology
and scientist. Aristotles De Generatione was used in the field of genetics. Bateson sug-
devoted in part to his theories on heredity. gested the term genetics (from the Greek
Aristotle believed the semen of the male word meaning descent) to apply to the
contributes a form-giving principle (eidos), field of the study of heredity.
while the menstrual blood of the female is Beadle, George Wells (1903-1989): Beadles
shaped by the eidos. The philosophy implied studies of the bread mold Neurospora demon-
it was the father only who supplied form to strated that the function of a gene is to en-
the offspring. code an enzyme. Beadle and Edward Tatum
Auerbach, Charlotte (1899-1994): German- were awarded the 1958 Nobel Prize in Physi-
born geneticist who fled to England follow- ology or Medicine for their one gene-one
ing the rise of the Nazi Party. Demonstrated enzyme hypothesis.
that the mutations produced by mustard Beckwith, Jonathan R. (1935- ): Deter-
gases and other chemicals in Drosophila mined role of specific genes in regulating
(fruit flies) were similar to those induced by bacterial cell division. During the 1960s, he
X rays, suggesting a common mechanism. was among the first to isolate a specific gene.
Avery, Oswald Theodore (1877-1955): Immu- Beckwith is also known as a social activist in
nologist and biologist who determined DNA his arguments for the use of science for im-
to be the genetic material of cells. Averys provement of society.
early work involved classification of the Bell, Julia (1879-1979): British geneticist who
pneumococci, the common cause of pneu- applied statistical analysis in understanding
768 Biographical Dictionary of Important Geneticists
hereditary medical disorders of the nervous of a linkage map involving human genes
system and limbs. contributed to the progress of the Human
Benacerraf, Baruj (1920- ): Won the 1980 Genome Project.
Nobel Prize in Physiology or Medicine, with Boyer, Herbert W. (1936- ): His isolation of
Jean Dausset and George D. Snell. Bena- restriction enzymes that produced a stag-
cerraf, Dausset, and Snell each explained gered cut on the DNA allowed for creation
the genetic components of the major histo- of so-called sticky ends, which allowed
compatibility complex (MHC), the key to a DNA from different sources or species to be
persons immune system, and how the sys- spliced together.
tem produces antibodies to such a wide vari- Brenner, Sydney (1927- ): Molecular ge-
ety of foreign molecules and pathogens, neticist whose observations of mutations in
such as viruses, fungi, and bacteria. nematodes (long, unsegmented worms)
Berg, Paul (1926- ): Developed DNA re- helped in understanding the design of the
combination techniques for insertion of nervous system. Brenner was among the first
genes in chromosomes. The techniques be- to clone specific genes. He was awarded the
came an important procedure in under- Nobel Prize in Physiology or Medicine in
standing gene function and for the field of 2002.
genetic engineering. Berg was awarded the Brown, Michael S. (1941- ): By studying the
1980 Nobel Prize in Chemistry. role of cell receptors in uptake of lipids from
Bishop, John Michael (1936- ): Deter- the blood, Brown discovered the genetic de-
mined that oncogenes, genetic information fect in humans associated with abnormally
initially isolated from RNA tumor viruses, ac- high levels of cholesterol. He was awarded
tually originate in normal host cells. Bishop the 1985 Nobel Prize in Physiology or Medi-
was awarded the 1989 Nobel Prize in Physiol- cine.
ogy or Medicine for his discovery. Burnet, Frank Macfarlane (1899-1985): Pro-
Bluhm, Agnes (1862-1943): German physician posed a theory of clonal selection to explain
whose controversial theories on improve- regulation of the immune response. Burnet
ment of the Race through eugenics and was awarded the 1960 Nobel Prize in Physiol-
fertility selection provided a basis for Nazi ogy or Medicine.
race theories. Among other aspects of her Cairns, Hugh John (1922- ): British virolo-
theory was the use of enforced sterilization. gist whose investigations of rates and mecha-
Boring, Alice Middleton (1883-1955): Con- nisms of DNA replication helped to lay the
firmed existing theories of the chromo- groundwork in studying the replication pro-
somal basis of heredity. Her professional ca- cess.
reer consisted primarily in serving as a Carroll, Christiane Mendrez (1937-1978):
biology teacher to students in China be- French geneticist and paleontologist, most
tween the world wars. noted for her taxonomic interpretations of
Borlaug, Norman (1914- ): Won the 1970 early reptiles.
Nobel Prize in Peace. Borlaug was a key fig- Cech, Thomas R. (1947- ): Won the 1989
ure in the Green Revolution in agriculture. Nobel Prize in Chemistr y, with Sidney
Working as a geneticist and plant physiolo- Altman. Working independently, Cech and
gist in a joint Mexican-American program, Altman discovered that RNA, like proteins,
he developed strains of high-yield, short- can act as a catalyst; moreover, Cech found
strawed, disease-resistant wheat. His goal was that when ribosomal RNA participates in
to increase crop production and alleviate translation of mRNA and the synthesis of
world hunger. polypeptides, it acts as a catalyst in some
Botstein, David (1942- ): Developed meth- steps.
ods of localized mutagenesis for understand- Chargaff, Erwin (1905-2002): Determined that
ing the relationship between the structure the DNA composition in a cell is characteris-
and function of proteins. His development tic of that particular organism. His discovery
Biographical Dictionary of Important Geneticists 769
of base ratios, in which the concentration of oped by Jean-Baptiste Lamarck. Darwin was
adenine is equal to that of thymine, and gua- the grandfather of both Charles Darwin and
nine to that of cytosine, provided an impor- Francis Galton.
tant clue to the structure of DNA. Dausset, Jean (1916- ): Won the 1980 No-
Cohen, Stanley N. (1935- ): Developed the bel Prize in Physiology or Medicine, with
techniques for transfer of DNA between spe- Baruj Benacerraf and George D. Snell.
cies, a major factor in the process of genetic Dausset, Benacerraf, and Snell each ex-
engineering. plained the genetic components of the ma-
Collins, Francis Sellers (1950- ): In 1989, jor histocompatibility complex (MHC), the
Collins identified the gene that, when mu- key to a persons immune system, and how
tated, results in the genetic disease cystic fi- the system produces antibodies to such a
brosis. Collins was instrumental in the iden- wide variety of foreign molecules and patho-
tification of a number of genes associated gens, such as viruses, fungi, and bacteria.
with genetic diseases. Delbrck, Max (1906-1981): A leading figure in
Correns, Carl Erich (1864-1935): German bota- the application of genetics to bacteriophage
nist who confirmed Gregor Mendels laws research, and later, with Phycomyces, a fungal
through his own work on the garden pea. organism. His bacteriophage course, taught
Correns was one of several geneticists who re- for decades at Cold Spring Harbor, New
discovered Mendels work in the early 1900s. York, provided training for a generation of
Crick, Francis Harry Compton (1916- ): biologists. He was awarded the 1969 Nobel
Along with James Watson, Crick determined Prize in Physiology or Medicine.
the double-helix structure of DNA. Crick Demerec, Milislav (1895-1966): Croatian-born
was awarded the Nobel Prize in Physiology geneticist who was among the scientists who
or Medicine in 1962. brought the United States to the forefront of
Darlington, Cyril (1903-1981): British geneti- genetics research. Demerecs experiments,
cist who demonstrated changes in chromo- based on the genetics of corn, addressed the
somal patterns which occur during meiosis, question of what a gene represents. His work
leading to an understanding of chromo- with bacteria included the determination of
somal distribution during the process. He mechanisms of antibiotic resistance, as well
also described a role played by crossing over, as the existence of operons, closely linked
or genetic exchange, in changes of patterns. genes which are coordinately regulated.
Darwin, Charles Robert (1809-1882): Natural- Demerec was director of the biological labo-
ist whose theory of evolution established ratories in Cold Spring Harbor, New York,
natural selection as the basis for descent with for many years among the most important
modification, more commonly referred to sites of genetic research.
as evolution. His classic work on the subject, De Vries, Hugo (1848-1935): Dutch botanist
On the Origin of Species by Means of Natural Se- whose hypothesis of intracellular pangen-
lection (1859), based on his five-year voyage esis postulated the existence of pangenes,
during the 1830s on the British ship HMS factors which determined characteristics of
Beagle, summarized the studies and observa- a species. De Vries established the concept of
tions that initially led to the theory. Darwins mutation as a basis for variation in plants. In
pangenesis theory, first noted in The Varia- 1900, de Vries was one of several scientists
tion of Animals and Plants Under Domestication who rediscovered Mendels work.
(1868), later became the basis for the con- Dobzhansky, Theodosius (1900-1975): Rus-
cept of the gene. sian-born American geneticist who estab-
Darwin, Erasmus (1731-1802): British physi- lished evolutionary genetics as a viable disci-
cian, inventor, and writer. In his classic pline. His book Genetics and the Origin of
Zoonomia, he advanced a theory of the role of Species (1937) represented the first applica-
the environment on genetic changes in or- tion of Mendelian theory to Darwinian evo-
ganisms. A similar theory was later devel- lution.
770 Biographical Dictionary of Important Geneticists
Dulbecco, Renato (1914- ): Among the man plant biologist and geneticist. Though
first to study the genetics of tumor viruses. Gartner did not generalize as to the signifi-
Dulbecco was awarded the 1975 Nobel Prize cance of his work, his results provided the ex-
in Physiology or Medicine. perimental basis for questions later devel-
Ferguson, Margaret Clay (1863-1951): Plant ge- oped by Gregor Mendel and Charles Darwin.
neticist whose use of Petunia as a model Giblett, Eloise (1921- ): Discoverer of nu-
helped explain life cycles of various plants. merous genetic markers useful in defining
Also noted for her description of the life cy- blood groups and serum proteins. In the
cle of pine trees. 1970s, Giblett discovered that certain im-
Fink, Gerald R. (1940- ): Isolation of spe- munodeficiency diseases result from the ab-
cific mutants in yeast allowed the use of ge- sence of certain enzymes necessary for im-
netics in understanding biochemical mech- mune cell development.
anisms in that organism. Gilbert, Walter (1932- ): Developed
Fisher, Ronald Aylmer (1890-1962): British bi- method of sequencing DNA. With Paul Berg
ologist whose application of statistics pro- and Frederick Sanger, awarded the 1980 No-
vided a means by which use of small sam- bel Prize in Chemistry.
pling size could be applied to larger Gilman, Alfred G. (1941- ): Discovered the
interpretations. Fishers breeding of small role of G proteins in regulating signal
animals led to an understanding of genetic transduction in eukaryotic cells. With Mar-
dominance. He later applied his work to the tin Rodbell, won the Nobel Prize in Physiol-
study of inheritance of blood types in hu- ogy or Medicine for 1994.
mans. Goldschmidt, Richard B. (1878-1958): German-
Franklin, Rosalind Elsie (1920-1958): British born geneticist who proposed that the chemi-
crystallographer whose X-ray diffraction cal makeup of the chromosome determines
studies helped confirm the double-helix na- heredity rather than the quantity of genes.
ture of DNA. Franklins work, along with He theorized that large mutations, or ge-
that of Maurice Wilkins, was instrumental in netic monsters, were important in genera-
confirming the structure of DNA as pro- tion of new species.
posed by James Watson and Francis Crick. Goldstein, Joseph L. (1940- ): Won the
Franklins early death precluded her receiv- 1985 Nobel Prize in Physiology or Medicine,
ing a Nobel Prize for her research. with Michael S. Brown. Brown and Goldstein
Galton, Francis (1822-1911): British scientist conducted extensive research in the regula-
who was an advocate of eugenics, the belief tion of cholesterol in humans. They showed
that human populations could be improved that in families with a history of high choles-
through breeding of desired traits. Galton terol, individuals who carry two copies of a
was also the first to observe that fingerprints mutant gene (homozygotes) have choles-
were unique to the individual. terol levels several times higher than normal
Garnjobst, Laura Flora (1895-1977): Following and those who have one mutant gene (heter-
her training under Nobel laureate Edward ozygotes) have levels about double normal.
Tatum at both Stanford and Yale, Garnjobst Their discoveries proved invaluable in man-
spent her career in the study of genetics of aging heart disease and other cholesterol-
the mold Neurospora. related ailments.
Garrod, Archibald Edward (1857-1936): Ap- Griffith, Frederick (1877-1941): British micro-
plying his work on alkaptonuria, Garrod biologist who in 1928 reported the existence
proposed that some human diseases result of a transforming principle, an unknown
from a lack of specific enzymes. His theory of substance that could change the genetic
inborn errors of metabolism, published in properties of bacteria. In 1944, Oswald
1908, established the genetic basis for cer- Avery determined the substance to be DNA,
tain hereditary diseases. three years after Griffith was killed during
Gartner, Carl Friedrich von (1772-1850): Ger- the German bombing of London.
Biographical Dictionary of Important Geneticists 771
Gruhn, Ruth (1907-1988): German geneticist standing the replication and genetic struc-
who applied mathematical principles in the ture of viruses. His experiments with Martha
breeding of poultry and pigs. Chase confirmed that DNA carried the ge-
Haeckel, Ernst Heinrich (1834-1919): German netic information in some viruses. Hershey
zoologist whose writings were instrumental was awarded the 1969 Nobel Prize in Physiol-
in the dissemination of Charles Darwins ogy or Medicine.
theories. Haeckels biogenetic law, since Herskowitz, Ira (1946-2003): His studies of
discarded, stated that ontogeny repeats gene conversion pathways in yeast led to an
phylogeny, suggesting that embryonic de- understanding of gene switching in control
velopment mirrors the evolutionary rela- of mating types.
tionship of organisms. Hertwig, Paula (1889-1983): German embryol-
Haldane, John Burdon Sanderson (1892-1964): ogist who studied the effects of radiation on
British physiologist and geneticist who pro- embryonic development of fish and ani-
posed that natural selection, and not muta- mals.
tion per se, was the driving force of evolu- Hippocrates (c. 460-377 b.c.e.): Greek physi-
tion. Haldane was the first to determine an cian who proposed the earliest theory of in-
accurate rate of mutation for human genes, heritance. Hippocrates believed that seed
and he later demonstrated the genetic link- material was carried by body humors to the
age of hemophilia and color blindness. reproductive organs.
Hanafusa, Hidesaburo (1929- ): Japanese- Hogness, David S. (1925- ): One of the first
born scientist who played a key role in eluci- to clone a gene from Drosophila (fruit flies).
dating the role of oncogenes found among His technique of chromosomal walking al-
the RNA tumor viruses in transforming mam- lowed for the isolation of any known gene
malian cells. based on its ability to mutate. Also involved
Hanawalt, Philip C. (1931- ): In 1963, dis- in identification of homeotic genes, genes
covered the existence of a repair mechanism which regulate development of body parts.
associated with DNA replication in bacteria. Holley, Robert William (1922-1993): Deter-
He later found a similar mechanism in eu- mined the sequence of nucleotide bases in
karyotic cells. Hanawalts later work in- transfer RNA (tRNA), the molecule that car-
cluded development of the technique of site ries amino acids to ribosomes for protein
mutagenesis in gene mapping. synthesis. Holleys work provided a means
Hardy, Godfrey Harold (1877-1947): British for demonstrating the reading of the genetic
mathematician who, along with Wilhelm code. He was awarded the Nobel Prize in
Weinberg, developed the Hardy-Weinberg Physiology or Medicine in 1968.
law of population genetics. In a 1908 letter Horvitz, H. Robert (1947- ): Har vard
to the journal Science, Hardy used algebraic neurobiologist whose study of cell regula-
principles to confirm Mendels theories as tion in the nematode Caenorhabditis led to
applied to populations, an issue then cur- the discovery of genes that regulate cell
rently in dispute. death during embryonic development. With
Hartwell, Leland H. (1939- ): Discovered Sydney Brenner and John Sulston, he was
genes that regulate the movement of eukary- awarded the Nobel Prize in Physiology and
otic cells through the cell cycle. With Tim Medicine in 2002.
Hunt and Sir Paul Nurse, won the Nobel Hunt, R. Timothy (1943- ): Discovered the
Prize in Physiology or Medicine in 2001. existence and role of proteins called cyclins,
Haynes, Robert Hall (1931-1998): Canadian which regulate the cell cycle in eukaryotic
molecular biologist who carried out much of cells. With Leland Hartwell and Sir Paul
the early work in the understanding of DNA Nurse, won the Nobel Prize in Physiology or
repair mechanisms. Medicine in 2001.
Hershey, Alfred Day (1908-1997): Molecular Jacob, Franois (1920- ): French geneticist
biologist who played a key role in under- and molecular biologist who, along with
772 Biographical Dictionary of Important Geneticists
Jacques Monod, elucidated a mechanism of structure of transfer RNA (tRNA), which has
gene and enzyme regulation in bacteria. a shape similar to that of a bent hair pin.
The Jacob-Monod theory of gene regulation Knight, Thomas Andrew (1759-1853): Plant bi-
became the basis for understanding a wide ologist who first recognized the usefulness of
range of genetic processes; they were the garden pea for genetic studies because
awarded the 1965 Nobel Prize in Physiology of its distinctive traits. Knight was the first to
or Medicine. characterize dominant and recessive traits in
Jeffreys, Sir Alec (1950- ): British biochem- the pea, though, unlike Gregor Mendel, he
ist who discovered the existence of introns in never determined the mathematical rela-
mammalian genes. His study of the pattern tionships among his crosses.
of repeat sequences in DNA was shown to be Klreuter, Josef Gottlieb (1733-1806): A fore-
characteristic of individuals, and became runner of Gregor Mendel, Klreuter dem-
the theoretical basis for DNA fingerprinting onstrated the sexual nature of plant fertiliza-
and DNA profiles. tion, in which characteristics were derived
Johannsen, Wilhelm L. (1857-1927): Danish from each member of the parental genera-
botanist who introduced the term genes, tion in equivalent amounts.
derived from pangenes, factors suggested Kornberg, Arthur (1918- ): Carried out the
by Hugo de Vries to determine hereditary first purification of DNA polymerase, the
characteristics in plants. Johannsen also in- enzyme that replicates DNA. His work on
troduced the concepts of phenotype and ge- the synthesis of biologically active DNA in a
notype to distinguish between physical and test tube culminated with his being awarded
hereditary traits. the 1959 Nobel Prize in Physiology or Medi-
Kenyon, Cynthia J. (1976- ): Discovered cine.
the role of specific genes in regulation of cell Kossel, Albrecht (1853-1927): Won the 1910
migration and the aging process in the nem- Nobel Prize in Physiology or Medicine. Iso-
atode Caenorhabditis, helping to clarify simi- lated and described molecular constituents
lar processes in more highly evolved eukary- of the cells nucleus, notably cytosine, thy-
otic organisms. mine, and uracil. These molecules later
Khorana, Har Gobind (1922- ): Developed proved to be constituents of the codons in
methods for investigating the structure of DNA and RNA. Thus, Kossels research pre-
DNA and deciphering the genetic code. pared the way for understanding the bio-
Khorana synthesized the first artificial gene chemistry of genetics.
in the 1960s. He was awarded the Nobel Lamarck, Jean-Baptiste (1744-1829): French
Prize in Physiology or Medicine in 1968. botanist and evolutionist who introduced
King, Helen Dean (1869-1955): By selective many of the earliest concepts of inheritance.
breeding of rodents, developed a method Lamarck proposed that hereditary changes
for production of inbred strains of animals occur as a result of an organisms needs; his
for laboratory studies. The methodology was theory of inherited characteristics, since dis-
later applied to development of more desir- credited, postulated that organisms trans-
able breeds of horses. mit acquired characteristics to their off-
Klug, Aaron (1759-1853): Won the 1982 Nobel spring.
Prize in Chemistry. Klug used X-ray crystal- Leder, Philip (1934- ): Along with Marshal
lography to investigate biochemical struc- Nirenberg, identified the genetic code
tures, especially that of viruses. He was able words for amino acids. His later work has in-
to link the assembly of viral protein subunits volved the transplantation of human onco-
with specific sites on viral RNA, which genes into mice, for the purpose of studying
helped in fighting viruses that cause disease the effects of such genes in development of
in plants and, more basically, in understand- cancer.
ing the mechanism of RNA transfer of ge- Lederberg, Joshua (1925- ): Established
netic information. He also determined the the occurrence of sexual reproduction in
Biographical Dictionary of Important Geneticists 773
bacteria. Lederberg demonstrated that ge- geneticist who proposed what became known
netic manipulation of the DNA during bac- as the Lyon hypothesis, that only a single X
terial conjugation could be used to map bac- chromosome is active in a cell. Any other X
terial genes. He was awarded the 1958 Nobel chromosomes are observed as Barr bodies.
Prize in Physiology or Medicine. McClintock, Barbara (1902-1992): Demon-
Levene, Phoebus Aaron (1869-1940): Ameri- strated the existence in plants of transpos-
can biochemist who determined the compo- able elements, or transposons, genes that
nents found in DNA and RNA. Levene de- jump from one place on a chromosome
scribed the presence of ribose sugar in RNA to another. The process was discovered to
and of 2-deoxyribose in DNA, thereby dif- be widespread in nature. McClintock was
ferentiating the two molecules. He also iden- awarded the 1983 Nobel Prize in Physiology
tified the nitrogen bases found in nucleic or Medicine.
acid, though he was never able to determine Macklin, Madge Thurlow (1893-1962): De-
the acids molecular structure. veloped a method to apply statistical analysis
Lewis, Edward B. (1918- ): Through the to understanding congenital diseases in hu-
use of X-ray-induced mutations in Drosophila man families. Her arguments were used to
(fruit flies), Lewis was able to discover and introduce genetics as a component of the
map genes that regulate embryonic develop- curriculum in medical schools. Her support
ment. Among Lewiss discoveries was the ex- of eugenics for improvement of humans
istence of homeotic genes, genes that regu- later made her views controversial.
late development of body parts. Along with McKusick, Victor A. (1921- ): Cataloged
Christiane Nsslein-Volhard and Eric Wie- and indexed many of the genes responsible
schaus, awarded the Nobel Prize in Physiol- for disorders that are passed in Mendelian
ogy or Medicine in 1995. fashion.
Linnaeus, Carolus (1707-1778): Swedish natu- Margulis, Lynn (1938- ): Developed the
ralist and botanist most noted for establish- endosymbiont theory, which suggests that
ing the modern method for classification of internal eukaryotic organelles, such as mito-
plants and animals. In his Philosophia chondria and chloroplasts, originated as
Botanica (1751; The Elements of Botany, 1775), free-living prokaryotic ancestors. She pro-
Linnaeus proposed that variations in plants posed that free-living bacteria became incor-
or animals are induced by environments porated in a larger, membrane-bound struc-
such as soil. ture and developed a symbiotic relationship
Luria, Salvador E. (1912-1991): A pioneer in within the larger cell.
understanding replication and genetic Mendel, Johann Gregor (1822-1884): The fa-
structure in viruses. The Luria-Delbrck ther of genetics, Mendel was an Austrian
fluctuation test, developed by Luria and Max monk whose studies on the transmission of
Delbrck, demonstrated that genetic muta- traits in the garden pea established the
tions precede environmental selection. mathematical basis of inheritance. Mendels
Luria was awarded the 1969 Nobel Prize in pioneering theories, including such funda-
Physiology or Medicine. mental genetic principles as the law of segre-
Lwoff, Andr (1902-1994): French biochemist gation and the law of independent assort-
and protozoologist. Lwoffs early work dem- ment, were published in 1866 but received
onstrated that vitamins function as compo- scant attention until the beginning of the
nents of living organisms. He is best known twentieth century.
for demonstrating that the genetic material Meselson, Matthew Stanley (1930- ): Dem-
of bacteriophage can become part of the onstrated the nature of DNA replication, in
host bacteriums DNA, a process known as ly- which the two parental DNA strands are sep-
sogeny. Lwoff was awarded the 1965 Nobel arated, each passing into one of the two
Prize in Physiology or Medicine. daughter molecules. Also noted as a social
Lyon, Mary Frances (1925- ): British cyto- activist.
%%" Biographical Dictionary of Important Geneticists
Nurse, Sir Paul M. (1949- ): British scientist ruses are often discontinuous, with interven-
who discovered the role of chemical modifi- ing sequences between segments of genetic
cation (phosphorylation) in regulation of material. With Philip Sharp, Roberts re-
the cell cycle. With Tim Hunt and Leland ceived the Nobel Prize in Physiology or Med-
Hartwell, he was awarded the Nobel Prize in icine in 1993.
Physiology or Medicine in 2001. Rodbell, Martin (1925-1998): Discovered the
Nsslein-Volhard, Christiane (1942- ): Ger- role of membrane-bound G proteins in
man biologist whose genetic studies in Dro- regulation of signal transduction in eukary-
sophila (fruit flies) led to the discovery of otic cells. With Alfred Gilman, awarded the
genes that regulate body segmentation in Nobel Prize in Physiology or Medicine in
the embryo. Along with Edward Lewis and 1994.
Eric Wieschaus, won the Nobel Prize in Phys- Rowley, Janet (1925- ): Cytogeneticist who
iology or Medicine in 1995. developed the staining techniques for ob-
Ochoa, Severo (1905-1993): Won the 1959 No- servation of cell structures. She demon-
bel Prize in Physiology or Medicine, with Ar- strated the role of chromosomal transloca-
thur Kornberg. Ochoa and Kornberg iso- tion as the basis for chronic myeloid
lated enzymes involved in the synthesis of leukemia, the first example of translocation
DNA and RNA, representing the first steps as a cause of cancer.
in decoding the biochemical instructions Rubin, Gerald M. (1950- ): Major figure in
preserved in the structure of genes. developing a structure/functional relation-
Olson, Maynard V. (1943- ): Studied base- ship of genes in Drosophila (fruit flies)
pair polymorphisms in the human genome through the use of insertion mutagenesis to
and their significance to evolution. In 1987, inactivate specific genes.
with David Burke, Olson developed a new Russell, Elizabeth Shull (1913-2001): Contrib-
type of cloning vector, artificial chromo- uted to the understanding of the role played
somes, that filled the need created by the by specific genes in creating coat variations
Human Genome Project to clone very large in animals. Her later work involved the iden-
insert DNAs (hundreds of thousands to mil- tification of genetic defects in the aging pro-
lions of base pairs in length). cess and in the development of diseases such
Pauling, Linus (1901-1994): American chemist as muscular dystrophy.
who received the Nobel Prize in Chemistry Russell, William (1910-2003): A pioneer in the
in 1954 for his work on the nature of the genetic effects of radiation at Oak Ridge Na-
chemical bond and the 1962 Nobel Peace tional Laboratory whose testing of mice led
Prize for his antinuclear activism. His 1950s to standards for acceptable levels of human
investigations of protein structure contrib- exposure to radiation. Winner of the 1976
uted to the determination of the structure of Fermi Award.
DNA. Sager, Ruth (1918-1997): During the 1950s,
Punnett, Reginald C. (1875-1967): English biol- demonstrated the existence of nonchromo-
ogist who collaborated with William Bateson somal heredity, also known as cytoplasmic
in a series of important breeding experi- inheritence, and hence the role of cytoplas-
ments that confirmed the principles of Men- mic genes in organelle development. Later
delian inheritance. Punnett also introduced involved in study of tumor suppressor and
the Punnett square, the standard graphical breast cancer genes.
method of depicting hybrid crosses. Sageret, Augustin (1763-1851): French botanist
Rhabar, Shemooil (1929- ): Iranian direc- who discovered the ability of different traits
tor at the University of Tehran, who became to segregate independently in plants.
known as the most important immunologist Sanger, Frederick (1918- ): Determined
in the Muslim world. the method for sequencing DNA. His
Roberts, Richard J. (1943- ): Discovered method separated the strands of DNA and
that genes in eukaryotic cells and animal vi- then rebuilt them in stages that allowed the
776 Biographical Dictionary of Important Geneticists
terminal nucleotides to be identified. This mice, led to the later discovery of the equiva-
made it possible to sequence the entire ge- lent HLA complex in humans. Awarded the
nomes of organisms. With Paul Berg and Nobel Prize in Physiology or Medicine in
Walter Gilbert, Sanger received the 1980 No- 1980.
bel Prize in Chemistry. Sonneborn, Tracy Morton (1905-1981): Dis-
Sharp, Phillip A. (1944- ): Discovered that covered crossbreeding and mating types in
genes in eukaryotic cells or animal viruses paramecia, integrating the genetic princi-
are discontinuous, with segments divided by ples as applied to multicellular organisms
sections separated by intervening sequences with single-celled organisms such as pro-
of genetic material. With Richard Roberts, tozoa.
received the Nobel Prize in Physiology or Spemann, Hans (1869-1941): Won the 1935
Medicine in 1993. Nobel Prize in Physiology or Medicine. By
Simpson, George Gaylord (1902-1984): Ameri- transplanting bits of one embryo into a sec-
can paleontologist who applied population ond, viable embryo, Spemann compiled evi-
genetics to the study of the evolution of ani- dence that an organizer center directs the
mals. Simpson was instrumental in establish- development of an embryo and that differ-
ing a neo-Darwinian theory of evolution ent parts of the organizer governed distinct
(the rejection of Lamarcks inheritance of portions of the embryo. His experiments
acquired characteristics) during the early provided clues to the genetic control of
twentieth century. growth from the earliest stages of an or-
Singer, Maxine (1931- ): Applied the use ganism.
of the newly discovered restriction enzymes Spencer, Herbert (1820-1903): English philos-
in formation of recombinant DNA. Singer opher influenced by the work of Charles
is most noted as a voice of calm in the Darwin. Spencer proposed the first general
debate over genetic research, emphasizing theory of inheritance, postulating the exis-
the application of such research, and the tence of self-replicating units within the indi-
self-policing of scientists carrying out such vidual which determine the traits. Spencer is
work. more popularly known as the source of the
Smith, Hamilton Othanel (1931- ): Pio- notion of survival of the fittest as applied
neered the purification of restriction en- to natural selection.
zymes, winning the 1978 Nobel Prize in Phys- Stanley, Wendell Meredith (1904-1971): Ameri-
iology or Medicine, with Werner Arber and can biochemist who was the first to crystal-
Daniel Nathans. Arber and the team of lize a virus (tobacco mosaic virus), demon-
Nathans and Smith separately described the strating its protein nature. Stanley was later a
restriction-modification system by studying member of the team that determined the
bacteria and bacteriophages; the system in- amino acid sequence of the TMV protein.
volves the action of site-specific endonucle- Stanley spent the last years of his long ca-
ase and other enzymes that cleave DNA into reer studying the relationship of viruses and
segments. cancer.
Smith, Michael (1932- ): Won the 1995 No- Stein, William H. (1911-1980): Won the 1972
bel Prize in Chemistry. Smith developed site- Nobel Prize in Chemistry, with Stanford
directed mutagenesis, a means for recon- Moore. Stein and Moore supplemented
figuring genes in order to create altered Alfinsens research by identifying the se-
proteins with distinct properties. Smiths ge- quence of amino acids in ribonuclease, a
netic engineering tool made it possible to clue to the structure of the gene responsible
treat genetic disease and cancer and to cre- for it.
ate novel plant strains. Stevens, Nettie Maria (1861-1912): Discovered
Snell, George D. (1903-1996): Snells discovery the existence of the specific chromosomes
of the H-2 histocompatibility complex, that determine sex, now known as the X and
which regulates the immune response in Y chromosomes. Described the existence of
Biographical Dictionary of Important Geneticists 777
genome. His sequencing work was also ap- flies) led to the discovery of genes that regu-
plied in the Human Genome Project led by late cell patterns and shape in the embryo.
Francis Collins. Along with Edward Lewis and Christiane
Watson, James Dewey (1928- ): Along with Nsslein-Volhard, he was awarded the Nobel
Francis Crick, determined the double-helix Prize in Physiology or Medicine in 1995.
structure of DNA. Together with Crick and Wilkins, Maurice Hugh Frederick (1916- ):
Maurice Wilkins, Watson was awarded the Studies on the X-ray diffraction patterns ex-
1962 Nobel Prize in Physiology or Medicine hibited by DNA confirmed the double-helix
for their work in determining the structure structure of the molecule. Wilkins was a col-
of DNA. league of Rosalind Franklin, and it was their
Weinberg, Robert Allan (1942- ): Molecu- work that confirmed the nature of DNA as
lar biologist who isolated the first human on- proposed by Watson and Crick. Wilkins was
cogene, the ras gene, associated with a vari- awarded the Nobel Prize for Physiology and
ety of cancers, including those of the colon Medicine in 1962, along with Watson and
and brain. Weinberg later isolated the first Crick.
tumor suppressor gene, the retinoblastoma Wilmut, Ian (1944- ): Scottish embryolo-
gene. Weinberg is considered among the gist and leader of a research team at the
leading researchers in understanding the Roslin Institute near Edinburgh. In 1996,
role played by oncogenes in development of Wilmut and his colleagues succeeded in
cancer. cloning an adult sheep, Dolly, the first adult
Weinberg, Wilhelm (1862-1937): German ob- mammal to be successfully produced by
stetrician who demonstrated that hereditary cloning.
characteristics of humans such as multiple Wilson, Edmund Beecher (1856-1939): His
births and genetic diseases were subject to study of chromosomes in collaboration with
Mendels laws of heredity. The mathemati- Nettie Stevens led to the discovery of the X
cal application of such characteristics, pub- and Y chromosomes, playing a key role in the
lished simultaneously (and independently) foundation of modern genetics. His later
by Godfrey Hardy, became known as the work involved the study of development and
Hardy-Weinberg equilibrium. The equation differentiation of the fertilized egg.
demonstrates that dominant genes do not Witkin, Evelyn Maisel (1921- ): Through
replace recessive genes in a population; her studies of induced or spontaneous muta-
gene frequencies would not change from tions in bacterial DNA, discovered processes
one generation to the next if certain criteria of enzymatic repair of DNA.
such as random mating and lack of natural Woese, Carl R. (1928- ): Based on his
selection were met. studies of ribosomal RNA differences in pro-
Weismann, August (1834-1914): German zoolo- karyotes and eukaryotes, proposed that all
gist noted for his chromosome theory of he- life-forms exist in one of three domains:
redity. Weismann proposed that the source Bacteria, Archaea (ancient bacteria), and
of heredity is in the nucleus only and that in- Eukarya (eukaryotic organisms, from micro-
heritance is based on transmission of a chem- scopic plants to large animals). Woese ex-
ical or molecular substance from one gener- panded his theory in arguing that the Ar-
ation to the next. Weismanns theory, which chaea represent the earliest form of life on
rejected the inheritance of acquired charac- Earth, and that they later formed a branch
teristics, came to be called neo-Darwinism. which became the eukaryotes.
Though portions of Weismanns theory were Wright, Sewall (1889-1988): Discovered genetic
later disproved, the nature of the chromo- drift of genetic traits. The Sewall Wright ef-
some was subsequently demonstrated by fect, the random drift of characters in small
Thomas Hunt Morgan and his colleagues. populations, was explained by the random
Wieschaus, Eric F. (1947- ): Wieschauss loss of genes, even in the absence of natural
studies of genetic control in Drosophila (fruit selection.
Biographical Dictionary of Important Geneticists 779
Physiology or Medicine
1910 Albrecht Kossel (German) isolated and described molecular constituents of the cells
nucleus, notably cytosine, thymine, and uracil. These molecules later proved to be
constituents of the codons in deoxyribonucleic acid (DNA) and ribonucleic acid
(RNA). Thus, Kossels research prepared the way for understanding the biochemis-
try of genetics.
1933 Thomas Hunt Morgan (American). Experimenting with the fruit fly Drosophila melano-
gaster, Morgan discovered that the mechanism for the Mendelian laws of heredity lies
in the chromosomes inside the nucleus of cells and that specific genes on the chro-
mosomes govern specific somatic traits in the flies. Morgan confirmed the accuracy
of Mendels laws and ended a controversy over their physiological source.
1935 Hans Spemann (German). By transplanting bits of one embryo into a second, viable em-
bryo, Spemann compiled evidence that an organizer center directs the develop-
ment of an embryo and that different parts of the organizer governed distinct por-
tions of the embryo. His experiments provided clues to the genetic control of growth
from the earliest stages of an organism.
1946 Hermann J. Muller (American). Muller proved that X rays damage genes by altering
their structure: radiation-induced mutation. Consequently, X rays also modify the
structure of chromosomes. The mutations most often produce recessive and harmful
traits in the irradiated organism.
1958 George Beadle and Edward Tatum (both American). In research on the fungus Neuro-
spora crassa, Beadle and Tatum found that biotin was essential to cultivating certain
mutant strains of the fungus; this fact demonstrated that genes regulate the synthesis
of specific cellular chemicals, one or more of these genes being mutated in the biotin-
dependent strain.
1958 Joshua Lederberg (American). Lederberg showed that the bacterium Escherichia coli, al-
though not able to reproduce sexually, is capable of genetic recombination between
chromosomes from different cells through a process called conjugation.
1959 Severo Ochoa (Spanish) and Arthur Kornberg (American). Ochoa and Kornberg iso-
lated enzymes involved in the synthesis of deoxyribonucleic acid (DNA) and ribonu-
cleic acid (RNA), representing the first steps in decoding the biochemical instruc-
tions preserved in the structure of genes.
1962 Francis Crick (British), James Watson (American), and Maurice Wilkins (British). Using
X-ray diffraction analysis and molecular modeling, Wilkins, Crick, and Watson found
that deoxyribonucleic acid (DNA) is structured in a double helix. They were able to
identify the specific three-dimensional structure that is the basis for the ability of
DNA to be replicated and transcribed.
1965 Franois Jacob and Jacques Monod (both French). Studying enzyme action, Jacob and
Monod proved that messenger ribonucleic acid (mRNA) carries instructions from
the nucleus to ribosomes, where molecules are assembled for use in the body, and
they distinguished structural genes from regulatory genes.
1965 Andr Lwoff (French). Lwoff proposed that viral deoxyribonucleic acid (DNA) can be-
come active after invading cells and cause the cells to divide out of control, producing
cancerous tumors.
1968 Robert W. Holley (American), Har Gobind Khorana (Indian), and Marshall W. Niren-
berg (American). Working separately, Holley, Khorana, and Nirenberg deciphered
Nobel Prizes for Discoveries in Genetics 781
the genetic code in ribonucleic acid (RNA) and deoxyribonucleic acid (DNA). Their
work anticipated DNA sequencing and genetic engineering.
1969 Max Delbrck (German), Alfred D. Hershey (American), and Salvador E. Luria (Ital-
ian). In joint studies of bacteriophages and their bacterial hosts, Delbrck, Hershey,
and Luria described the conformation of bacteriophage deoxyribonucleic acid
(DNA), showed that different strains exchange genetic information, and proved that
bacterial DNA mutated to confer protection from attack, demonstrating that bacte-
rial heredity is based on genetic exchange. The discovery explained why bacteria
gradually become resistant to pharmaceuticals.
1975 David Baltimore and Howard M. Temin (both American). Working separately, Balti-
more and Temin discovered reverse transcriptase, the enzyme that inserts viral deoxy-
ribonucleic acid (DNA) into cellular DNA, which can cause cancer, They also identi-
fied retroviruses, a class of virus that includes the human immunodeficiency virus
(HIV) that causes acquired immunodeficiency syndrome (AIDS).
1975 Renato Dulbecco (Italian). Dulbecco described how tumor viruses cause cellular trans-
formation in somatic cells by suppressing the regulatory system that controls division;
the cells then divide out of control.
1978 Werner Arber (Swiss), Daniel Nathans (American), and Hamilton O. Smith (American).
Arber and the team of Nathans and Smith separately described the restriction-modifi-
cation system by studying bacteria and bacteriophages; the system involves the action
of site-specific endonuclease and other enzymes that cleave deoxyribonucleic acid
(DNA) into segments.
1980 Baruj Benacerraf (Venezuelan), Jean Dausset (French), and George D. Snell (Ameri-
can). Benacerraf, Dausset, and Snell each explained the genetic components of the
major histocompatibility complex (MHC), the key to a persons immune system, and
how the system produces antibodies to such a wide variety of foreign molecules and
pathogens, such as viruses, fungi, and bacteria.
1983 Barbara McClintock (American) investigated the genetics of maize (corn) and discov-
ered a new mechanism of gene modification: Some jumping genes (now called
transposable elements or transposons) move to new sites on chromosomes and either
suppress nearby structural genes or inactivate suppressor genes. The discovery was a
major breakthrough in understanding novel, non-Mendelian types of genetic varia-
tion.
1985 Michael S. Brown and Joseph L. Goldstein (both American). Brown and Goldstein con-
ducted extensive research in the regulation of cholesterol in humans. They showed
that in families with a history of high cholesterol, individuals who carry two copies of a
mutant gene (homozygotes) have cholesterol levels several times higher than normal
and those who have one mutant gene (heterozygotes) have levels about double nor-
mal. Their discoveries proved invaluable in managing heart disease and other choles-
terol-related ailments.
1987 Susumu Tonegawa (Japanese) explained the diversity of antibodies by showing that the
antigen-sensitive part of each antibody is created by segments of three genes; since
the segments from each gene can vary in length, the possible combinations from
three genes can produce billions of distinct antibodies.
1989 J. Michael Bishop and Harold E. Varmus (both American). Bishop and Varmus discov-
ered that oncogenes (genes that play a role in initiating cancer) originate in normal
cells and control cellular growth and are not solely derived from retroviruses, as previ-
ously thought. Their work greatly influenced subsequent studies of tumor develop-
ment.
782 Nobel Prizes for Discoveries in Genetics
1993 Richard J. Roberts (British) and Phillip A. Sharp (American). Roberts and Sharp sepa-
rately studied the relationship between deoxyribonucleic acid (DNA) and ribonu-
cleic acid (RNA). They discovered that portions of a human gene can be divided
among several DNA segments, called introns, separated by noncoding segments
called exons. This discovery became important to genetic engineering and to under-
standing the mechanism for hereditary diseases.
1995 Edward B. Lewis (American). Lewis found that an array of master genes governs embryo
development.
1995 Christiane Nsslein-Volhard (German) and Eric F. Wieschaus (American). Nsslein-
Volhard and Wieschaus worked together to extend Lewiss investigations into the ge-
netic control of embryo development through studies of fruit flies. They isolated
more than five thousand participating genes and distinguished four types of master
control genes: gap, pair-rule, segment polarity, and even-skipped.
2001 Leland H. Hartwell (American), R. Timothy Hunt (British), and Paul M. Nurse (British).
Hartwell, Hunt, and Nurse conducted research on the regulation of cell cycles. Hart-
well identified a class of genes that controls the cycle, including a gene that initiates it.
Nurse cloned and described the genetic model of a key regulator, cyclin dependent
kinase, while Hunt discovered cyclins, a class of regulatory proteins.
2002 Sydney Brenner (American) used the transparent nematode Caenorhabditis elegans to es-
tablish a simple model organism for studying how genes control the development of
organs.
2002 John E. Sulston (British) studied cell division and cell lineages in Caenorhabditis elegans
following Brenners methods. He demonstrated that genetic control of specific lin-
eages includes programmed cell death, called apoptosis, as part of the regulatory
process, and he isolated the protein that degrades the deoxyribonucleic acid (DNA)
of dead cells.
2002 H. Robert Horvitz (American). Using Brenners Caenorhabditis elegans model, Horvitz
discovered the first two death genes which instigate cell death. He further found
that another gene helps protect cells from cell death.
Chemistry
1957 Alexander Robertus Todd (British). As part of wide-ranging research in organic chemis-
try, Todd revealed how ribose and deoxyribose bond to the nitrogenous bases on one
side of a nucleotide unit and to the phosphate group on the other side. These discov-
eries provided necessary background for work by others that explained the structure
of the deoxyribonucleic acid (DNA) molecule.
1972 Christian B. Anfinsen (American). Anfinsen, studying the three-dimensional structure
of the enzyme ribonuclease, proved that its conformation was determined by the se-
quence of its amino acids and that to construct a complete enzyme molecule no sepa-
rate structural information was passed on from the deoxyribonucleic acid (DNA) in
the cells nucleus.
1972 Stanford Moore and William H. Stein (both American). Moore and Stein supplemented
Alfinsens research by identifying the sequence of amino acids in ribonuclease, a clue
to the structure of the gene responsible for it.
1980 Paul Berg (American). Berg invented procedures for removing a gene from a chromo-
some of one species and inserting it into the chromosome of an entirely different spe-
cies, enabling him to study how the genetic information of the contributing organism
interacts with hosts deoxyribonucleic acid (DNA). The recombinant DNA technol-
ogy, sometimes called gene splicing, became fundamental to the genetic engineering
of transgenic species.
Nobel Prizes for Discoveries in Genetics 783
1980 Walter Gilbert (American) and Frederick Sanger (British). Gilbert and Sanger indepen-
dently developed methods for determining the sequence of nucleic acids in DNA,
thus decoding the genetic information. Gilberts method cuts DNA into small units
that reveals their structure when exposed to specific chemicals; Sangers method sep-
arates the strands of DNA and then rebuilds them in stages that allow the terminal nu-
cleotides to be identified. Their methods later made it possible to sequence the entire
genomes of organisms.
1982 Aaron Klug (British). Klug used X-ray crystallography to investigate biochemical struc-
tures, especially that of viruses. He was able to link the assembly of viral protein
subunits with specific sites on viral ribonucleic acid (RNA), which helped in fighting
viruses that cause disease in plants and, more basically, in understanding the mecha-
nism of RNA transfer of genetic information. He also determined the structure of
transfer RNA (tRNA), which has a shape similar to that of a bent hair pin.
1989 Sidney Altman (Canadian) and Thomas R. Cech (American). Working independently
Altman and Cech discovered that ribonucleic acid (RNA), like proteins, can act as a
catalyst; moreover, Cech found that when ribosomal RNA participates in translation
of mRNA and the synthesis of polypeptides, it acts as a catalyst in some steps.
1995 Kary B. Mullis (American). Mullis invented polymerase chain reaction (PCR), a method
for swiftly making millions of copies of deoxyribonucleic acid (DNA). PCR soon be-
came an important tool in genetic engineering, DNA fingerprinting, and medicine.
1995 Michael Smith (British). Smith developed site-directed mutagenesis, a means for
reconfiguring genes in order to create altered proteins with distinct properties.
Smiths genetic engineering tool made it possible to treat genetic disease and cancer
and to create novel plant strains.
Peace
1970 Norman Borlaug (American). Borlaug was a key figure in the green revolution of agri-
culture. Working as a geneticist and plant physiologist in a joint Mexican-American
program, he developed strains of high-yield, short-strawed, disease-resistant wheat.
His goal was to increase crop production and alleviate world hunger.
Roger Smith
Time Line of Major Developments in Genetics
12,000 b.c.e. Humans begin domesticating plants and animals, the earliest form of artificial selec-
tion. Domestication involves selective breeding for certain traits. This form of ge-
netic engineering allows for transition from hunter-gatherer societies to agrarian
civilizations.
c. 323 b.c.e. Aristotle theorizes about the nature of species, reproduction, and hybrids.
1677 Antoni van Leeuwenhoek describes sperm and eggs and collects evidence that helps
disprove the theory of spontaneous generation.
1691-1694 German botanist Rudolph Jacob Camerarius establishes the existence of sex in
plants.
1759 Kaspar Friedrich Wolff publishes his epigenesis hypothesis, which states that the
complex structures of chickens develop from initially homogeneous, structureless
areas of the embryo. Many questions remain before this new hypothesis can be vali-
dated; other researchers focus their efforts on the sea squirt, a simpler organism
with fewer differentiated tissues.
1760 Josef Gottlieb Klreuter conducts studies on fertilization and hybridization, discov-
ering the principle of incomplete dominance and laying the groundwork for later
hybridizers.
1798 Thomas Robert Malthus publishes An Essay on the Principle of Population, in which he
analyzes population growth and relates it to the struggle for existence, setting the
stage for evolutionary theory.
1798 Edward Jenner develops vaccination. Jenner used the cowpox virus as a vaccine to
induce immunity against the genetically and structurally similar, but lethal, virus
that causes smallpox in humans.
1838 G. J. Mulder precipitates a fibrous material from cells. He calls this material pro-
tein and believes it is the most important of the known components of living
matter.
Time Line of Major Developments in Genetics 785
1850 Theodore Schwann, Matthias Jakob Schleiden, and Rudolph Virchow recognize
that tissues are made up of cells. The cell theory contradicts the prevailing view of
vitalism, which states that no single part of an organism is alive (it was thought
properties of living matter were somehow shared by the whole organism). The new
theory considers the cell to be the basic and most fundamental unit of life.
1855 Alfred Russel Wallace publishes On the Law Which Has Regulated the Introduction of New
Species; later, in 1858, he sends Charles Darwin a manuscript, On the Tendency of
Varieties to Depart Indefinitely from the Original Type. Today Wallace is recog-
nized as having developed the theory of natural selection along with Darwin.
1857 Louis Pasteur begins research into fermentation. His pasteurization process is
originally proposed as a means of preserving beer and wines. Through his work, Pas-
teur makes the important discovery that life must be derived from life.
1859 Charles Darwin publishes On the Origin of Species by Means of Natural Selection, in which
he sets forth his theory of natural selection. The actual mechanism of evolution is
not understood at the time. Once genetics was studied as a discipline, it became
clear that genetics and evolution are intimately associated. Genetic theories would
later explain and prove the theory of evolution.
1862 The Organic Act establishes the U.S. Department of Agriculture (USDA). As one of
its functions, the USDA is responsible for the collection of new and valuable seeds
and plants and the distribution of them to agriculturists. The preservation and dis-
semination of agriculturally important plants was a necessity for maintaining and in-
creasing the worlds food supply.
1866 Ernst Haeckel develops the hypothesis that hereditary information is transmitted by
the cell nucleus.
1866 Gregor Mendel, an Austrian monk, publishes a paper titled Experiments in Plant
Hybridization. Working with garden peas, Mendel used a systematic approach to
study heredity, forming the theories of segregation and independent assortment.
Although his work lies unnoticed for more than thirty years, it will eventually be re-
discovered and become the foundation for the discipline of genetics.
1869 Francis Galton publishes Hereditary Genius, on the heredity of intelligence, which
lays the foundation for the eugenics movement.
1869 Friedrich Miescher isolates nuclein from the nuclei of white blood cells. This sub-
stance is later found to be the nucleic acids DNA and RNA.
1880 Walter Fleming first describes mitosis, one of the two major processes of cell division
in higher organisms (the other being meiosis). This discovery is key to the under-
standing of inheritance, since microscopic observations of dividing cells helped
early researchers connect Mendelian genetics with cellular biology.
786 Time Line of Major Developments in Genetics
1883 Galton founds the field of eugenics with the publication of Inquiries into Human Fac-
ulty and Its Development. The notion that the human species can be improved by selec-
tive breeding helps perpetuate racism and provides a scientific rationale for subse-
quent ethnic cleansing programs such as those of the Nazi Party fifty years later.
1883 Wilhelm Roux theorizes that mitosis must result in equal sharing of all chromo-
somal particles by the daughter cells and describes the process, but his work is gen-
erally ignored.
1883 E. van Beneden studies the processes of meiosis and fertilization in the parasitic
worm Ascaris. Van Beneden was the first to observe that the chromosome number in
somatic, or body, cells is twice the number that exist in gametes, or sex cells. He also
realized that when fertilization occurs (the combination of two gametes, the egg
from the female and the sperm from the male), the chromosome number of so-
matic cells is established.
1883 The first absolutely pure yeast culture (yeast propagated from a single cell) is intro-
duced at Denmarks Carlsberg Brewery. The ability to propagate and maintain pure
strains of organismsgenetically identical strains, or cloneswill prove pivotal to
future genetic research.
1886 August Weismann publishes The Germ-Plasm: A Theory of Heredity, in which he main-
tains that only the germ cells (eggs and sperm), not somatic cells, can transmit he-
reditary information and changes from one generation to the next; he disproved
the Larmarckian notion of acquired characteristics.
1887-1890 Theodor Boveri investigates and describes chromosomes and their behavior, noting
that they are preserved through the process of cell division and that sperm and egg
contribute equal numbers of chromosomes.
1889 Richard Altmann renames nuclein (isolated by Miescher in 1869) nucleic acid.
1896 Edmund B. Wilson publishes The Cell in Development and Heredity, in which he dis-
cusses the role of cells and chromosomes in inherited traits.
1897 Eduard Buchner shows that organic chemical transformations can be performed by
cell extracts. He discovers that yeast extracts can convert glucose to ethyl alcohol.
Buchners was one of the first in vitro experiments. Performing such experiments
outside the body allowed researchers to control conditions and to observe the ef-
fects of individual variables.
1899 The Royal Horticultural Society holds a meeting in Chiswick, London, in which Wil-
liam Bateson calls for research on discontinuous variations. The meeting later is re-
named the First International Congress of Genetics, still held annually as of 2003.
1900 Hugo de Vries, Erich Tschermak von Seysenegg, and Carl Correns independently
rediscover and reproduce Mendels work. Mendels theories provided a framework
Time Line of Major Developments in Genetics 787
for other researchers. Studies in cytology, cellular biology, plant hybridization, and
biochemistry support Mendels assertions.
1901 Clarence McClung describes the role of the X chromosome in determining sex.
1902 Lucien Cunot, William Bateson, and others begin to confirm Mendelian inheri-
tance in animals.
1902 Austrian botanist Gottlieb Haberlandt completes the cell theory with his idea of toti-
potency: Cells must contain all of the genetic information necessary to create an en-
tire, multicellular organism. Therefore, every plant cell is capable of developing
into an entire plant.
1902 William Ernest Castle, director of the Bussey Institute at Harvard University, and his
students begin research into mouse genetics. His laboratory produces some of the
most influential mammalian geneticists of the twentieth century, including L. C.
Dunn, Clarence Little, Sewall Wright, and George Snell.
1902 Theodor Boveri recognizes the correlation between Mendels laws of inheritance
and current studies of cellular biology; he deduces the haploid nature of sperm
and egg cells (that each had equal amounts of hereditary information) and deter-
mines, by experimenting with sea urchin sperm and egg cells, that each must con-
tribute half the total number of chromosomes to offspring for their normal devel-
opment.
1903 Working independently of Boveri, Walter Sutton comes to similar conclusions using
grasshoppers. Both Boveri and Sutton have formed the chromosomal theory of he-
redity. Mendels notions of segregation and independent assortment coincided
with Suttons observations of how chromosomes segregated during cell division.
This provided a cellular explanation for Mendels observations.
1903 P. A. T. Levene establishes the distinction between DNA and RNA, showing that the
thymine in DNA is replaced by uracil in RNA.
1905 Nettie Stevens and Edmund Wilson independently describe the behavior of sex
chromosomes. Their observations provide the first direct evidence to support the
chromosomal theory of heredity.
1905-1933 The eugenics movement grows in popularity. It influences social policies and immi-
gration and sterilization laws in the United States and other countries. The idea that
human traits, notably behavior, are governed by simple genetic rules was used to dis-
criminate against the mentally deficient, immigrants from specific countries, and
788 Time Line of Major Developments in Genetics
even the poor and homeless. The U.S. eugenics movement effectively ended after
the theory became associated with the policies of Nazi Germany.
1908 Sir Archibald Garrod proposes that some human diseases are inborn errors of me-
tabolism. By studying the inheritance of human disorders, Garrod provides the
first evidence of a specific relationship between genes and enzymes.
1908 George Shull self-pollinates plants for many generations to produce pure-breeding
lines. Donald Jones performs similar experiments to increase productivity. These
two researchers develop the scientific basis of modern agricultural genetics.
1908 Godfrey Hardy and Wilhelm Weinberg discover mathematical relationships be-
tween genotypic and phenotypic frequencies in populations. Known as the Hardy-
Weinberg law, the rules governing these mathematical relationships help research-
ers understand the dynamics of population genetics and the evolution of species.
1909 Wilhelm Johannsen, working on the statistical analysis of continuous variation, ex-
pands the modern genetic vocabulary, coining the terms gene, genotype, and
phenotype.
1909 Carl Correns discovers another class of exceptions to Mendelian inheritance, one of
the first examples of extranuclear inheritance. The notion that other cellular
organelles besides the nucleus carry DNA was not recognized for decades. However,
Correnss experiments in the plant Mirabilis jalapa showed inheritance of leaf color
via the DNA in the chloroplasts.
1910-1928 Thomas Hunt Morgan clearly establishes the chromosomal theory of heredity after
investigating a white-eyed fruit fly and finding that the trait does not segregate ex-
actly according to Mendelian principles, but rather is influenced by the sex of the
fly. This fly experiment becomes the cornerstone upon which theories of Mendel-
ian, chromosomal, and sexual inheritance are built into a cohesive whole. Morgan
also establishes the Fly Room at Columbia University, where he and his students
will conduct groundbreaking experiments using Drosophila for the next quarter cen-
tury. He will win the Nobel Prize in Physiology or Medicine in 1933.
1910 Albrecht Kossel wins the 1910 Nobel Prize in Physiology or Medicine for earlier
work isolating and describing molecular constituents of the cells nucleus, notably
cytosine, thymine, and uracil.
1911 Peyton Rous produces cell-free extracts from chicken tumors that, when injected,
can induce tumors in other chickens. The tumor-producing agent in the extract is
later found to be a virus. Thus, Rous has discovered a link between cancer and vi-
ruses. He wins the Nobel Prize in Physiology or Medicine in 1966.
Time Line of Major Developments in Genetics 789
1913 Alfred H. Sturtevant, a student of Morgan, constructs the first gene maps of chromo-
somes. Maps indicate the order of genes as they exist physically on the chromosome.
Knowledge of gene locations on chromosomes provided insights into inheritance,
genetic diseases, and the function and regulation of DNA. In addition, isolation of
specific genes often required knowledge of their chromosomal location.
1913 Eleanor Carothers reports her discovery of the chromosomal basis of independent
assortment. By examining grasshopper chromosomes, Carothers observed the be-
havior of the X chromosome, responsible for sex determination, during cell divi-
sion. These observations corresponded with Mendels principle of independent as-
sortment.
1914 Calvin Blackman Bridges uses the phenomenon of primary nondisjunction (a fault
in cell division resulting in the failure of chromosomes to separate during meta-
phase I) to prove that genes are carried on chromomsomes.
1915 The Mechanism of Mendelian Heredity, by Morgan, Sturtevant, Muller, and Bridges, is
published, establishing Drosophila as a model organism for genetics research and de-
scribing fundamentals of gene mapping.
1916 Research on the major histocompatibility complex begins with Clarence Little and
E. E. Tyzzers experiments transplanting tumors between mice.
1917 Flix dHerelle discovers bacteriophages, viruses that infect bacteria. Bacterio-
phages played an important role in early genetics research, including confirmation
that DNA is the hereditary material. Bacteriophages also became important in re-
combinant DNA applications.
1917 O. Winge publishes The Chromosomes: Their Number and General Importance,
which for the first time describes the relationship between chromosome doubling
and allopolyploidy in plants.
1922-1932 In what would become known as the modern synthesis, Ronald A. Fisher, J. B. S.
Haldane, Sewall Wright, and S. S. Chetverikov independently publish papers on
evolution, Mendelian inheritance, and natural selection, merging Darwins the-
ory of natural selection with Mendels theory of genetic inheritance to create a field
of population genetics that allows for genetic change through genetic drift. Hal-
dane develops quantitative methods of studying the effects of selection, identify-
ing the number of generations needed to alter gene frequencies for recessive and
dominant traits, autosomal and sex-linked genes, and haploid and diploid organ-
isms.
1925-1926 A. H. Sturtevant describes the position effect: An inversion may place a gene in an-
other location in the chromosome, removing the gene from its regulatory elements
and altering its expression. He also provides genetic proof of inversion.
1927 Hermann J. Muller, another student of Morgan, uses X rays to induce mutations in
organisms. The ability to mutate DNA was a powerful tool to determine the function
of specific genes. Muller receives the Nobel Prize in Physiology or Medicine in 1946.
790 Time Line of Major Developments in Genetics
1928 Frederick Griffith uses the bacterium that causes pneumonia to initiate his investi-
gations into the transforming principle, or transformation. The hereditary mate-
rial has not yet been identified, but Griffiths experiments indicate that the trans-
forming principle is DNA. Although not absolute proof, his experiment contributes
significantly to the field and sparks ideas in other researchers.
1929 Clarence Little helps found the Jackson Laboratory in Bar Harbor, Maine, which
will become one of the most influential genetics research institutions in North
America, particularly in mouse (mammalian) genetics.
1931 Barbara McClintock and Harriet Creighton discover physical exchange between
chromosomes in corn, a process known as crossing over. Curt Stern uses a similar
approach in the study of the X chromosome in Drosophila. Crossing over, or recom-
bination, will be vital to mapping genes on chromosomes and to understanding in-
heritance involving linkage.
1932 Sewall Wright describes the relationship of genetic drift and evolution.
1933 Less than 1 percent of all the agricultural land in the Corn Belt has hybrid corn
growing on it. However, by 1943, hybrids cover more than 78 percent of the same
land. Techniques used to produce crops with desired properties rely heavily on an
understanding of genetics. Through the process of producing hybrids, researchers
attempt to breed the best traits of several varieties into one. This time-consuming
and inexact process is to be superseded by the techniques of recombinant DNA
technology.
1934 John Desmond Bernal examines protein structure by using X-ray crystallography.
1935 Ronald Aylmer publishes statistical analyses of Mendels work. He finds errors in
Mendels interpretation of his data for a series of experiments. Aylmer does not dis-
pute Mendels theories but instead implies that an assistant was ultimately responsi-
ble for the error.
1935 Hans Spemann wins the 1935 Nobel Prize in Physiology or Medicine. By transplant-
ing bits of one embryo into a second, viable embryo, Spemann compiled evidence
that an organizer center directs the development of an embryo and that different
parts of the organizer governed distinct portions of the embryo. His experiments
provided clues to the genetic control of growth from the earliest stages of an or-
ganism.
1937 Theodosius Dobzhansky publishes Genetics and the Origin of Species. He shows that, in
natural and experimental populations of Drosophila species, frequency changes and
geographic patterns of variation in chromosome variants are consistent with the ef-
fects of natural selection.
Time Line of Major Developments in Genetics 791
1939 R. J. Gautheret demonstrates the first successful culture of isolated plant tissues as a
continuously dividing callus tissue.
1941 George Wells Beadle and Edward Tatum, working with a bread mold, Neurospora,
publish results indicating that genes mediate cellular chemistry through the pro-
duction of specific enzymes: the one gene-one enzyme experiment. This estab-
lishes the use of simple organisms as model systems to study genetics. Beadle and
Tatum will receive the Nobel Prize in Physiology or Medicine in 1958.
1943 The Rockefeller Foundation, in collaboration with the Mexican government, initi-
ates the Mexican Agricultural Program, the first use of plant breeding in foreign aid.
1944 Oswald T. Avery, Colin MacLeod, and Maclyn McCarty purify DNA and identify it as
the transforming principle of Frederick Griffiths work. Although this experiment
provides solid evidence that DNA is the hereditary material, most scientists still do
not accept the notion.
1945 R. D. Owen conducts studies with two sets of cattle twins which demonstrate that
their blood antigens could have come only from the opposite sires. These findings
suggest the reciprocal passage of ancestral red blood cells. Owens work has signifi-
cant implications for immunology.
1945 Max Delbrck, Salvador Luria, and Alfred Hershey work on bacteriophage as a
model system to study the mechanism of heredity. Delbrck organizes a course at
Cold Spring Harbor, New York, to introduce researchers to the methods of working
with bacteriophage. His course will be taught for twenty-six years, helping countless
researchers to understand the use of model organisms in genetic investigations.
Delbrck, Luria, and Hershey later share the 1969 Nobel Prize in Physiology or
Medicine.
1946 Joshua Lederberg and Edward Tatum discover genetic recombination (conjuga-
tion) in bacteria, leading them to believe that bacteria, like eukaryotes, have a sex-
ual reproductive cycle. This discovery forces researchers to realize that bacteria are
genetic organisms, similar to the eukaryotes studied at the time. Lederberg wins the
Nobel Prize in Physiology or Medicine in 1958; Tatum and George Beadle will also
share in the 1958 prize, for their work with cellular chemistry, enzymes, and ge-
netics.
1949 Linus Pauling proposes that sickle-cell disease is the result of a change in the normal
amino acid sequence of hemoglobin that interferes with its binding properties. His
later investigations into protein structure help determine the structure of DNA. He
receives the Nobel Prize in Chemistry in 1954.
1950 Barbara McClintock first describes the theory that DNA is mobile and that certain of
its elements can insert into different regions on the chromosome. The technical
name for this phenomenon is transposition, and the genes affected are casually
dubbed jumping genes and, more properly, transposable elements or trans-
posons. McClintocks ideas were far ahead of her time. While most scientists were
792 Time Line of Major Developments in Genetics
still trying to determine just how DNA works, McClintock is turning the field upside
down. Her work will not be accepted until more evidence of transposons surfaces
decades later. She will win the Nobel Prize in Physiology or Medicine in 1983.
1950 Erwin Chargaff discovers consistent one-to-one ratios of adenine to thymine and of
guanine to cytosine in DNA. These four chemicals are the basic building blocks of
DNA. Chargaffs observations become an important clue in determining the exact
structure of DNA.
1951 Maurice Wilkins and Rosalind Franklin obtain X-ray diffraction photographs of
DNA. These data indicate the exact shape of the DNA molecule; joined with
Chargaffs data, these photographs begin to bring DNA into focus.
1952 Joshua and Esther Lederberg and Norton Zinder discover transduction, the trans-
fer of genetic information by viruses. Using Escherichia coli and a bacteriophage
called P1, the Lederbergs and Zinder are able to show that transduction can be used
to map genes to the bacterial chromosome.
1952 Alfred Hershey and Martha Chase use bacteriophage and a blender to identify the
transforming principle as DNA. They are able to show that DNA, and not protein, is
responsible for transforming organisms. This experiment forms the conclusive
piece of evidence confirming that DNA is the hereditary material.
1952 Investigations into bacteriophage by Salvador Luria and M. L. Human, and inde-
pendently J. J. Weigle, lay the groundwork for the discovery of restriction endo-
nucleases.
1953 The three-dimensional structure of DNA is outlined by James Watson and Francis
Crick in a 900-word manuscript published in Nature, Molecular Structure of Nu-
cleic Acids: A Structure for Deoxyribose Nucleic Acid. This elegant and concise pa-
per describes the structure of DNA and provides insight into its function. Watson
and Crick, along with Maurice Wilkins, will win the Nobel Prize in Physiology or
Medicine in 1962. Rosalind Franklin, who with Wilkins delineated the shape of
DNA, did not share in the prize, having died several years earlier of cancer, almost
certainly caused by her work with X rays.
1954 The first whole plant is regenerated, or cloned, from a single adult plant cell by
W. H. Muir and colleagues.
1956 J. H. Tjio and A. Levan determine the chromosome number in humans to be forty-
six. Until that time, the chromosome number was thought to be forty-eight. The
advances that Tjio and Levan pioneered were instrumental in obtaining good
chromosome preparations, allowing for significant advances in the field of cytogen-
etics.
1956-1958 Arthur Kornberg purifies the enzyme DNA polymerase from Escherichia coli. This is
the enzyme responsible for DNA replication, making it possible to synthesize DNA.
Kornberg, along with Severo Ochoa, wins the Nobel Prize in Physiology or Medicine
in 1959.
Time Line of Major Developments in Genetics 793
1957 Heinz Fraenkel-Conrat and B. Singer show that tobacco mosaic virus contains
RNAthe first concrete evidence that RNA, in addition to DNA, serves as the ge-
netic material.
1957 In a landmark address to the British Society of Experimental Biology titled On Pro-
tein Synthesis, Francis Crick articulates both the sequence hypothesis (the order of
bases on a section of DNA codes for an amino acid sequence on a protein) and the
central dogma of molecular genetics (genetic information moves from DNA to
RNA to proteins, but not from proteins back to DNA).
1957 Alexander Robertus Todd wins the 1957 Nobel Prize in Chemistry. As part of wide-
ranging research in organic chemistry, Todd revealed how ribose and deoxyribose
bond to the nitrogenous bases on one side of a nucleotide unit and to the phosphate
group on the other side. These discoveries provide a foundation for work by others
that explains the structure of the DNA molecule.
1958 Matthew Meselson and Frank Stahl determine that DNA replicates in a semi-
conservative manner: Each strand of the molecule serves as a template for the syn-
thesis of a new, complementary strand.
1959 Jrme Lejeune discovers that Down syndrome is caused by the presence of an extra
chromosome. This was the first evidence that genetic disorders could be the result
of changes in chromosome number, as opposed to changes in individual genes in-
herited in a Mendelian fashion.
1960s Mitochondriaextranuclear organelles that are the site for ATP synthesisare dis-
covered to have their own DNA that is passed down maternally. In 1967, Lynn
Margulis, resurrecting a theory proposed by Ivan Wallin in the 1920s, proposes that
mitochondria in eukaryotic cells may have evolved from a symbiotic relationship be-
tween bacteria (prokaryotes) and ancient eukarotes.
1961 Sol Spiegelman and Benjamin Hall discover that single-stranded DNA will hydro-
gen bond to its complementary RNA. The discovery of the ability of DNA and RNA
to form an association contributed greatly to the study of genes and their organiza-
tion.
1961 Working initially with Johann Matthaei, biochemist Marshall Nirenberg discovers
the first sequence of three bases of DNA that codes for an amino acid and cracks
the genetic code. H. Gobind Khorana and Robert W. Holley extend the work and
elucidate how the sequence of amino acids in a protein is encoded by the sequence
of nucleic acids in a gene. Nirenberg, Khorana, and Holley receive the Nobel Prize
in Physiology or Medicine in 1968.
1961 Jacques Monod, Franois Jacob, Sydney Brenner, and Francis Crick discover mes-
senger RNA, reporting that it is the mechanism that carries the information from
DNA to create proteins. This missing link between the genetic material of DNA and
proteins was critical to the understanding of protein synthesis and hence gene ex-
pression. Monod and Jacob win the 1965 Nobel Prize in Physiology or Medicine for
this work.
794 Time Line of Major Developments in Genetics
1962 Mary Lyon hypothesizes that during development, one of the two X chromosomes
in normal mammalian females is inactivated at random. The inactivated X chromo-
some is called a Barr body, and her hypothesis is known as the Lyon hypothesis.
1962 Werner Arber finds bacteria that are resistant to infection by bacteriophage. It ap-
pears that some cellular enzymes destroy phage DNA, while others modify the bac-
terial DNA to prevent self-destruction. Several years later, Arber, Stuart Linn, Mat-
thew Meselson, and Robert Yuan isolate the first restriction endonuclease and
identify the modification of bacterial DNA as methylation. By this time, scientists are
looking at how DNA regulates, and is regulated by, cellular activities in a new
disciplne, molecular genetics. Arber wins the Nobel Prize in Physiology or Medicine
in 1978.
1964 Robin Holliday proposes a model for the recombination of DNA. Although recom-
bination, or crossing over, is not a new idea, the molecular mechanism behind the
exchange of genetic information between DNA strands was not known. Hollidays
model, widely accepted, explains the phenomenon.
1964 John Gurden transfers nuclei from adult toad cells into toad eggs. F. C. Steward
grows single adult cells from a carrot into fully formed, normal plants. These experi-
ments produced viable organisms, ushering in the era of cloning.
1964 The International Rice Research Institute introduces new strains of rice that double
the yield of previous strains. This marks the beginning of the Green Revolution,
which sought to enable all nations to grow sufficient quantities of food to sustain
their own populations. The father of this movement, Norman Borlaug, will win
the Nobel Peace Prize in 1970 for his role in developing high-yield grain varieties.
1965 Andr Lwoff shares the Nobel Prize in Physiology or Medicine with Monod and Ja-
cob. Lwoff earlier demonstrated that the genetic material of bacteriophage can be-
come part of the host bacteriums DNA, a process known as lysogeny.
1966 Victor McKusick publishes the first catalog of single genes responsible for traits,
Mendelian Inheritance in Man, which will appear in many subsequent editions.
1967 Mary Weiss and Howard Green improve the process of gene mapping by using so-
matic cell hybridization.
1967 DNA ligase, the enzyme that joins DNA molecules, is discovered.
1968 Reiji Okazaki reports the discovery of short fragments of RNA later known as
Okazaki fragments, showing the discontinuous synthesis of the lagging DNA strand.
1970 M. Mandel and A. Higa discover a method to increase the efficiency of bacterial
transformation. They make the cells competent to take up DNA by treating bacte-
ria with calcium chloride and then heat-shocking the cells. Introducing foreign
DNA into cells was a key to the success of recombinant DNA methods.
Time Line of Major Developments in Genetics 795
1970 H. Gobind Khorana and twelve associates synthesize the first gene: the gene for an
alanine transfer RNA in yeast.
1970 David Baltimore and Howard Temin independently discover reverse transcriptase,
an enzyme used by viruses to convert their RNA into DNA. The reverse transcriptase
enzyme becomes a key tool in genetic engineering, for which Baltimore and Temin
will win the 1975 Nobel Prize in Physiology or Medicine.
1970 Hamilton O. Smith isolates the first restriction endonuclease that cuts at a specific
DNA sequencethe first site-specific restriction enzyme. Daniel Nathans uses this
enzyme to create a restriction map of the virus SV40. The use of restriction enzymes,
those that cut DNA, allowed for the detailed mapping and analysis of genes. It also
was pivotal for recombinant DNA techniques, including the production of trans-
genic organisms. Nathans and Smith win the Nobel Prize in Physiology or Medicine
in 1978 for their work on restriction enzymes.
1972 Paul Berg is the first to create a recombinant DNA molecule. He shows that restric-
tion enzymes can be used to cut DNA in a predictable manner and that these DNA
fragments can be joined together with fragments from different organisms. He is
awarded the Nobel Prize in Physiology or Medicine in 1980.
1972 Stanford Moore and William H. Stein win the 1972 Nobel Prize in Chemistry for ear-
lier work identifying the sequence of amino acids in ribonuclease, a clue to the
structure of the gene responsible for it.
1973 Joseph Sambrook and other researchers at Cold Spring Harbor improve the
method of separating DNA fragments based on size, a technique called agarose gel
electrophoresis. This method makes it possible to acheive an accurate interpreta-
tion of the information in DNA.
1973 Stanley Cohen and Herbert Boyer develop recombinant DNA technology by pro-
ducing the first recombinant plasmid in bacteria. Plasmidssmall, circular pieces
of DNAoccur naturally in bacteria. Using the newly discovered tools of molecular
biology, Cohen and Boyer inserted a new, or foreign, piece of DNA into an existing
plasmid and had it propagate in a bacterial cell.
Feb., 1975 The Asilomar Conference is held in response to increasing concerns over safety and
ethics of genetic engineering. Convening in Pacific Grove, California, under the
auspices of the National Institutes of Health, 140 prominent international research-
ers and academicians, including Nobel laureate Phillip A. Sharp, air their opinions
about recombinant DNA experimentation and advocate adoption of ethical guide-
lines. NIH later issues guidelines for recombinant DNA research to minimize poten-
tial hazards if genetically altered bacteria were released into the environment. The
guidelines will be relaxed by 1981.
1975 Mary-Claire King and Allan Wilson report, based on results of a survey of pro-
tein and nucleic acid studies, that the average human protein is more than 99 per-
cent identical to that of chimpanzees, which is confirmed by later research. The
question of why two species that are so different can be as genetically similar as
sibling species of other organisms remains open but is assumed to be a function of
796 Time Line of Major Developments in Genetics
gene regulation as well as those relatively few mutations that make human DNA dif-
ferent.
1975 Edward Southern develops a method for transferring DNA from an agarose gel to a
solid membrane. This technique, known as Southern blotting, becomes one of the
most important methods used to identify cloned genes.
1975 Renato Dulbecco, David Baltimore, and Howard Temin receive the Nobel Prize in
Physiology or Medicine for their work on the interaction between tumor viruses and
the genetic material of the cell. Dulbecco applied phage genetic techniques to the
study of animal viruses.
1976 Herbert Boyer and Robert Swanson form Genentech, a company devoted to the
development and promotion of biotechnology and applications of genetical engi-
neering.
1976 Susumu Tonegawa discovers the genetic principles for generation of antibody diver-
sity. Tonegawa identified a novel mode of regulation of the genetic material. The ge-
nomic DNA of immune cells is actually cut and rejoined in different combinations.
This explains how millions of different antibodies can be produced from a very
small number of genes. Tonegawa wins the Nobel Prize in Physiology or Medicine in
1987.
1977 Allan Maxam and Walter Gilbert develop a method to determine the sequence of a
piece of DNA. At the same time, Frederick Sanger develops a different method, the
chain termination (dideoxy) sequencing method. It becomes possible, and rela-
tively simple, to determine the exact sequence of adenine, guanine, thymine, and
cytosine in any DNA molecule. Although both the Gilbert-Maxam and the Sanger
methods are effective, the Sanger method becomes the dominant technique be-
cause it does not involve toxic chemicals. Gilbert and Sanger both receive the Nobel
Prize in Physiology or Medicine in 1980.
1977 James Alwine develops the Northern blotting technique, which expands the basic
blotting technique introduced by Southern to allow analysis of RNA and proteins.
1977 The U.S. Court of Customs and Patent Appeals rules that an inventor can patent
new forms of microorganisms. The first patent granted for a recombinant organ-
ism, an oil-eating bacterium, is awarded in 1980. The legality and ethics of patenting
recombinant organisms and other biological systems are highly controversial.
1977 Herbert Boyer synthesizes the human hormone somatostatin in Escherichia colithe
first successful use of recombinant DNA to produce a substance from the gene of a
higher organism. Before, the first isolation of mammalian somatostatin required a
half million sheep brains to produce 5 milligrams of the hormone. Now, with the use
of recombinant DNA, only two gallons of bacterial culture are required to produce
the same amount.
1977 Phillip A. Sharp and Richard Roberts discover that portions of a human gene can be
divided among several DNA segments, called introns, separated by noncoding seg-
ments called exons. This discovery becomes important to genetic engineering and
Time Line of Major Developments in Genetics 797
to understanding the mechanism for hereditary diseases. Sharp and Roberts win
the 1993 Nobel Prize in Physiology or Medicine.
1978 Herbert Boyer discovers a synthetic version of the human insulin gene and inserts it
into Escherichia coli bacteria. The bacteria serve as cloning vectors to maintain and
replicate large amounts of human insulin. This application of recombinant DNA
technology to produce human insulin for diabetics becomes the foundation for fu-
ture industrial and medical applications of genetic engineering.
1978 P. C. Steptoe and R. G. Edwards successfully use in vitro fertilization and artificial im-
plantation in humans. Louise Brown, the first test-tube baby, is born July 25. The
process gives hope to many childless couples who, prior to this development, have
been unable to conceive. It also raises concerns from ethicists and others over the
potential effects on both the individual childs long-term health and social implica-
tions.
1980 A team headed by David Botstein measures restriction fragments and finds that
the length of such fragments often varies in individuals. Such variation, or restric-
tion fragment length polymorphism (RFLP), is used to allow rapid discovery of the
location of many human genes and genetic differences among individuals.
June 16, 1980 The U.S. Supreme Court votes 5-4 that living organisms can be patented under fed-
eral law, and Ananda M. Chakrabarty receives the first patent for a genetically engi-
neered organism, a form of bacteria, Pseudomona originosa, that can decompose
crude oil for use in cleaning up oil spills.
1980 George Snell, Baruj Benacerraf, and Jean Dausset win the Nobel Prize in Physiology
or Medicine for their discovery of and work on the major histocompatibility com-
plex (MHC), the key to a persons immune system, and how the system produces
antibodies to such a wide variety of foreign molecules and pathogens, such as vi-
ruses, fungi, and bacteria.
1981 J. Michael Bishop and Harold Varmus discover that oncogenes (genes that play a
role in initiating cancer) originate in normal cells as genes that control cellular
growth and are not solely derived from retroviruses, as previously thought. Their
work greatly influences subsequent studies of tumor development. Varmus and
Bishop win the Nobel Prize in Physiology or Medicine in 1989.
1982 The first genetically engineered product, human insulin, dubbed Humulin, is ap-
proved for sale by the U.S. government. The production of pharmaceuticals
through recombinant DNA technology is becoming a driving force behind both the
drug industry and agriculture.
1982 Aaron Klug wins a 1982 Nobel Prize in Chemistry. Klug used X-ray crystallography
to investigate biochemical structures, especially that of viruses. He was able to link
the assembly of viral protein subunits with specific sites on viral RNA, which helped
in fighting viruses that cause disease in plants and, more basically, in understand-
ing the mechanism of RNA transfer of genetic information. He also determined
798 Time Line of Major Developments in Genetics
the structure of transfer RNA (tRNA), which has a shape similar to that of a bent
hairpin.
1983 Nancy Wexler, Michael Conneally, and James Gusella determine the chromosomal
location of the gene for Huntingtons disease. Although close, they are unable to lo-
cate the gene itself; it will be discovered ten years later.
1983 Thomas Cech and Sidney Altman independently discover catalytic RNA. The idea
that RNA can have an enzymatic function changes researchers views on the role of
this molecule, leading to important new theories about the evolution of life. Cech
and Altman win the 1989 Nobel Prize in Chemistry.
1983 Bruce Cattanach provides evidence of genomic imprinting in mice. The phenome-
non of imprinting is the modification of genes in male and female gametes. This
leads to differential expression of these genes in the embryo after fertilization. Im-
printing represents another exception to the rules of Mendelian inheritance.
1983 John Sulston, Sydney Brenner, and H. Robert Horvitz describe the cell lineage of
the nematode Caenorhabditis elegans. The fixed developmental pattern of this small
worm provides researchers with insights into how cells determine their own fates
and how they influence the fates of neighboring cells. Sulston, Brenner, and Horvitz
win the 2002 Nobel Prize in Physiology or Medicine.
1983-1984 William Benders laboratory isolates and characterizes the molecular details of Dro-
sophila homeotic genes. William McGinnis and J. Weiner discover that the base se-
quences of the homeotic genes they examined contain nearly the same sequence in
the terminal 180 bases. They term the conserved 180-base sequence a homeobox.
These regulatory genes direct the development of body parts during gestation of
most animals.
1983-1985 Kary B. Mullis invents the polymerase chain reaction (PCR). This revolutionary
method of copying DNA from extremely small amounts of material changes the way
molecular research is done in only a few short years. It also becomes important in
medical diagnostics and forensic analysis. Mullis wins the Nobel Prize in Chemistry
in 1995.
1984 The Plant Gene Expression Center, a collaborative effort between academia and the
U.S. Department of Agriculture, is established to research plant molecular biology,
sequence plant genomes, and develop genetically modified plants.
1984 Alec Jeffreys is the first to use DNA in identifying individuals. This technique, popu-
larly known as DNA fingerprinting, makes identification of individuals and con-
struction of genetic relationships virtually indisputable.
1984 More than twenty-five scientists collaborate to isolate the gene that causes cystic fi-
brosis. As a result of technological advances, the identification, isolation, and se-
quencing of genes is becoming commonplace. Among the notable discoveries are
genes implicated in Alzheimers disease, diabetes, and even complex conditions
such as cancer and heart disease.
Time Line of Major Developments in Genetics 799
1985 Michael S. Brown and Joseph L. Goldstein win the Nobel Prize in Physiology or Med-
icine for their work on the regulation of cholesterol in humans. They showed that in
families with a history of high cholesterol, individuals who carry two copies of a mu-
tant gene (homozygotes) have cholesterol levels several times higher than normal,
and those who have one mutant gene (heterozygotes) have levels about double
normal.
1985-1987 Robert Sinsheimer, Renato Dulbecco, and Charles DeLisi begin investigating the
possibility of sequencing the entire human genome. DeLisi, head of the Depart-
ment of Energys Office of Health and Environmental Research, seeks federal fund-
ing. After the invention of automated sequencing (see below), the National Re-
search Council and later the Office of Technology Assessment support the idea.
1986 Leroy Hood, a biologist at the California Institute of Technology, invents the auto-
mated sequencer, the most important advance in DNA sequencing technology since
Gilbert and Sanger developed their sequencing methods in the 1970s. Automated
sequencing replaces the use of dangerous radioactive labels for identifying the four
DNA bases with colored fluorescent dyes. Each of the four DNA bases is coded with a
different dye color to eliminate the need to run several reactions. Laser and com-
puter technology are integrated at the end stage to gather data. The result is safer,
more accurate, and much faster sequencing.
1986 The first release of a genetically modified crop, genetically engineered tobacco
plants, is approved by the Environmental Protection Agency.
1987 Calgene receives a patent for a DNA sequence that extends the shelf life of toma-
toes.
1987 Carol Greider and Elizabeth Blackburn, using the model organism Tetrahymena (a
protozoan), report evidence that telomeres are regenerated through an enzyme
with an RNA component. Based on the action of DNA polymerase, telomeres (lo-
cated at the tips of chromosomes) should become shorter during each round of cell
division. Another enzyme, called telomerase, is found to be necessary to maintain
the telomeres. Research in this field sparks interest in the possibility that declining
levels of telomerase may contribute to aging and that the inappropriate expression
of this enzyme in cells may be a factor in cancer.
1988 The Human Genome Organization (HUGO) is founded to coordinate and collect
data from international efforts to sequence the human genome.
1988 The Food and Drug Administration (FDA) approves the sale of recombinant TPA
(tissue plasminogen activator) as a treatment for blood clots. TPA shows promise in
helping victims recovering from heart attack and stroke.
800 Time Line of Major Developments in Genetics
1989 Francis Collins, Lap-Chee Tsui, and researchers at Torontos Hospital for Sick
Children discover the CF gene, which codes the cystic fibrosis transmembrane con-
ductance regulator (CFTR) protein.
1990 Gene therapy for severe combined immunodefiency disorder (SCID) is tested in
clinical trials, with promising if not completely successful results.
1990 The Human Genome Project begins, initially headed by James Watson, under the
auspices of the National Institues of Health, National Center for Human Genome
Research. The project is to be completed by the year 2005. The ambitious project is
designed to sequence the entire human genome in order to identify genes involved
in biochemical processes such as disease pathology. Also included as part of the Hu-
man Genome Project is the sequencing of many model organisms.
1990 At the Plant Gene Expression Center, biologist Michael Fromm announces the use
of a high-speed gene gun to transform corn. Gene guns are used to inject genetic
material directly into cells via DNA-coated microparticles.
1990 The first human undergoes gene therapy. The patient is a four-year-old girl who was
born without a functioning immune system as a result of a faulty gene that makes an
enzyme called ADA (adenosine deaminase).
1991 J. Craig Venter of the National Institutes of Health demonstrates the use of auto-
mated sequencing and expressed sequence tags (ESTs)cloned sequences of com-
plementary DNA (cDNA) molecules stored in librariesto identify genes and
their functions rapidly and accurately.
1992 One of the first major accomplishments of the Human Genome Project is to publish
a low-resolution linkage map of the entire human genome.
1993 The mutation that causes Huntingtons disease is found, ten years after its chromo-
somal location was first identified. Fifty-eight scientists collaborated on the project.
1994 The Food and Drug Administration (FDA) approves the bovine hormone known as
BST or BGH. The hormone is made from recombinant bacteria containing the bo-
vine gene for BST. When injected into cows, the hormone increases milk produc-
tion by up to 20 percent. Many supermarkets and manufacturers of dairy products
refuse to carry or use milk from BST-injected cows, uncertain of what long-term ef-
fects this recombinant drug might have on the food chain.
1994 The Food and Drug Administration (FDA) gives approval for the marketing of the
Flavr Savr tomato. This genetically altered tomato can be ripened on the vine before
being picked and transported. Because the ripening process takes longer, the toma-
toes do not rot on their way to the market.
1994 Alfred G. Gilman and Martin Rodbell receive the Nobel Prize in Physiology or Medi-
cine for discovering the role of G proteins in regulating signal transduction in eu-
karyotic cells.
Time Line of Major Developments in Genetics 801
1995 A mutation in the gene BRCA1, found by Mark Skolnick and others, is implicated in
breast cancer. More than any other gene previously identified, this discovery has
wide potential for assessing cancer risk.
1995 J. Craig Venter of The Institute for Genome Research (TIGR) announces comple-
tion of the first DNA sequence of a nonviral, self-replicating, free-living organism,
the bacterium Haemophilus influenzae, using whole-genome random sequencing,
nicknamed shotgun sequencing. This method, which precludes the need for a
preliminary physical map of the genome, speeds the sequencing of other organisms
significantly.
1995 Completion of the sequence of the smallest known bacterium, Mycoplasma geni-
talium, identifies the minimum number of genes required for independent life.
1995 Edward B. Lewis, Christiane Nsslein-Volhard, and Eric Wieschaus win the Nobel
Prize in Physiology or Medicine for their work on the genetic control of early devel-
opment in Drosophila. These researchers took the fruit fly, a model organism from
the age of classical genetics, into the age of molecular biology and discovered how
genetics controls development. The same developmental mechanisms appear to be
at work in other organisms, including humans.
1995 Nsslein-Volhard completes a genetic mutation project involving zebra fish. Re-
peating her earlier work with Drosophila, Nsslein-Volhard used similar techniques
to begin an intensive study of development in a vertebrate system. This involved
screening thousand of mutants to determine if any had developmental defects.
1995 Michael Smith wins the 1995 Nobel Prize in Chemistry for developing site-directed
mutagenesis, a means of reconfiguring genes in order to create altered proteins
with distinct properties. Smiths technique makes it possible to treat genetic disease
and cancer and to create novel plant strains.
1996 Kristen L. Kroll and Enrique Amaya create a technique to make stable transgenic
Xenopus (frog) embryos.
1996 A group of more than six hundred researchers sequences the DNA of the yeast Sac-
charomyces cereviseae, the first eukaryotic organism to be sequenced.
1997 Ian Wilmut at the Roslin Institute in Scotland announces the successful cloning of a
sheep. The clone is named Dolly, the first vertebrate cloned from the cell of an adult
vertebrate. It is hoped that successful cloning of a mammal will allow for easier and
cheaper development and propagation of transgenic animals.
1997 The United Nations Educational, Scientific, and Cultural Organization (UNESCO)
adopts the Universal Declaration on the Human Genome and Human Rights.
1997 The genomic sequence of the bacterium Escherichia coli is reported by Frederick
Blattner and colleagues. Although E. coli is not the first complete bacterial sequence
reported, because of the importance of E. coli, the event represents a critical step
forward.
802 Time Line of Major Developments in Genetics
1998 The genome of the nematode Caenorhabditis elegans is the first genome of a multicel-
lular organism to be completely sequenced.
1999 Laboratory tests suggest that the pollen of corn bioengineered to release the pesti-
cide Bacillus thuringiensis (Bt) endangers monarch butterfly caterpillars. Although
later evidence calls the finding into question, it prompts controversy over the safety
of transgenic plants.
Sept., 1999 The first human death attributable to gene therapy during clinical trial is reported
when an eighteen-year-old participant in a trial on gene therapy for hereditary orni-
thine transcarbamylase (OTC) deficiency dies of multiorgan failure caused by a se-
vere immunological reaction to the disarmed adenovirus vector used in the trial.
Sept., 1999 Celera Genomics sequences the full genome of Drosophila and reports the results the
following year in the May 24 issue of Science. Of the flys 13,601 genes, many are
shown to be closely related to human genes.
Dec. 1, 1999 The first human chromosome, chromosome 22, is completely sequenced.
Jan. 28, 2000 At a meeting in Montreal, Canada, the United Nations Convention on Biological Di-
versity approves the Cartegena Protocol on Biosafety, which sets the criterion inter-
nationally for patenting genetically modified organisms, including agricultural
products.
2000 It is estimated that more than two-thirds of the processed foods in U.S. markets con-
tain genetically modified ingredients, primarily soybeans or corn.
2000 The environmental organization Friends of the Earth reveals that StarLink, a genet-
ically engineered corn variety meant only for animal fodder, has contaminated the
human food supply. The news ignites public debate over the use of genetically modi-
fied food crops.
Dec. 13, 2000 At a press conference, a team of more than three hundred scientists from through-
out the world announce that they have sequenced the genome of a plant for the first
time. The plant is the model organism Arabidopsis thaliana.
2001 The third and fourth human chromosomes, chromosomes 20 and 14, are com-
pletely sequenced.
Feb., 2001 The first working drafts of the human genome sequence are published in Science
(which reports the results from the private company Celera Genomics, headed by
Time Line of Major Developments in Genetics 803
J. Craig Venter) and in Nature (reporting the results from the publicly funded Hu-
man Genome Project). The relatively low number of human genes, estimated to be
about 30,000, makes it necessary to revise the one gene-one enzyme hypothesis,
since it appears that a single gene can encode more than one protein. The principle
is therefore renamed the one gene-one polypeptide hypothesis. The paper pub-
lished in Science notes that the DNA of all human beings is 99.9 percent the same,
which redefines the notion of human races as primarily a social, rather than a bio-
logical, construct.
2001 Researchers complete the genomic sequence for rice, Oryza sativa.
Nov., 2001 Scientists report that genetic material from transgenic corn has mysteriously turned
up in the genome of native corn species near Oaxaca, Mexico. Mexico banned
transgenic crops three years earlier, and the closest known crop was located beyond
the range of windborne pollen. The report raises concerns about the unintended
ecological consequences of transgenic-wild hybrids, which could create problems
such as superweeds.
2001 Leland H. Hartwell, R. Timothy Hunt, and Paul M. Nurse win the 2001 Nobel Prize
in Physiology or Medicine for their research on the regulation of cell cycles. Hart-
well identified a class of genes that controls the cycle, including a gene that initiates
it. Nurse cloned and described the genetic model of a key regulator, cyclin depen-
dent kinase (cdk), and Hunt discovered cyclins, a class of regulatory proteins.
Dec., 2002 The mouse genome sequence is completed, using the shotgun method; it is com-
pared with the draft of the human genome and found to be very similar; both organ-
isms have about 30,000 genes and about 2,000 non-gene, or junk DNA, regions.
Jan., 2003 A company called Clonaid announces the births of several babies they claim are the
result of human cloning but later fails to produce any scientific evidence that the ba-
bies are clones. The apparent hoax, initially a media event, energizes the public de-
bate over human cloning and its ramifications.
Feb., 2003 Dolly, the first vertebrate cloned from an adult cell, is euthanized after suffering ad-
vanced arthritis and lung disease. Researchers speculate about whether clones age
prematurely as a result of the shortened telomere length of the chromosomes in the
adult cells from which they are cloned.
Feb. 27, 2003 The U.S. House of Representatives passes the Human Prohibition Cloning Act of
2003, banning the cloning of human beings; the bill goes to the Senate.
April, 2003 The Human Genome Project completes its mission two years ahead of schedule:
The entire human genome has now been sequenced.
A: the abbreviation for adenine, a purine ni- of Ti plasmids, into plant cells; modified Ti
trogenous base found in the structure of plasmids can be used to produce transgenic
both DNA and RNA. plants.
acentric chromosome: a chromosome that albinism: the absence of pigment such as mela-
does not have a centromere and that is un- nin in eyes, skin, hair, scales, or feathers or of
able to participate properly in cell division; chlorophyll in plant leaves and stems.
often the result of a chromosomal mutation albino: a genetic condition in which an individ-
during recombination. ual does not produce the pigment melanin
acquired characteristic: a change in an individ- in the skin; other manifestations of the trait
ual organism brought about by its interac- may be seen in the pigmentation of the hair
tion with its environment. or eyes; albino individuals occur in many
acrocentric chromosome: a chromosome with animals and plants and are due to the ab-
its centromere near one end. See also meta- sence of a variety of different pigments.
centric chromosome and telocentric chro- alcoholism: a medical diagnosis given when
mosome. there is repeated use of alcohol over the
activator: a protein that binds to DNA, thus in- course of at least a year, despite the presence
creasing the expression of a nearby gene. of negative consequences; tolerance, with-
active site: the region of an enzyme that inter- drawal, uncontrolled use, unsuccessful ef-
acts with a substrate molecule; any alteration forts to quit, considerable time spent getting
in the three-dimensional shape of the active or using the drug, and a decrease in other
site usually has an adverse effect on the en- important activities because of the use are
zymes activity. part of this condition.
adaptation: the evolution of a trait by natural algorithm: a mathematical rule or procedure
selection, or a trait that has evolved as a re- for solving a specific problem.
sult of natural selection. alkaptonuria: a genetic disorder, first charac-
adaptive advantage: increased reproductive terized by geneticist Archibald Garrod, in
potential in offspring as a result of passing which a compound called homogentisic
on favorable genetic information. acid accumulates in the cartilage and is ex-
adenine (A): a purine nitrogenous base found creted in the urine of affected individuals,
in the structure of both DNA and RNA. turning both of these black (the name of the
adenosine triphosphate (ATP): the major en- disorder literally means black urine); the
ergy molecule of cells, produced either specific genetic defect involves an inability
through the process of cellular respiration to process by-products of phenylalanine and
or fermentation; it is also a component of tyrosine metabolism.
DNA and RNA. allele: a form of a gene at a locus; each locus in
adult stem cell: an undifferentiated cell found an individuals chromosomes has two alleles,
among differentiated cells in a tissue or or- which may be the same or different.
gan of an adult organism. allele frequency: the proportion of all the ge-
agarose: a chemical substance derived from al- netic variants at a locus within a population
gae and used to create gels for the electro- of organisms.
phoresis of nucleic acids. allergy: an abnormal immune response to a
aggression: behavior directed toward causing substance that does not normally provoke
harm to others. an immune response or that is not inher-
Agrobacterium tumefaciens: a species of bacteria ently dangerous to the body (such as plant
that causes disease in some plants and is able pollens, dust, or animal dander).
to transfer genetic information, in the form allopatric speciation: a model of speciation in
Glossary 805
which parts of a population may become geo- amyloid plaques: protein deposits in the brain
graphically isolated, effectively preventing formed by fragments from amyloid precur-
interbreeding, and over time may develop sor proteins; amyloid plaques are character-
differences that lead to reproductive isola- istic of Alzheimers disease.
tion and the development of a new species. anabolic steroids: drugs derived from andro-
allopolyploid: a type of polyploid species that gens and inappropriately used to enhance
contains genomes from more than one an- performance in sports.
cestral species. anabolism: the part of the cells metabolism
altruism: behavior that benefits others at the concerned with synthesis of complex mole-
evolutionary (reproductive) cost of the al- cules and cell structures.
truist. anaphase: the third phase in the process of mi-
Alu sequence: a repetitive DNA sequence of un- tosis; in anaphase, sister chromatids sepa-
known function, approximately three hun- rate at the centromere and migrate toward
dred nucleotides long, scattered through- the poles of the cell.
out the genome of primates; the name anaphylaxis: a severe, sometimes fatal allergic
comes from the presence of recognition reaction often characterized by swelling of
sites for the restriction endonuclease Alu I in the air passages, leading to inability to
these sequences. breathe.
Alzheimers disease: a degenerative brain dis- ancient DNA: DNA isolated from archaeologi-
order, usually found among the elderly, cal artifacts or fossils; it is typically exten-
characterized by brain lesions leading to loss sively degraded.
of memory, personality changes, and deteri- androgen receptors: molecules in the cyto-
oration of higher mental functions. plasm of cells that join with circulating male
amber codon: a stop codon (UAG) found in hormones.
messenger RNA (mRNA) molecules that sig- androgens: steroid hormones that cause
nals termination of translation. masculinization.
ambiguous genitalia: external sexual organs anencephalus: a neural tube defect character-
that are not clearly male or female. ized by the failure of the cerebral hemi-
Ames test: a test devised by molecular biologist spheres of the brain and the cranium to de-
Bruce Ames for determining the mutagenic velop normally.
or carcinogenic properties of various com- aneuploid: a cell or individual with one or a few
pounds based on their ability to affect the missing or extra chromosomes.
nutritional characteristics of the bacterium angstrom: a unit of measurement equal to one
Salmonella typhimurium. ten-millionth of a millimeter; a DNA mole-
amino acid: a nitrogen-containing compound cule is 20 angstroms wide.
used as the building block of proteins (poly- animal cloning: animal cloning is the process of
peptides); in nature, there are twenty amino generating a genetic duplicate of an animal
acids that can be used to build proteins. starting with one of its differentiated cells.
aminoacyl tRNA: a transfer RNA (tRNA) mole- annealing: the process by which two single-
cule with an appropriate amino acid mol- stranded nucleic acid molecules are con-
ecule attached; in this form, the tRNA mole- verted into a double-stranded molecule
cule is ready to participate in translation. through hydrogen bonding between com-
amniocentesis: a procedure in which a small plementary base pairs.
amount of amniotic fluid containing fetal anthrax: an acute bacterial disease caused by
cells is withdrawn from the amniotic sac sur- Bacillus anthracis that affects animals and hu-
rounding a fetus; fetal cells, found in the mans and that is especially deadly in its pul-
fluid, are then tested for the presence of ge- monary form.
netic abnormalities. antibiotic: any substance produced naturally by
amniotic fluid: the fluid in which the fetus is a microorganism that inhibits the growth of
immersed during pregnancy. other microorganisms; antibiotics are im-
806 Glossary
portant in the treatment of bacterial infec- apoptosis: cell suicide occurring after a cell is
tions. too old to function properly, as a response to
antibody: an immune protein (immunoglobu- irreparable genetic damage, or as a function
lin) that specifically recognizes an antigen; of genetic programming; apoptosis prevents
produced by B cells of the immune system. cells from developing into a cancerous state
anticodon: the portion of a transfer RNA and is a natural event during many parts of
(tRNA) molecule that is complementary in organismal development.
sequence to a codon in a messenger RNA Archaea: the domain of life that includes di-
(mRNA) molecule; because of this comple- verse prokaryotic organisms distinct from
mentarity, the tRNA molecule can bind the historically familiar Bacteria and which
briefly to mRNA during translation and di- often require severe conditions for growth,
rect the placement of amino acids in a poly- such as high temperatures, high salinity, or
peptide chain. lack of oxygen.
antigen: any molecule that is capable of being artificial selection: selective breeding of desir-
recognized by an antibody molecule or of able traits, typically in domesticated organ-
provoking an immune response. isms.
antigenic drift or shift: minor changes in the H ascomycetes: organisms of the phylum Asco-
and N proteins of the influenza virus that en- mycota, a group of fungi known as the sac
able the virus to evade the immune system of fungi, which are characterized by a saclike
a potential host. structure, the ascus.
antioxidant: a molecule that preferentially re- ascospore: a haploid spore produced by meio-
acts with free radicals, thus keeping them sis in ascomycete fungi.
from reacting with other molecules and ascus: a reproductive structure, found in asco-
causing cellular damage. mycete fungi, that contains ascospores.
antiparallel: a characteristic of the Watson- asexual reproduction: reproduction of cells or
Crick double-helix model of DNA, in which organisms without the transfer or reassort-
the two strands of the molecule can be visual- ment of genetic material; results in offspring
ized as oriented in opposite directions; this that are genetically identical to the parent.
characteristic is based on the orientation of assortative mating: mating that occurs when in-
the deoxyribose molecules in the sugar- dividuals make specific mate choices based
phosphate backbone of the double helix. on the phenotype or appearance of others.
antirejection medication: drugs developed to ATP: See adenosine triphosphate.
counteract the human bodys natural im- ATP synthase: the enzyme that synthesizes ATP.
mune systems reaction to transplanted or- autoimmune disorders: chronic diseases that
gans. arise from a breakdown of the immune sys-
antisense: a term referring to any strand of tems ability to distinguish between the
DNA or RNA that is complementary to a bodys own cells (self) and foreign sub-
coding or regulatory sequence, for example, stances, leading to an individuals immune
the strand opposite the coding strand (the system attacking the bodys own organs or
sense strand) in DNA is called the antisense tissues.
strand. autoimmune response: an immune response of
antisense RNA: an small RNA molecule that is an organism against its own cells.
complementary to the coding region of a automated fluorescent sequencing: a modifica-
messenger RNA (mRNA) and when bound tion of dideoxy termination sequencing
to the mRNA prevents it from being trans- which uses fluorescent markers to identify
lated. the terminal nucleotides, allowing the auto-
antitoxin: a vaccine containing antibodies mation of sequencing.
against a specific toxin. autopolyploid: a type of polyploid species that
Apo-B: a protein essential for cholesterol trans- contains more than two sets of chromo-
port. somes from the same species.
Glossary 807
terized fragments of DNA to walk into notype to determine whether or not the mu-
uncharacterized regions of the chromo- tations occur within the same gene.
some that overlap with these fragments. See composite transposon: a transposable element
also chromosome jumping. that contains genes other than those re-
circadian rhythm: a cycle of behavior, approxi- quired for transposition.
mately twenty-four hours long, that is ex- concerted evolution: a process in which the
pressed independent of environmental members of a gene family evolve together.
changes. concordance: the presence of a trait in both
cirrhosis: a disease of the liver, marked by the members of a pair of twins.
development of scar tissue that interferes cones: the light-sensitive structures in the ret-
with organ function, that can result from ina that are the basis for color vision.
chronic alcohol consumption. congenital defect: a defect or disorder that oc-
cistron: a unit of DNA that is equivalent to a curs during prenatal development.
gene; it encodes a single polypeptide. conjugation: a form of genetic transfer among
clinical trial: an experimental research study bacterial cells involving the F pilus.
used to determine the safety and effective- consanguine: of the same blood or origin; in ge-
ness of a medical treatment or drug. netics, the term implies the sharing of ge-
clone: a molecule, cell, or organism that is a netic traits or characteristics from the same
perfect genetic copy of another. ancestors (as cousins, for example).
cloning: the technique of making a perfect ge- consensus sequence: a sequence with no or
netic copy of an item such as a DNA mole- only slight differences commonly found in
cule, a cell, or an entire organism. DNA molecules from various sources, imply-
cloning vector: a DNA molecule that can be ing that the sequence has been actively con-
used to transport genes of interest into cells, served and plays an important role in some
where these genes can then be copied. genetic process.
codominance: a genetic condition involving cosmid: a cloning vector partially derived from
two alleles at a locus in a heterozygous or- genetic sequences of lambda, a bacterio-
ganism; each of these alleles is fully ex- phage; cosmids are useful in cloning rela-
pressed in the phenotype of the organism. tively large fragments of DNA.
codon: a group of three nucleotides in messen- cross: the mating of individuals to produce off-
ger RNA (mRNA) that represent a single spring by sexual reproduction.
amino acid in the genetic code; this is medi- crossing over: the exchange of genetic material
ated through binding of a transfer RNA between two homologous chromosomes
(tRNA) anticodon to the codon during during prophase I of meiosis, providing an
translation. important source of genetic variation; also
color blindness: an inherited condition in peo- called recombination or crossover.
ple whose eyes lack one or more of the three cultivar: a variety of plant developed through
color receptors. controlled breeding techniques.
complementary base pairing: hydrogen bond cyclic adenosine monophosphate (cAMP): an
formation in DNA and RNA that occurs important cellular molecule involved in cell
only between cytosine and guanine (in both signaling and regulation pathways.
DNA and RNA) or between adenine and thy- cyclins: a group of eukaryotic proteins with
mine (in DNA) or adenine and uracil (in characteristic patterns of synthesis and deg-
RNA). radation during the cell cycle; part of an
complementary DNA (cDNA): a DNA mole- elaborate mechanism of cell cycle regulation,
cule that is synthesized using messenger and a key to the understanding of cancer.
RNA (mRNA) as a template and which is cat- cystic fibrosis: the most common recessive le-
alyzed by the enzyme reverse transcriptase. thal inherited disease among Caucasians in
complementation testing: performing a cross the United States and the United Kingdom.
between two individuals with the same phe- cytogenetics: the study of chromosome num-
Glossary 811
DNA: See deoxyribonucleic acid. more or fewer genes for specific traits than
DNA fingerprinting: a DNA test used by foren- normal.
sic scientists to aid in the identification of double helix: a model of DNA structure pro-
criminals or to resolve paternity disputes posed by molecular biologists James Watson
which involves looking at known, highly vari- and Francis Crick; the major features of this
able DNA sequences; more correctly called model are two strands of DNA wound
DNA genotyping. around each other and connected by hydro-
DNA footprinting: a molecular biology tech- gen bonds between complementary base
nique involving DNA-binding proteins that pairs.
are allowed to bind to DNA; the DNA is down-regulation: generally used in reference
then degraded by DNases, and the binding to gene expression and refers to reducing
sites of the proteins are revealed by the nu- the amount that a gene is transcribed and/
cleotide sequences protected from degrada- or translated; up-regulation is the opposite.
tion. Down syndrome: a genetic defect caused by
DNA gyrase: a bacterial enzyme that reduces possession of an extra copy of chromosome
tension in DNA molecules that are being un- 21; symptoms include mental retardation,
wound during replication; a type of cellular mongoloid facial features, and premature
enzyme called a topoisomerase. aging.
DNA library: a collection of cloned DNA frag- downstream: in relation to the left-to-right di-
ments from a single source, such as a ge- rection of DNA whose nucleotides are ar-
nome, chromosome, or set of messenger ranged in sequence with the 5 carbon on
RNA (mRNA) molecules; most common ex- the left and the 3 on the right, downstream
amples are genomic and cDNA libraries. is to the right.
DNA ligase: a cellular enzyme used to connect drug resistance: a phenomenon in which
pieces of DNA together; important in ge- pathogens no longer respond to drug thera-
netic engineering procedures. pies that once controlled them; resistance
DNA polymerase: the cellular enzyme respon- can arise by recombination, by mutation, or
sible for making new copies of DNA mole- by several methods of gene transfer, and is
cules through replication of single-stranded made worse by misuse of existing drugs.
DNA template molecules or, more rarely, us- duplication: a type of chromosomal mutation
ing an RNA template molecule as in the case in which a chromosome region is duplicated
of RNA-dependent DNA polymerase or re- because of an error in recombination dur-
verse transcriptase. ing prophase I of meiosis; thought to play an
DNA replication: synthesis of new DNA strands important role in gene evolution.
complementary to template strands result- dwarfism: the condition of adults of short stat-
ing in new double-stranded DNA molecules ure who are less than 50 inches in height,
comprising the old template and the newly which can be caused by genetic factors,
synthesized strand joined by hydrogen endocrine malfunction, acquired condi-
bonds; described as a semiconservative pro- tions, or growth hormone deficiency; many
cess in that half (one strand) of the original dwarfs prefer to be called little people.
template is retained and passed on.
DNase: refers to a class of enzymes, deoxyribo- E. coli: See Escherichia coli.
nucleases, which specifically degrade DNA electron transport chain: a series of protein
molecules. complexes that use high-energy electrons
domain: the highest-level division of life, some- to do work such as pumping H+ ions out
times called a superkingdom. of the mitochondrial matrix into the inter-
dominant: an allele or a trait that will mask the membrane space as a way of storing energy
presence of a recessive allele or trait. that is then used by ATP synthase to make
dosage compensation: an equalization of gene ATP.
products that can occur whenever there are electrophoresis: See gel electrophoresis.
Glossary 813
embryo: the term for a complex organism (par- types remains the same although sister chro-
ticularly humans) during its earliest period matids are separated from one another; af-
of development, the stage of development ter equational division occurs, functional
that begins at fertilization and ends with the haploid gametes are present.
eighth week of development, after which the Escherichia coli: a bacterium widely studied in
embryo is called a fetus. genetics research and extensively used in
embryology: the study of developing embryos. biotechnological applications.
embryonic stem cell: a cell derived from an estrogens: steroid hormones or chemicals that
early embryo that can replicate indefinitely stimulate the development of female sexual
in vitro and can differentiate into other cells characteristics and control the female repro-
of the developing embryo. ductive cycle.
emerging disease: a disease whose incidence in ethidium bromide: a chemical substance that
humans or other target organisms has in- inserts itself (intercalates) into the DNA
creased. double helix; when exposed to ultraviolet
endemic: prevalent and recurring in a particu- light, ethidium bromide fluoresces, making
lar geographic region; for example, an or- it useful for the visualization of DNA mole-
ganism that is specific to a particular region cules in molecular biology techniques.
is characterized as endemic to that region. etiology: the cause or causes of a disease or dis-
endocrine gland: a gland that secretes hor- order.
mones into the circulatory system. euchromatin: chromatin that is loosely coiled
endonuclease: an enzyme that degrades a nu- during interphase; thought to contain
cleic acid molecule by breaking phosphodi- transcriptionally active genes.
ester bonds within the molecule. eugenics: a largely discredited field of genetics
endosymbiotic hypothesis: a hypothesis stating that seeks to improve humankind by selec-
that mitochondria and chloroplasts were tive breeding; can be positive eugenics, in
once free-living bacteria that entered into a which individuals with desirable traits are
symbiotic relationship with early pre-eukary- encouraged or forced to breed, or negative
otic cells; structural and genetic similarities eugenics, in which individuals with undesir-
between these organelles and bacteria pro- able traits are discouraged or prevented
vide support for this hypothesis. from breeding.
enhancer: a region of a DNA molecule that fa- eukaryote: a cell with a nuclear membrane
cilitates the transcription of a gene, usually surrounding its genetic material (a charac-
by stimulating the interaction of RNA poly- teristic of a true nucleus) and a variety of
merase with the genes promoter. subcellular, membrane-bound organelles;
enzyme: a protein that acts as a catalyst to speed eukaryotic organisms include all known or-
up or facilitate a specific biochemical reac- ganisms except bacteria, which are prokary-
tion in a cell. otic. See also prokaryote.
epigenesis: the formation of differentiated cell euploid: the normal number of chromosomes
types and specialized organs from a single, for a cell or organism.
homogeneous fertilized egg cell without any eusociality: an extreme form of altruism and
preexisting structural elements. kin selection in which most members of the
epistasis: a genetic phenomenon in which a society do not reproduce but rather feed
gene at one locus influences the expression and protect their relatives; bees, for exam-
of a second gene at another locus, usually by ple, are eusocial.
masking the effect of the second gene; how- euthanasia: the killing of suffering individuals;
ever, only one trait is being controlled by sometimes referred to as mercy killing.
these two genes, so epistasis is characterized exogenous gene: a gene produced or originat-
by modified dihybrid ratios. ing from outside an organism.
equational division: refers to meiosis II, in exon: a protein-coding sequence in eukaryotic
which the basic number of chromosome genes, usually flanked by introns.
814 Glossary
exonuclease: an enzyme that degrades a nu- foreign DNA: DNA taken from a source other
cleic acid molecule by breaking phosphodi- than the host cell that is joined to the DNA of
ester bonds at either end of the molecule. the cloning vector; also known as insert
expressed sequence tags (EST): an STS (se- DNA.
quence tagged site) that has been derived forensic genetics: the use of genetic tests and
from a cDNA library. principles to resolve legal questions.
expression vector: a DNA cloning vector de- formylmethionine (fMet): the amino acid used
signed to allow genetic expression of in- to start all bacterial proteins; it is attached
serted genes via promoters engineered into to the initiator transfer RNA (tRNA) mole-
the vector sequence. cule.
expressivity: the degree to which a genotype is frameshift mutation: a DNA mutation involv-
expressed as a phenotype. ing the insertion or deletion of one of sev-
extranuclear inheritance: inheritance involv- eral nucleotides that are not in multiples of
ing genetic material located in the mito- three, resulting in a shift of the codon read-
chondria or chloroplasts of a eukaryotic cell; ing frame; usually produces nonfunctional
also known as maternal inheritance (be- proteins. See also open reading frame; read-
cause these organelles are generally inher- ing frame.
ited from the mother) and cytoplasmic in- fraternal twins: twins that develop and are born
heritance (because the organelles are found simultaneously but are genetically unique,
in the cells cytoplasm rather than its nu- being produced from the fertilization of two
cleus). separate eggs; a synonymous term is dizy-
extreme halophiles: microorganisms that re- gotic twins.
quire extremely high salt concentrations for free radical: See oxygen free radical.
optimal growth.
G: the abbreviation for guanine, a purine ni-
F pilus: also called the fertility pilus; a repro- trogenous base found in the structure of
ductive structure found on the surface of both DNA and RNA.
some bacterial cells that allows the cells to G0: a point in the cell cycle at which a cell is no
exchange plasmids or other DNA during the longer progressing toward cell division; can
process of conjugation. be considered a resting stage.
F1 generation: first filial generation; offspring G1 checkpoint: a point in the cell cycle at which
produced from a mating of P (parental) gen- a cell commits either to progressing toward
eration individuals. cell division (by replicating its DNA and
F2 generation: second filial generation; off- eventually engaging in mitosis) or to enter-
spring produced from a mating of F1 genera- ing the G0 phase, thereby withdrawing from
tion individuals. the cell cycle either temporarily or perma-
fate map: a description of the adult fate of em- nently.
bryonic cells. gamete: a sex cell, either sperm or egg, contain-
fertilization: the fusion of two cells (egg and ing half the genetic material of a normal
sperm) in sexual reproduction. cell.
fitness: a measure of the ability of a genotype or gel electrophoresis: a technique of molecular
individual to survive and reproduce; when biology in which biological molecules are
fitness is compared to other genotypes or in- placed into a gel-like matrix (such as agarose
dividuals it is called relative fitness. or polyacrylamide) and then subjected to an
fluorescent in situ hibridization (FISH): an ex- electric current; using this technique, re-
tremely sensitive assay for determining the searchers can separate molecules of varying
presence of deletions on chromosomes, sizes and properties.
which uses a fluorescence-tagged segment of GenBank: a comprehensive, annotated collec-
DNA that binds to the DNA region being tion of publicly available DNA sequences
studied. maintained by the National Center for
Glossary 815
Biotechnology Information and available particular genetic defect within a given fam-
through its Web site. ily, including the determination of the risk
gene: a portion of a DNA molecule containing associated with the presence of the genetic
the genetic information necessary to pro- defect in future generations and options for
duce a molecule of messenger RNA (via the treatment of existing genetic defects.
process of transcription) that can then be genetic drift: chance fluctuations in allele fre-
used to produce a protein (via the process of quencies within a population, resulting
translation); also includes regions of DNA from random variation in the number and
that are transcribed to RNA that does not get genotypes of offspring produced by differ-
translated, but carries out other roles in the ent individuals.
cell. genetic engineering: a term encompassing a
gene expression: the combined biochemical wide variety of molecular biology tech-
processes, called transcription and trans- niques, all concerned with the modification
lation, that convert the linearly encoded in- of genetic characteristics of cells or organ-
formation in the bases of DNA into the isms to accomplish a desired effect.
three-dimensional structures of proteins. genetic load: the average number of the reces-
gene families: multiple copies of the same or sive deleterious (lethal or sublethal) alleles
similar genes in the same genome; the cop- in individuals in a population.
ies can be identical and tandemly repeated, genetic map: a map showing distances be-
or they may differ slightly and be scattered tween genes in terms of recombination fre-
on the same or different chromosomes. quency; using DNA sequence data a physical
gene flow: movement of alleles from one popu- map with distance in base pairs can also be
lation to another by the movement of indi- produced.
viduals or gametes. genetic marker: a distinctive DNA sequence
gene frequency: the occurrence of a particular that shows variation in the population and
allele present in a population, expressed as a can therefore potentially be used for identi-
percentage of the total number of alleles fication of individuals and for discovery of
present for the locus. disease genes.
gene pool: the complete assortment of genes genetic screening: the testing of individuals for
present in the gametes of the members of a disease-causing genes or genetic disease.
population that are eligible to reproduce. genetic testing: the use of the techniques of ge-
gene silencing: any form of genetic regulation netics research to determine a persons risk
in which the expression of a gene is com- of developing, or status as a carrier of, a dis-
pletely repressed, either by preventing tran- ease or other disorder.
scription (pre-transcriptional gene silenc- genetically modified (GM) foods: foods pro-
ing) or after a messenger RNA (mRNA) has duced through the application of recombi-
been transcribed (post-transcriptional gene nant DNA technology, whereby genes from
silencing). the same or different species are transferred
gene therapy: any procedure to alleviate or and expressed in crops that do not naturally
treat the symptoms of a disease or condition harbor those genes.
by genetically altering the cells of the patient. genetically modified organism (GMO): an or-
gene transfer: the movement of fragments of ganism produced by using biotechnology to
genetic information, whole genes, or groups introduce a new gene or genes, or new regu-
of genes between organisms. latory sequences for genes, into it for the
genetic code: the correspondence between the purpose of giving the organism a new trait,
sequence of nucleotides in DNA or messen- usually to adapt the organism to a new envi-
ger RNA (mRNA) molecules and the amino ronment, provide resistance to pest species,
acids in the polypeptide a gene codes for. or enable the production of new products
genetic counseling: a discipline concerned from the organism. See also transgenic or-
with analyzing the inheritance patterns of a ganism.
816 Glossary
genetics: an area of biology involving the scien- standing for the diploid number of chromo-
tific study of heredity. somes.
genome: all of the DNA in the nucleus or in one haplotype: a sequential set of genes on a single
of the organelles, such as a chloroplast or chromosome inherited together from one
mitochondrion. parent; the other parent provides a match-
genomic imprinting: a genetic phenomenon in ing chromosome with a different set of
which the phenotype associated with a par- genes.
ticular allele depends on which parent do- Hardy-Weinberg law: a concept in population
nated the allele. genetics stating that, given an infinitely large
genomic library: a collection of clones that in- population that experiences random mat-
cludes the entire genome of a single species ing without mutation or any other such af-
as fragments ligated to vector DNA. fecting factor, the frequency of particular al-
genomics: that branch of genetics dealing with leles will reach a state of equilibrium, after
the study of genetic sequences, including which their frequency will not change from
their structure and arrangement. one generation to the next.
genotype: the genetic characteristics of a cell or HeLa cells: the first human tumor cells shown
organism, expressed as a set of symbols rep- to form a continuous cell line; they were de-
resenting the alleles present at one or more rived from a cervical cancer tumor removed
loci. from a woman known as Henrietta Lacks.
germ cells: reproductive cells such as eggs and helicase: a cellular enzyme that breaks hydro-
sperm. gen bonds between the strands of the DNA
germ-line gene therapy: a genetic modification double helix, thus unwinding the helix and
in gametes or fertilized ova so all cells in the facilitating DNA replication.
organism will have the change which poten- helper T cells: a class of white blood cells (lym-
tially can be passed on to offspring. phocytes) derived from bone marrow that
germ-line mutation: a heritable change in the prompts the production of antibodies by B
genes of an individuals reproductive cells, cells in the presence of an antigen.
often linked to hereditary diseases. hemizygous: characterized by having a gene
gonad: an organ that produces reproductive present in a single copy, such as any gene on
cells and sex hormones; termed ovaries in the X chromosome in a human male.
females and testes in males. hemoglobin: a molecule made up of two alpha
Green Revolution: the introduction of scientif- and two beta amino acid chains whose pre-
ically bred or selected varieties of grain cise chemical and structural properties nor-
(such as rice, wheat, and maize) that, with mally allow it to bind with oxygen in the
high enough inputs of fertilizer and water, lungs and transport it to other parts of the
can greatly increase crop yields. body.
guanine (G): a purine nitrogenous base found hemophilia: an X-linked recessive disorder in
in the structure of both DNA and RNA. which an individuals blood does not clot
properly because of a lack of blood-clotting
H substance: a carbohydrate molecule on the factors; as in all X-linked recessive traits, the
surface of red blood cells; when modified by disease is most common in males, the allele
certain monosaccharides, this molecule pro- for the disease being passed from mother to
vides the basis of the ABO blood groups. son.
haplodiploidy: a system of sex determination heredity: the overall mechanism by which char-
in which males are haploid (developing acteristics or traits are passed from one gen-
from unfertilized eggs) and females are dip- eration of organisms to the next; genetics is
loid. the scientific study of heredity.
haploid: refers to a cell or an organism with one heritability: a proportional measure of the ex-
set of chromosomes; usually represented as tent to which differences among organisms
the N number of chromosomes, with 2N within a population for a particular charac-
Glossary 817
ter result from genetic rather than environ- body plan early in development; the prod-
mental causes (a measure of nature versus ucts of homeotic genes are transcription fac-
nurture). tors that control the expression of other
hermaphrodite: an individual who has both genes.
male and female sex organs. homogametic sex: the particular sex of an or-
heterochromatin: a highly condensed form of ganism that produces gametes containing
chromatin, usually transcriptionally inac- only one type of sex chromosome; in hu-
tive. mans, females are the homogametic sex,
heterochrony: a change in the timing or rate of producing eggs with X chromosomes.
development of characters in an organism homologous: refers to chromosomes that are
relative to those same events in its evolution- identical in terms of types of genes present
ary ancestors. and the location of the centromere; because
heteroduplex: a double-stranded molecule of of their high degree of similarity, homolo-
nucleic acid with each strand from a differ- gous chromosomes can synapse and recom-
ent source, formed either through natural bine during prophase I of meiosis.
means such as recombination or through ar- homology: similarity resulting from descent
tificial means in the laboratory. from a common evolutionary ancestor.
heterogametic sex: the particular sex of an or- homozygote: an individual with two identical
ganism that produces gametes containing alleles at a gene locus.
two types of sex chromosome; in humans, homozygous: characterized by a genotype com-
males are the heterogametic sex, producing posed of two alleles at the same locus that are
sperm that can carry either an X chromo- the same, for example AA or aa; synonymous
some or a Y chromosome. with purebred.
heterogeneous nuclear RNA (hnRNA): an as- Human Genome Project: a multi-year genetic
sortment of RNA molecules of various types research endeavor to sequence the entire
found in the nucleus of the cell and in vari- human genome, as well as the genomes of
ous stages of processing prior to their export related organisms; the human genome se-
to the cytoplasm. quence was officially completed in 2003.
heterozygote: an individual with two different human leukocyte antigens (HLA): molecules
alleles at a gene locus. found on the surface of cells that allow the
heterozygous: composed of two alleles that are immune system to differentiate between for-
different, for example Aa; synonymous with eign, invading cells and the bodys own cells.
hybrid. hybrid: any cell or organism with genetic mate-
histones: specialized proteins in eukaryotic rial from two different sources, through ei-
cells that bind to DNA molecules and cause ther natural processes such as sexual repro-
them to become more compact; thought to duction or more artificial processes such as
be involved in regulation of gene expression genetic engineering.
as well. hybridization: a process of base pairing involv-
HLA: See human leukocyte antigens. ing two single-stranded nucleic acid mole-
hnRNA: See heterogeneous nuclear RNA. cules with complementary sequences; the
holandric: refers to a trait passed from father to extent to which two unrelated nucleic acid
son via a sex chromosome such as the Y chro- molecules will hybridize is often used as a
mosome in human males. way to determine the amount of similarity
homeobox: a DNA sequence encoding a highly between the sequences of the two molecules.
basic protein known as a homeodomain; a hybridoma: a type of hybrid cancer cell created
homeodomain functions as a transcription by artificially joining a cancer cell with an an-
factor and is thought to help regulate major tibody-producing cell; hybridomas have use-
events in the embryonic development of ful applications in immunological research.
higher organisms. hydrogen bond: a bond formed between mole-
homeotic gene: a gene that helps determine cules containing hydrogen atoms with posi-
818 Glossary
tive charges and molecules containing at- standard Mendelian genetics referring to
oms such as nitrogen or oxygen that can the random assortment or shuffling of al-
possess a negative charge; a relatively weak leles and chromosomes that occurs during
but important bond in nature that, among meiosis I; independent assortment is re-
other things, connects water molecules, al- sponsible for the offspring ratios observed
lows DNA strands to base-pair, and contrib- in Mendelian genetics.
utes to the three-dimensional shape of pro- inducer: a molecule that activates some bacte-
teins. rial operons, usually by interacting with reg-
ulatory proteins bound to the operator re-
identical twins: a pair of genetically identical gion.
offspring that develop from a single fertil- induction: a process in which a cell or group of
ized egg; also known as monozygotic twins. cells signals an adjacent cell or group of cells
immune system: the system in the body that to pursue a different developmental path-
normally responds to foreign agents by pro- way and so become differentiated from
ducing antibodies and stimulating antigen- neighboring cells.
specific lymphocytes, leading to destruction informed consent: the right of patients to know
of these agents. the risks of medical treatment and to deter-
in vitro: literally, in glass; an event occurring mine what is done to their bodies, including
in an artificial setting such as in a test tube, as the right to accept or refuse treatment based
opposed to inside a living organism. on this information.
in vivo: literally, in the living; an event occur- initiation codon: also called the start codon, a
ring in a living organism, as opposed to an codon, composed of the nucleotides AUG,
artificial setting. that signals the beginning of a protein-cod-
inborn error of metabolism: a genetic defect in ing sequence in a messenger RNA (mRNA)
one of a cells metabolic pathways, usually at molecule; in the genetic code, AUG always
the level of an enzyme, that causes the path- represents the amino acid methionine.
way to malfunction; results in phenotypic al- insert DNA: See foreign DNA.
terations at the cellular or organismal level. insertion sequence: a small, independently
inbreeding: mating between genetically related transposable genetic element.
individuals. intelligence quotient (IQ): the most common
inbreeding depression: a reduction in the measure of intelligence; it is based on the
health and vigor of offspring from closely re- view that there is a single capacity for com-
lated individuals, a common and widespread plex mental work and that this capacity can
phenomenon among nonhuman organ- be measured by testing.
isms. intercalary deletion: a type of chromosome de-
inclusive fitness: an individuals total genetic letion in which DNA has been lost from
contribution to future generations, compris- within the chromosome (as opposed to a ter-
ing both direct fitness, which results from in- minal deletion involving a region of DNA
dividual reproduction, and indirect fitness, lost from the end of the chromosome).
which results from the reproduction of close interference: in genetic linkage, a mathemati-
relatives. cal expression that represents the difference
incomplete dominance: a phenomenon involv- between the expected and the observed
ing two alleles, neither of which masks the number of double recombinant offspring;
expression of the other; instead, the combi- this can be a clue to the physical location of
nation of the alleles in the heterozygous linked genes on the chromosome.
state produces a new phenotype that is usu- interphase: the period of the cell cycle in which
ally intermediate to the phenotypes pro- the cell is preparing to divide, consisting of
duced by either allele alone in the homozy- two distinct growth phases (G1 and G2) sepa-
gous state. rated by a period of DNA replication (S
independent assortment: a characteristic of phase).
Glossary 819
introgression: the transfer of genes from one knockout: the inactivation of a specific gene
species to another or the movement of genes within a cell (or whole organism, as in the
between species (or other well-marked ge- case of knockout mice) to determine the ef-
netic populations) mediated by backcros- fects of loss of function of that gene.
sing.
intron: an intervening sequence within eukary- lactose: a disaccharide that is an important part
otic DNA, transcribed as part of a messenger of the metabolism of many bacterial species;
RNA (mRNA) precursor but then removed lactose metabolism in these species is geneti-
by splicing before the mRNA molecule is cally regulated via the lac operon.
translated; introns are thought to play an im- lagging strand: in DNA replication, the strand
portant role in the evolution of genes. of DNA being synthesized in a direction op-
inversion: a chromosomal abnormality result- posite to that of replication fork movement;
ing in a region of the chromosome where this strand is synthesized in a discontinuous
the normal order of genes is reversed. fashion as a series of Okazaki fragments later
isotope: an alternative form of an element with joined together. See also Okazaki fragments.
a variant number of neutrons in its atomic Lamarckianism: the theory, originally pro-
nucleus; isotopes are frequently radioactive posed by Jean-Baptiste Lamarck, that traits
and are important tools for numerous mo- acquired by an organism during its lifetime
lecular biology techniques. can be passed on to offspring.
lambda () phage: a bacteriophage that infects
jumping: See chromosome jumping bacteria and then makes multiple copies of
junk DNA: a disparaging (and now known to be itself by taking over the infected bacterias
inaccurate) characterization of the noncod- cellular machinery.
ing DNA content of a genome. lateral gene transfer: the movement of genes
between organisms; also called horizontal
karyokinesis: division of a cells nuclear con- gene transfer.
tents, as opposed to cytokinesis (division of leading strand: in DNA replication, the strand
the cytoplasm). See also cytokinesis. of DNA being synthesized in the same direc-
karyotype: the complete set of chromosomes tion as the movement of the replication fork;
possessed by an individual, usually isolated this strand is synthesized in a continuous
during metaphase and arranged by size and fashion.
type as a method of detecting chromosomal leptotene: a subphase of prophase I of meiosis
abnormalities. in which chromosomes begin to condense
kilobase (kb): a unit of measurement for nu- and become visible.
cleic acid molecules, equal to 1,000 bases or lethal allele: an allele capable of causing the
nucleotides. death of an organism; a lethal allele can be
kinase: an enzyme that catalyzes phosphate ad- recessive (two copies of the allele are re-
dition to molecules. quired before death results) or dominant
kinetochore: a chromosome structure found (one copy of the allele produces death).
in the region of the centromere and used leucine zipper: an amino acid sequence, found
as an attachment point for the microtu- in some DNA-binding proteins, character-
bules of the spindle apparatus during cell di- ized by leucine residues separated by sets of
vision. seven amino acids; two molecules of this
Klinefelter syndrome: a human genetic disor- amino acid sequence can combine via the
der in males who possess an extra X chromo- leucine residues and zip together, creating
some; Klinefelter males have forty-seven a structure that can then bind to a specific
chromosomes instead of the normal forty- DNA sequence.
six and suffer from abnormalities such as ste- linkage: a genetic phenomenon involving two
rility, body feminization, and mental retar- or more genes inherited together because
dation. they are physically located on the same chro-
820 Glossary
mosome; Gregor Mendels principle of in- melting: a term sometimes used to describe the
dependent assortment does not apply to denaturation of a DNA molecule as it is
linked genes, but genotypic and phenotypic heated in solution; as the temperature rises,
variation is possible through crossing over. hydrogen bonds between the DNA strands
linkage mapping: a form of genetic mapping are broken until the double-strand molecule
that uses recombination frequencies to esti- has been completely converted into two sin-
mate the relative distances between linked gle-strand molecules.
genes. Mendelian genetics: the genetics of traits that
locus (pl. loci): the specific location of a partic- show simple inheritance patterns; based on
ular gene on a chromosome. the work of Gregor Mendel, a nineteenth
lymphocytes: sensitized cells of the immune century monk who studied the genetics of
system that recognize and destroy harmful pea plants.
agents via antibody and cell-mediated re- messenger RNA (mRNA): a type of RNA mole-
sponses that include B lymphocytes from the cule containing the genetic information
bone marrow and T lymphocytes from the necessary to produce a protein through the
thymus. process of translation; produced from the
Lyon hypothesis: a hypothesis stating that one DNA sequence of a gene in the process of
X chromosome of the pair found in all fe- transcription.
male cells must be inactivated in order for metabolic pathway: a series of enzyme-cata-
those cells to be normal; the inactivated X lyzed reactions leading to the breakdown or
chromosome is visible by light microscopy synthesis of a particular biological molecule.
and stains as a Barr body. metabolism: the collection of biochemical re-
lysis: the breaking open of a cell. actions occurring in an organism.
lysogeny: a viral process involving repression metacentric chromsome: a chromosome with
and integration of the viral genome into the the centromere located at or near the mid-
genome of the host bacterial cell. dle of the chromosome. See also acrocentric
chromosome; telocentric chromosome.
major histocompatibility complex (MHC): a metafemale: a term used to describe Drosophila
group of molecules found on the surface of (fruit fly) females that have more X chromo-
cells, allowing the immune system to differ- somes than sets of autosomes (for example,
entiate between foreign, invading cells and a female that has two sets of autosomes and
the bodys own cells; in humans, this group three X chromosomes); also used in refer-
of molecules is called HLA (human leuko- ence to human females with more than two
cyte antigens). See also human leukocyte anti- X chromosomes.
gens. metaphase: the second phase in the process of
map unit: See centiMorgan. mitosis, involving chromosomes lined up in
maternal inheritance: See extranuclear inheri- the middle of the cell on a line known as the
tance. equator.
Maxam-Gilbert sequencing: a method of base- methylation: the process of adding a methyl
specific chemical degradation to determine chemical group (one carbon atom and three
DNA sequence; this method has largely hydrogen atoms) to a particular molecule,
been supplanted by the Sanger method. See such as to the base portion of a nucleotide in
also Sanger sequencing. a DNA nucleotide.
meiosis: a process of cell division in which the metric trait: See quantitative trait.
cells genetic material is reduced by half and microarray: a flat surface on which 10,000 to
sex cells called gametes are produced; im- 100,000 tiny spots of short DNA molecules
portant as the basis of sexual reproduction. (oligonucleotides) are fixed and are used to
melanism: the opposite of albinism, a condi- detect the presence of DNA or RNA mole-
tion that leads to the overproduction of mel- cules that are homologous to the oligonu-
anin. cleotides.
Glossary 821
microsatellite DNA: a type of variable number model organism: an organism well suited for
tandem repeat (VNTR) in which the re- genetic research because it has a well-known
peated motif is 1 to 6 base pairs; also called a genetic history, a short life cycle, and genetic
simple sequence repeat (SSR) or a short tan- variation between individuals in the popula-
dem repeat (STR). tion.
microtubule: a cell structure involved in the modern synthesis: the merging of the Dar-
movement and division of chromosomes winian mechanisms for evolution with Men-
during mitosis and meiosis; part of the cells delian genetics to form the modern fields
cytoskeleton, microtubules can be rapidly of population genetics and evolutionary bi-
assembled and disassembled. ology; also called the neo-Darwinian syn-
microtubule organizing center (MTOC): See thesis.
centriole. molecular clock hypothesis: a hypothesis that
minimal media: an environment that contains predicts that amino acid changes in proteins
the simplest set of ingredients that a micro- and nucleotide changes in DNA are approxi-
organism can use to produce all the sub- mately constant over time.
stances required for reproduction and molecular cloning: the process of splicing a
growth. piece of DNA into a plasmid, virus, or phage
minisatellite DNA: a type of variable number vector to obtain many identical copies of
tandem repeat (VNTR) in which the re- that DNA.
peated motif is 12 to 500 base pairs in length. molecular genetics: the branch of genetics con-
miscegenation: sexual activity or marriage be- cerned with the central role that molecules,
tween members of two different human particularly the nucleic acids DNA and RNA,
races. play in heredity.
mismatch repair: a cellular DNA repair process monoclonal antibodies: identical antibodies
in which improperly base-paired nucleo- (having specificity for the same antigen)
tides are enzymatically removed and re- produced by a single type of antibody-pro-
placed with the proper nucleotides. ducing cell, either a B cell or a hybridoma
missense mutation: a DNA mutation that cell line; important in various types of immu-
changes an existing amino acid codon in a nology research techniques.
gene to some other amino acid codon; de- monoculture: the agricultural practice of grow-
pending on the nature of the change, this ing the same cultivar on large tracts of land.
can be a harmless or a serious mutation (for monohybrid: an organism that is hybrid with
example, sickle-cell disease in humans is the respect to a single gene (for example, Aa);
result of a missense mutation). when two monohybrid organisms are
mitochondrial genome (mtDNA): DNA found mated, the offspring will generally appear in
in mitochondria, which contains some of a 3:1 ratio involving the trait controlled by
the genes that code for proteins involved in the gene in question.
energy metabolism; it is a circular molecule monosomy: a genetic condition in which one
similar in structure to the genome of bac- chromosome from a homologous chromo-
teria. some pair is missing, producing a 2n1 ge-
mitochondrion: the organelle responsible for notype; usually causes significant problems
production of ATP through the process of in the phenotype of the organism.
cellular respiration in a eukaryotic cell; monozygotic: developed from a single zygote;
sometimes referred to as the powerhouse of identical twins are monozygotic because
the cell. they develop from a single fertilized ovum
mitosis: a process of cell division in which a that splits in two.
cells duplicated genetic material is evenly morphogen: a protein or other molecule made
divided between two daughter cells, so that by cells in an egg that creates a concentra-
each daughter cell is genetically identical to tion gradient affecting the developmental
the original parent cell. fate of surrounding cells by altering their
822 Glossary
gene expression or their ability to respond neurotransmitter: a chemical that carries mes-
to other morphogens. sages between nerve cells.
morphogenesis: the induction and formation neutral mutation: a mutation in a gene, or
of organized body parts or organs. some other portion of the genome, that is
mosaicism: a condition in which an individual considered to have no effect on the fitness of
has two or more cell populations derived the organism.
from the same fertilized ovum, or zygote, as neutral theory of evolution: Motoo Kimuras
in sex chromosome mosaics, in which some theory that nucleotide substitutions in the
cells contain the usual XY chromosome pat- DNA often have no effect on fitness, and
tern and others contain extra X chromo- thus changes in allele frequencies in popula-
somes. tions are caused primarily by genetic drift.
mRNA: See messenger RNA. nondisjunction: refers to the improper division
mtDNA: See mitochondrial genome. of chromosomes during anaphase of mitosis
MTOC: See centriole. or meiosis, resulting in cells with abnormal
multifactorial: characterized by a complex in- numbers of chromosomes and sometimes
teraction of genetic and environmental fac- seriously altered phenotypes.
tors. nonhistone proteins: a heterogeneous group of
multiple alleles: a genetic phenomenon in acidic or neutral proteins found in chroma-
which a particular gene locus is represented tin that may be involved with chromosome
by more than two alleles in a population; the structure, chromatin packaging, or the con-
greater the number of alleles, the greater trol of gene expression.
the genetic diversity. nonsense codon: another term for a termina-
mutagen: any chemical or physical substance tion or stop codon (UAA, UAG, or UGA).
capable of increasing mutations in a DNA se- nonsense mutation: a DNA mutation that
quence. changes an existing amino acid codon in a
mutant: a trait or organism different from the message to one of the three termination,
normal, or wild-type, trait or organism seen or stop, codons; this results in an abnor-
commonly in nature; mutants can arise ei- mally short protein that is usually nonfunc-
ther through expression of particular alleles tional.
in the organism or through spontaneous or Northern blot: a molecular biology procedure
intentional mutations in the genome. in which a labeled single-stranded DNA
mutation: a change in the genetic sequence of probe is exposed to cellular RNA immobi-
an organism, usually leading to an altered lized on a filter; under the proper condi-
phenotype. tions, the DNA probe will seek out and bind
to its complementary sequence in the RNA
N terminus: the end of a polypeptide with an molecules if such a sequence is present.
amino acid that has a free amino group. nuclease: an enzyme that degrades nucleic ac-
natural selection: a process involving genetic ids by breaking the phosphodiester bond
variation on the genotypic and phenotypic that connects nucleosides.
levels that contributes to the success or failure nucleic acid: the genetic material of cells,
of various species in reproduction; thought found in two forms: deoxyribonucleic acid
to be the primary force behind evolution. (DNA) and ribonucleic acid (RNA); com-
negative eugenics: improving human stocks posed of repeating subunits called nucleo-
through the restriction of reproduction by tides.
individuals with inferior traits or who are nucleocapsid: a viral structure including the
known to carry alleles for inferior traits. capsid, or outer protein coat, and the nu-
neural tube: the embryonic precursor to the cleic acid of the virus.
spinal cord and brain, which normally closes nucleoid: a region of a prokaryotic cell contain-
at small openings, or neuropores, by the ing the cells genetic material.
twenty-eighth day of gestation in humans. nucleolus: a eukaryotic organelle located in
Glossary 823
the nucleus of the cell; the site of ribosomal open reading frame (ORF): a putative protein-
RNA (rRNA) synthesis. coding DNA sequence, marked by a start
nucleoside: a building block of nucleic acids, codon at one end and a stop codon at the
composed of a sugar (deoxyribose or ribose) other end.
and one of the nitrogenous bases: adenine operator: a region of a bacterial operon serving
(A), cytosine (C), guanine (G), thymine as a control point for transcription of the
(T), or uracil (U). operon; a regulatory protein of some type
nucleosome: the basic unit molecule of chro- usually binds to the operator.
matin, composed of a segment of a DNA operon: a genetic structure found only in bac-
molecule that is bound to and wound teria, whereby a set of genes are controlled
around histone molecules; DNA with together by the same control elements; usu-
nucleosomes appears as beads on a string ally these genes have a common function,
when viewed by electron microscopy. such as the genes of the lactose operon in Es-
nucleotide: a building block of nucleic acids, cherichia coli for the metabolism of lactose.
composed of a sugar (deoxyribose or oxygen free radical: a highly reactive form of
ribose), one of the nitrogenous bases (ade- oxygen in which a single oxygen atom has a
nine, cytosine, guanine, thymine, or uracil) free, unpaired electron; free radicals are
and one or more phosphate groups. common by-products of chemical reactions.
nucleus: the control center of eukaryotic
cells, where the genetic material is separated P generation: parental generation; the original
from the rest of the cell by a membrane; site individuals mated in a genetic cross.
of DNA replication and transcription. pachytene: a subphase of prophase I in meiosis
nullisomy: a genetic condition in which both in which tetrads become visible.
members of a homologous chromosome palindrome: in general, a word that reads the
pair are absent; usually, embryos with this same forwards and backwards (such as the
type of genetic defect are not viable. words noon and racecar); in genetics, a
DNA sequence that reads the same on each
ochre codon: a stop codon (UAA) found in strand of the DNA molecule, although in op-
messenger RNA (mRNA) molecules that sig- posite directions because of the antiparallel
nals termination of translation. nature of the double helix; most DNA palin-
Okazaki fragments: short DNA fragments, ap- dromes serve as recognition sites for restric-
proximately two thousand or fewer bases in tion endonucleases.
length, produced during discontinuous rep- pandemic: a worldwide outbreak of a disease.
lication of the lagging strand of a DNA paracentric inversion: an inversion of a chro-
molecule. mosomes sequence that does not involve
oligonucleotide: a short molecule of DNA, gen- the centromere, taking place on a single arm
erally fewer than twenty bases long and usu- of the chromosome.
ally synthesized artificially; an important parthenogenesis: production of an organism
tool for numerous molecular biology proce- from an unfertilized egg.
dures, including site-directed mutagenesis. paternal: coming from the father.
oncogene: any gene capable of stimulating cell pedigree: a diagram of a particular family,
division, thereby being a potential cause of showing the relationships between all mem-
cancer if unregulated; found in all cells and bers of the family and the inheritance pat-
in many cancer-causing viruses. tern of a particular trait or genetic defect; es-
oogenesis: the process of producing eggs in a pecially useful for research into human traits
sexually mature female organism; another that may otherwise be difficult to study.
term for meiosis in females. penetrance: a quantitative term referring to
opal codon: a stop codon (UGA) found in mes- the percentage of individuals with a certain
senger RNA (mRNA) molecules; signals ter- genotype that also exhibit the associated
mination of translation. phenotype.
824 Glossary
peptide bond: a bond found in proteins; occurs pluripotency: the ability of a cell to give rise
between the carboxyl group of one amino to all the differentiated cell types in an em-
acid and the amino group of the next, link- bryo.
ing them together. point mutation: a DNA mutation involving a
pericentric inversion: an inversion of a chro- single nucleotide.
mosomes sequence involving the centro- polar body: a by-product of oogenesis used to
mere. dispose of extra, unnecessary chromosomes
pharmacogenomics: the branch of human while preserving the cytoplasm of the devel-
medical genetics that evaluates how an indi- oping ovum.
viduals genetic makeup influences his or polycistronic: characterizing messenger RNA
her response to drugs. (mRNA) molecules that contain coding se-
phenotype: the physical appearance or bio- quences for more than one protein, com-
chemical and physiological characteristics mon in prokaryotic cells.
of an individual, which is determined by polygenic inheritance: expression of a trait de-
both heredity and environment. pending on the cumulative effect of multi-
phenotypic plasticity: the ability of a genotype ple genes; human traits such as skin color,
to produce different phenotypes when ex- obesity, and intelligence are thought to be
posed to different environments. examples of polygenic inheritance.
phosphodiester bond: in DNA, the phosphate polymerase: a cellular enzyme capable of creat-
group connecting one nucleoside to the ing a phosphodiester bond between two nu-
next in the polynucleotide chain. cleotides, producing a polynucleotide chain
photoreactivation repair: a cellular enzyme sys- complementary to a single-stranded nucleic
tem responsible for repairing DNA damage acid template; the enzyme DNA polymerase
caused by ultraviolet light; the system is acti- is important for DNA replication, and the
vated by light. enzyme RNA polymerase is involved in tran-
phylogeny: often called an evolutionary tree, scription.
the branching patterns that show evolution- polymerase chain reaction (PCR): a technique
ary relationships, with the taxa on the ends of molecular biology in which millions of
of the branches. copies of a single DNA sequence can be arti-
pilus: a hairlike reproductive structure pos- ficially produced in a relatively short period
sessed by some species of bacterial cells that of time; important for a wide variety of appli-
allows them to engage in a transfer of ge- cations when the source of DNA to be cop-
netic material known as conjugation. ied is either scarce or impure.
plasmid: a small, circular DNA molecule com- polymorphism: the presence of many different
monly found in bacteria and responsible for alleles for a particular locus in individuals of
carrying various genes, such as antibiotic re- the same species.
sistance genes; important as a cloning vector polypeptide: a single chain of amino acids con-
for genetic engineering. nected to one another by peptide bonds; all
pleiotropy: a genetic phenomenon in which a proteins are polypeptides, but a protein may
single gene has an effect on two or more comprise one or more polypeptide mole-
traits. cules.
-ploid, -ploidy: a suffix that refers to a chromo- polyploid: a cell or organism that possesses
some set; humans have two sets of chromo- multiple sets of chromosomes, usually more
somes and are referred to as being diploid, than two.
whereas some plants may have four sets, polysome: a group of ribosomes attached to
called tetraploid. Other terms include the same messenger RNA (mRNA) mole-
autoploidy and polyploidy. See also allo- cule and producing the same protein prod-
polyploid; aneuploid; autopolyploid; dip- uct in varying stages of completion.
loid; euploid; haplodiploidy; haploid; poly- population: a group of organisms of the same
ploid; triploid. species in the same place at the same time
Glossary 825
and thus potentially able to mate; popula- gins to form, and chromatin takes on the
tions are the basic unit of speciation. form of chromosomes by becoming shorter
population genetics: the study of how genes be- and thicker.
have in populations; often a highly mathe- propositus: the individual in a human pedigree
matical branch of genetics in which evolu- who is the focus of the pedigree, usually by
tionary processes are modeled. being the first person who came to the atten-
positive eugenics: selecting individuals to re- tion of the geneticist.
produce who have desirable genetic traits, as protein: a biological molecule composed of
seen by those in control. amino acids linked together by peptide
post-translational modification: chemical alter- bonds; used as structural components of the
ations to proteins after they have been pro- cell or as enzymes; the term protein can re-
duced at a ribosome that alters their proper- fer to a single chain of amino acids or to
ties. multiple chains of amino acids functioning
prenatal testing: testing that is done during in a concerted way, as in the molecule hemo-
pregnancy to examine the chromosomes or globin.
genes of a fetus to detect the presence or ab- proteomics: the study of which proteins are ex-
sence of a genetic disorder. pressed in different types of cells, tissues,
primer: a short nucleic acid molecule used as a and organs during normal and abnormal
beginning point for the enzyme DNA poly- conditions.
merase as it replicates a single-stranded tem- proto-oncogene: a gene, found in eukaryotic
plate. cells, that stimulates cell division; ordinarily,
prion: an infectious agent composed solely of expression of this type of gene is tightly con-
protein; thought to be the cause of various trolled by the cell, but in cancer cells, proto-
human and animal diseases characterized by oncogenes have been converted into onco-
neurological degeneration, including scra- genes through alteration or elimination of
pie in sheep, mad cow disease in cattle, and controlled gene expression.
Creutzfeldt-Jakob disease in humans. pseudodominance: a genetic phenomenon in-
probe: in genetics research, typically a single- volving a recessive allele on one chromo-
stranded nucleic acid molecule or antibody some that is automatically expressed be-
that has been labeled in some way, either cause of the deletion of its corresponding
with radioactive isotopes or fluorescent dyes; dominant allele on the other chromosome
this molecule is then used to seek out its of the homologous pair.
complementary nucleic acid molecule or pseudogenes: DNA sequences derived from
protein target in a variety of molecular biol- partial copies, mutated complete copies, or
ogy techniques such as Southern, Northern, normal copies of functional genes that have
or Western blotting. lost their control sequences and therefore
product rule: a rule of probability stating that cannot be transcribed; may originate by
the probability associated with two simulta- gene duplication or retrotransposition and
neous yet independent events is the product are apparently nonfunctional regions of the
of the events individual probabilities. genome that may evolve at a maximum rate,
prokaryote: a cell that lacks a nuclear mem- free from the evolutionary constraints of
brane (and therefore has no true nucleus) natural selection.
and membrane-bound organelles; bacteria pseudohermaphrodite: individual born with
are the only known prokaryotic organisms. either ambiguous genitalia or external geni-
promoter: a region of a gene that controls tran- talia that are the opposite of the chromo-
scription of that gene; a physical binding site somal sex.
for RNA polymerase. punctuated equilibrium: a model of evolution-
prophase: the first phase in the process of mito- ary change in which new species originate
sis or meiosis, in which the nuclear mem- abruptly and then exist through a long peri-
brane disappears, the spindle apparatus be- od of stasis; important as an explanation of
826 Glossary
the stepwise pattern of species change seen recombination: an exchange of genetic mate-
in the fossil record. rial, usually between two homologous chro-
purine: either of the nitrogenous bases ade- mosomes; provides one of the foundations
nine or guanine; used in the structure of nu- for the genetic reassortment observed dur-
cleic acids. ing sexual reproduction.
pyrimidine: any of the nitrogenous bases cyto- reductional division: refers to meiosis I, in
sine, thymine, or uracil; used in the struc- which the amount of genetic material in the
ture of nucleic acids. cell is reduced by half through nuclear divi-
sion; it is at this stage that the diploid cell is
quantitative trait: a trait, such as human height converted to an essentially haploid state.
or weight, that shows continuous variation in reductionism: the explanation of a complex
a population and can be measured; also system or phenomenon as merely the sum of
called a metric trait. its parts.
quantitative trait loci (QTLs): genomic regions replication: the process by which a DNA or
that affect a quantitative trait, generally RNA molecule is enzymatically copied.
identified via DNA-based markers. replicon: a region of a chromosome under con-
trol of a single origin of replication.
reaction norm: the relationship between envi- replisome: a multiprotein complex that func-
ronment and phenotype for a given geno- tions at the replication fork during DNA rep-
type. lication; it contains all the enzymes and
reading frame: refers to the manner in which a other proteins necessary for replication, in-
messenger RNA (mRNA) sequence is inter- cluding DNA polymerase.
preted as a series of amino acid codons by repressor: a protein molecule capable of pre-
the ribosome; because of the triplet nature of venting transcription of a gene, usually by
the genetic code, a typical messenger RNA binding to a regulatory region close to the
(mRNA) molecule has three possible reading gene.
frames, although usually only one of these resistance plasmid (R plasmid): a small, circu-
will actually code for a functional protein. lar DNA molecule that replicates indepen-
receptors: molecules to which signaling mole- dently of the bacterial host chromosome
cules bind in target cells. and encodes a gene for antibiotic resistance.
recessive: a term referring to an allele or trait restriction endonuclease: a bacterial enzyme
that will only be expressed if another, domi- that cuts DNA molecules at specific sites;
nant, trait or allele is not also present. part of a bacterial cells built-in protection
reciprocal cross: a mating that is the reverse of against infection by viruses; an important
another with respect to the sex of the organ- tool of genetic engineering.
isms that possess certain traits; for example, restriction enzyme: See restriction endonu-
if a particular cross were tall male short fe- clease.
male, then the reciprocal cross would be restriction fragment length polymorphism
short male tall female. (RFLP): a genetic marker, consisting of vari-
reciprocal translocation: a two-way exchange of ations in the length of restriction fragments
genetic material between two nonhomolo- in DNA from individuals being tested, al-
gous chromosomes, resulting in a wide vari- lowing researchers to compare genetic se-
ety of genetic problems depending on which quences from various sources; used in a vari-
chromosomes are involved in the transloca- ety of fields, including forensics and the
tion. Human Genome Project.
recombinant DNA: DNA molecules that are the retrotransposon (retroposon): a DNA se-
products of artificial recombination be- quence that is transcribed to RNA and re-
tween DNA molecules from two different verse transcribed to a DNA copy able to in-
sources; important as a foundation of ge- sert itself at another location in the genome.
netic engineering. retrovirus: a virus that carries reverse transcrip-
Glossary 827
tase that converts its RNA genome into a RNA polymerase: the cellular enzyme required
DNA copy that integrates into the host chro- for making an RNA copy of genetic informa-
mosome. tion contained in a gene; an integral part of
reverse transcriptase: a form of DNA polymer- transcription.
ase, discovered in retroviruses, that uses an RNase: refers to a group of enzymes, ribonu-
RNA template to produce a DNA molecule; cleases, capable of specifically degrading
the name indicates that this process is the re- RNA molecules.
verse of the transcription process occurring rRNA: See ribosomal RNA.
naturally in the cell.
reverse-transcriptase polymerase chain reac- Sanger sequencing: also known as dideoxy ter-
tion (RT-PCR): a technique, requiring iso- mination sequencing, a method using nu-
lated RNA, for quickly determining if a gene cleotides that are missing the 3 hydroxyl
or a small set of genes are transcribed in a group in order to terminate the polymeriza-
population of cells. tion of new DNA at a specific nucleotide; the
RFLP analysis: See restriction fragment length most common sequencing method, used al-
polymorphism. most exclusively.
Rh factor: a human red-blood-cell antigen, first segregation: a characteristic of Mendelian ge-
characterized in rhesus monkeys, that con- netics, resulting in the division of homolo-
tributes to blood typing; individuals can be gous chromosomes into separate gametes
either Rh positive (possessing the antigen during the process of meiosis.
on their red blood cells) or Rh negative semiconservative replication: a characteristic
(lacking the antigen). of DNA replication, in which every new DNA
ribonucleic acid (RNA): a form of nucleic acid molecule is actually a hybrid molecule, be-
in the cell used primarily for genetic expres- ing composed of a parental, preexisting
sion through transcription and translation; strand and a newly synthesized strand.
in structure, it is virtually identical to DNA, sex chromosome: a chromosome carrying
except that ribose is used as the sugar in each genes responsible for determination of an
nucleotide and the nitrogenous base thy- organisms sex; in humans, the sex chromo-
mine is replaced by uracil; present in three somes are designated X and Y.
major forms in the cell: messenger RNA sex-influenced inheritance: inheritance in
(mRNA), transfer RNA (tRNA), and ribo- which the expression of autosomal traits is
somal RNA (rRNA). influenced or altered relative to the sex of
ribose: a five-carbon sugar used in the structure the individual possessing the trait; pattern
of ribonucleic acid (RNA). baldness is an example of this type of inheri-
ribosomal RNA (rRNA): a type of ribonucleic tance in humans.
acid in the cell that constitutes some of the sex-limited inheritance: inheritance of traits
structure of the ribosome and participates in expressed in only one sex, although these
the process of translation. traits are usually produced by non-sex-
ribosome: a cellular structure, composed of ri- linked genes (that is, they are genes located
bosomal RNA (rRNA) and proteins, that is on autosomes instead of sex chromosomes).
the site of translation. sexual reproduction: reproduction of cells or
ribozyme: an RNA molecule that can function organisms involving the transfer and
catalytically as an enzyme. reassortment of genetic information, result-
RNA: See ribonucleic acid. ing in offspring that can be phenotypically
RNA interference (RNAi): an artificial tech- and genotypically distinct from either of the
nique using small, interfering RNAs that parents; mediated by the fusion of gametes
cause gene silencing by binding to the part produced during meiosis.
of a messenger RNA (mRNA) to which they Shine-Dalgarno sequence: a short sequence in
are complementary, thus blocking transla- prokaryotic messenger RNA (mRNA) mole-
tion. cules complementary to a sequence in the
828 Glossary
prokaryotic ribosome; important for proper immobilized on a filter; under the proper
positioning of the start codon of the mRNA conditions, the DNA probe will seek out and
relative to the P site of the ribosome. bind to its complementary sequence among
short interspersed sequences (SINES): short the cellular DNA molecules, if such a se-
repeats of DNA sequences scattered through- quence is present.
out a genome. speciation: the process of evolutionary change
shotgun cloning: a technique by which random that leads to the formation of new species.
DNA fragments from an organisms genome species: a group of organisms that can inter-
are inserted into a collection of vectors to breed with one another but not with organ-
produce a library of clones, which can then isms outside the group; generally, members
be used in a variety of molecular biology pro- of a particular species share the same gene
cedures. pool; defining a species is still controversial
sigma factor: a molecule that is part of RNA and remains a debated concept.
polymerase molecules in bacterial cells; al- spermatogenesis: the process of producing
lows RNA polymerase to select the genes sperm in a sexually mature male organism;
that will be transcribed. another term for meiosis in males.
signal transduction: all of the molecular events spindle apparatus: a structure, composed of
that occur between the arrival of a signaling microtubules and microfilaments, impor-
molecule at a target cell and its response; tant for the proper orientation and move-
typically involves a cascading series of reac- ment of chromosomes during mitosis and
tions that can eventually determine expres- meiosis; appears during prophase and be-
sion of many dozens of genes. gins to disappear during anaphase.
single nucleotide polymorphism (SNP): differ- spliceosome: a complex of nuclear RNA and
ences at the individual nucleotide level protein molecules responsible for the exci-
among individuals. sion of introns from messenger RNA
site-directed mutagenesis: a molecular genet- (mRNA) precursors before they are trans-
ics procedure in which synthetic oligonu- lated.
cleotide molecules are used to induce care- SRY: the sex-determining region of the Y chro-
fully planned mutations in a cloned DNA mosome; a gene encoding a protein product
molecule. called testis determining factor (TDF), re-
small nuclear RNA (snRNA): small, numerous sponsible for conversion of a female embryo
RNA molecules found in the nuclei of eu- to a male embryo through the development
karyotic cells and involved in splicing of of the testes.
messenger RNA (mRNA) precursors to pre- stem cell: an undifferentiated cell that retains
pare them for translation. the ability to give rise to other, more special-
snRNA: See small nuclear RNA. ized cells.
snRNP: See small nuclear ribonucleoprotein. sum rule: a rule of probability theory stating
sociobiology: the study of social structures, or- that the probability of either of two mutually
ganizations, and actions in terms of underly- exclusive events occurring is the sum of the
ing biological principles. events individual probabilities.
solenoid: a complex, highly compacted DNA supercoil: a complex DNA structure in which
structure consisting of many nucleosomes the DNA double helix is itself coiled into a
packed together in a bundle. helix; usually observed in circular DNA mol-
somatic mutation: a mutation occurring in a so- ecules such as bacterial plasmids.
matic, or nonsex, cell; because of this, so- sympatric speciation: the genetic divergence of
matic mutations cannot be passed to the populations, not separated geographically,
next generation. that eventually results in formation of new
Southern blot: a molecular biology technique species.
in which a labeled single-stranded DNA synapsis: the close association of homologous
probe is exposed to denatured cellular DNA chromosomes occurring during early pro-
Glossary 829
binding site for a particular amino acid and pair that has been duplicated in some way,
a region complementary to a messenger giving rise to a 2N + 1 genotype and causing
RNA (mRNA) codon (an anticodon). serious phenotypic abnormalities; a well-
transformation: the process by which a normal known example is trisomy 21, or Down syn-
cell is converted into a cancer cell; also refers drome, in which the individual possesses
to the change in phenotype accompanying three copies of chromosome 21 instead of
entry of foreign DNA into a cell, such as in the normal two copies.
bacterial cells being used in recombinant tRNA: See transfer RNA.
DNA procedures. tumor-suppressor genes: any of a number of
transgenic organism: an organism possessing genes that limit or halt cell division under
one or more genes from another organism, certain circumstances, thereby preventing
such as mice that possess human genes; im- the formation of tumors in an organism; two
portant for the study of genes in a living or- well-studied examples are the retinoblas-
ganism, especially in the study of mutations toma gene and the p53 gene; mutations in
within these genes. See also genetically modi- tumor suppressor genes can lead to cancer.
fied organism (GMO). Turner syndrome: a human genetic defect in
transition mutation: a DNA mutation in which which an individual has only forty-five chro-
one pyrimidine (cytosine or thymine) takes mosomes, lacking one sex chromosome;
the place of another, or a purine (adenine or the sex chromosome present is an X chro-
guanine) takes the place of another. mosome, making these individuals pheno-
translation: the cellular process by which ge- typically female, although with serious ab-
netic information in the form of a messen- normalities such as sterility and anatomical
ger RNA (mRNA) molecule is converted defects.
into the amino acid sequence of a protein,
using ribosomes and RNA molecules as ac- uracil (U): a pyrimidine nitrogenous base
cessory molecules. found in the structure of RNA; in DNA, ura-
translocation: the movement of a chromosome cil is replaced by thymine.
segment to a nonhomologous chromosome
as a result of an error in recombination; also variable number tandem repeat (VNTR): a re-
refers to the movement of a messenger RNA petitive DNA sequence of approximately
(mRNA) codon from the A site of the ribo- fifty to one hundred nucleotides; important
some to the P site during translation. in the process of forensic identification
transposable element: See transposon. known as DNA fingerprinting.
transposon: a DNA sequence capable of mov- vector: a DNA molecule, such as a bacterial
ing to various places in a chromosome, dis- plasmid, into which foreign DNA can be in-
covered by geneticist Barbara McClintock; serted and then transported into a cell for
transposons are thought to be important as further manipulation; important in a wide
mediators of genetic variability in both pro- variety of recombinant DNA techniques.
karyotes and eukaryotes. virions: mature infectious virus particles.
transversion: a DNA mutation in which a py- viroids: naked strands of RNA, 270 to 380 nu-
rimidine (cytosine or thymine) takes the cleotides long, that are circular and do not
place of a purine (adenine or guanine), or code for any proteins that are able to cause
vice versa. disease in susceptible plants, many of them
triploid: possessing three complete sets of economically important. See also virusoid.
chromosomes, or 3N; important in the de- virus: a microscopic infectious particle com-
velopment of desirable characteristics in the posed primarily of protein and nucleic acid;
flowers or fruit of some plants; triploids are bacterial viruses, or bacteriophages, have
often sterile. been important tools of study in the history
trisomy: a genetic condition involving one of molecular genetics.
chromosome of a homologous chromosome virusoids: similar to viroids, microscopic infec-
Glossary 831
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Web Sites
The sites listed below were visited by the editors of Salem Press in May of 2003. Because URLs
frequently change or are moved, their accuracy cannot be guaranteed; however, long-standing
sitessuch as those of university departments, national organizations, and government agencies
generally maintain links when sites move or otherwise may upgrade their offerings and hence re-
main useful. Sites with an N/A affiliation are, to our knowledge, unallied, mounted by an individ-
ual, or uncredited. Roger Smith
Netspace Bioinformatics
MendelWeb Bioinformatics.org
http://www.mendelweb.org Home Page
An educational site for teachers and stu- http://bioinformatics.org
dents concerning the origins of classical genet- The site belongs to an international organi-
ics and elementary plant science. It reproduces zation dedicated to the exchange of genetic in-
early publications by such pioneers as Gregor formation and includes online databases and
Mendel and William Bateson, accompanied by analysis tools, software, explanations of fre-
commentaries and reference resources. quently asked questions about bioinformatics,
and news postings.
Rutgers University
Morgan N/A
http://morgan.rutgers.edu/ Earls Forensic Page
MorganWebFrames/How_to_use/ http://members.aol.com/EarlNMeyer/
HTU_intro.html DNA.html
A multimedia tutorial for advanced high With a variety of illustrations, Earl Meyer
school students or beginning college students. summarizes how genetic fingerprinting works
Its six levels review basic principles in genetics and its use in crime investigations and in deter-
with particular attention to molecular interac- mining paternity.
tions.
European Bioinformatics Institute
U.S. Department of Energy Office of Science The Path to Knowledge
Virtual Library on Genetics http://www.ebi.ac.uk
http://www.ornl.gov/TechResources/ A research center, this institute maintains
Human_Genome/genetics.html databases concerning nucleic acids, protein se-
A comprehensive catalog of Web site links, quences, and macromolecular structures. Also
arranged by subject, pertaining to the Human posts news, events, and descriptions of ongoing
Genome Project. The links lead to gene and scientific projects.
chromosome databases and specific informa-
tion on genetics, bioinformatics, and genetic Technical University of Denmark
disorders. Center for Biological Sequencing Analysis
http://www.cbs.dtu.dk
University of Massachusetts The Center conducts basic research in bioin-
DNA Structure formatics and here offers its sequencing analy-
http://molvis.sdsc.edu/dna/index.htm sis databases, genome atlases, analysis tools,
An interactive, animated tutorial on the mo- and news. Primarily meant for researchers and
lecular composition and structure of DNA for university students.
high school students and college freshmen. It
can be downloaded and is available in Spanish,
Biotechnology
German, and Portuguese.
Bio-Link
Educating the Bio-Link Workforce
University of Utah
http://Bio-Link.org
Genetic Science Learning Center
Intended for technicians, this site offers in-
http://gslc.genetics.utah.edu
formation and instruction covering recent ad-
Designed for students, this site posts essays
vances in biotechnology, as well as a virtual lab-
on the basics of DNA, genetic disorders, clon-
oratory and library, news postings, and details
ing, stem cells, and genetic testing. It also de-
about regional education centers.
scribes simple experiments, such as how to ex-
tract DNA material.
Web Sites 861
National Human Genome Research Institute Designed for physicians, this site also con-
Home Page tains information for patients about treat-
http://www.genome.gov ments, research, standards for gene therapy,
In addition to information for researchers, and health, along with news articles and links to
this site contains a comprehensive introduc- related sites.
tion to the Human Genome Project, a glossary
of genetic terms, fact sheets, multimedia edu- Genethon
cation kits, and links to online education re- Gene Therapies Research and Applications
sources, all for the general public. Center
http://www.genethon.fr/php/index_us.php
New York University/Bell Atlantic/Center for Supported by the French Muscular Dystro-
Advanced Technology phy Association, Genethon sponsors research
The Student Genome Project in genetic and cellular therapies for rare dis-
http://www.cat.nyu.edu/sgp/parent.html eases. This site discusses research methods, the
Uses interactive multimedia and three- organizations services, and, in a section ac-
dimensional technology to present tutorials companied by computer graphics, the theory
and games related to the human genome and of gene therapy.
genetics for middle school and high school
students. Also provides news about New York- National Center for Biotechnology
based science events and links. Information
Online Mendelian Inheritance in Man
Sanger Institute, Wellcome Trust http://www.ncbi.nlm.nih.gov/Omim
Home Page The Online Mendelian Inheritance in Man
http://www.sanger.ac.uk (OMIM) is a catalog of human genes and ge-
This research institute is dedicated to netic disorders for scientists. The site also of-
genomics. Accordingly, the site offers news up- fers maps of genes and diseases, statistical sum-
dates, a searchable database, explanations of maries, and links to similar sites devoted to
gene sequencing and computer software aids, medical literature and biotechnology.
and descriptions of genomics research proj-
ects. All information is intended for scientists. National Fragile X Foundation
Xtraordinary Accomplishments
U.S. Department of Energy Biological and http://www.nfxf.org
Environmental Research Program Provides extensive general information
Human Genome Research about fragile X syndrome, a cause of inherited
http://www.er.doe.gov/production/ober/ mental impairments, and advises care-givers on
hug_top.html testing, medical treatment, education, and life-
This site describes the Department of En- planning.
ergys contribution to the Human Genome
Project with pages containing a history, a time National Organization for Rare Disorders
line, project information, an essay on the sci- (NORD).
ence of genetics, and abstracts of recent re- Home Page
search. There is also a section of links designed http://www.rarediseases.org.
for young students and science teachers, as well Offers a very useful and long list of geneti-
as information about fellowships and research cally related disorders and diseases, each of
opportunities. which links to a fact sheet that ends with a list of
organizations for additional information. Also
Medicine and Genetics posts articles about rare genetic conditions and
American College of Medical Genetics diseases, accessible through searchable data-
Home Page bases.
http://www.acmg.net
Web Sites 863