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Emery’s Elements of Medical
Genetics and Genomics
SIXTEENTH EDITION
Peter D. Turnpenny, BSc MB ChB

FRCP FRCPCH FRCPath FHEA
Consultant Clinical Geneticist, Royal Devon and Exeter NHS Foundation
Trust, and Professor in Clinical Genomics, University of Exeter Medical
School
Sian Ellard, OBE BSc PhD FRCPath

Consultant Clinical Scientist, Royal Devon and Exeter NHS Foundation
Trust, and Professor of Genomic Medicine, University of Exeter Medical
School
Ruth Cleaver, BSc MB ChB PGCert

MRCP
Consultant Clinical Geneticist, Royal Devon and Exeter NHS Foundation
Trust
Table of Contents
Title page
Copyright
Preface
Acknowledgments
Dedication
1. The History and Impact of Genetics in Medicine
Abstract
Gregor Mendel and the Laws of Inheritance
DNA as the Basis of Inheritance
The Fruit Fly
The Origins of Medical Genetics
Major New Developments
The Societal Impact of Advances in Genetics

Databases
Further Reading
Section A: The Scientific Basis of Human Genetics
2. The Cellular and Molecular Basis of Inheritance
Abstract
The Cell
DNA: The Hereditary Material
Chromosome Structure
Types of DNA Sequence
Transcription
Translation
The Genetic Code
Regulation of Gene Expression
RNA-Directed DNA Synthesis
Mutations
Mutations and Mutagenesis
Further Reading
3. Chromosomes and Cell Division

Abstract
Human Chromosomes
Methods of Chromosome Analysis
Molecular Cytogenetics
Chromosome Nomenclature
Cell Division
Gametogenesis
Chromosome Abnormalities
Further Reading
4. Finding the Cause of Monogenic Disorders by Identifying Disease

Genes
Position-Independent Identification of Human Disease Genes
Positional Cloning
The Human Genome Project
Identifying the Genetic Etiology of Monogenic Disorders by

Next-Generation Sequencing
Further Reading
5. Laboratory Techniques for Diagnosis of Monogenic Disorders
Abstract
Polymerase Chain Reaction

Application of DNA Sequence Polymorphisms
Nucleic Acid Hybridization Techniques
Mutation Detection
Sequencing-Based Methods
Dosage Analysis
Genome Sequencing as a Clinical Diagnostic Test
Further Reading
6. Patterns of Inheritance
Abstract
Family Studies
Mendelian Inheritance
Multiple Alleles and Complex Traits
Anticipation
Mosaicism
Uniparental Disomy
Genomic Imprinting
Mitochondrial Inheritance
Further Reading
7. Population and Mathematical Genetics

Abstract
Allele Frequencies in Populations
Genetic Polymorphism
Segregation Analysis
Genetic Linkage
Medical and Societal Intervention
Conclusion
Further Reading
8. Risk Calculation
Abstract
Probability Theory
Autosomal Dominant Inheritance
Autosomal Recessive Inheritance
X-Linked Recessive Inheritance
The Use of Linked Markers
Bayes’ Theorem and Prenatal Screening
Empiric Risks
Further Reading
9. Developmental Genetics
Abstract
Fertilization and Gastrulation
Developmental Gene Families
The Pharyngeal Arches
The Role of Cilia in Developmental Abnormalities
The Limb as a Developmental Model
Developmental Genes and Cancer
Positional Effects and Developmental Genes
Hydatidiform Moles
Epigenetics and Development
Sex Determination and Disorders of Sex Development
Twinning
Further Reading
Section B: Genetics in Medicine and Genomic

Medicine
10. Common Disease, Polygenic, and Multifactorial Genetics
Types and Mechanisms of Genetic Susceptibility
Approaches to Demonstrating Genetic Susceptibility to Common

Diseases
Polygenic Inheritance and the Normal Distribution
Multifactorial Inheritance—the Liability/Threshold Model
Identifying Genes That Cause Multifactorial Disorders
Polygenic Risk Scores
Disease Models for Multifactorial Inheritance
Further Reading
11. Screening for Genetic Disease
Abstract
Screening Those at High Risk
Carrier Testing for Autosomal Recessive and X-Linked Disorders
Presymptomatic Diagnosis of Autosomal Dominant Disorders
Ethical Considerations in Carrier Detection and Predictive

Testing
Population Screening
Criteria for a Screening Program
Prenatal and Postnatal Screening
Population Carrier Screening
Genetic Registers
Further Reading
Websites
12. Hemoglobin and the Hemoglobinopathies
Abstract
Structure of Hemoglobin
Developmental Expression of Hemoglobin
Globin Chain Structure
Synthesis and Control of Hemoglobin Expression
Disorders of Hemoglobin
Clinical Variation of the Hemoglobinopathies
Antenatal and Newborn Hemoglobinopathy Screening
Further Reading
Websites
13. Immunogenetics
Abstract
Immunity
Innate Immunity
Specific Acquired Immunity
Inherited Immunodeficiency Disorders
Blood Groups
Further Reading
14. The Genetics of Cancer…and Cancer Genetics
Abstract
Differentiation Between Genetic and Environmental Factors in

Cancer
Oncogenes
Tumor Suppressor Genes
Epigenetics and Cancer
Genetics of Common Cancers
DNA Tumor Profiling, Mutational Signatures, and Tumor

Mutational Burden
Inherited Cancer Syndromes
Genetic Counseling in Familial Cancer
Screening for Familial Cancer
What Treatment Is Appropriate?
Further Reading
15. Pharmacogenomics, Precision Medicine, and the Treatment of

Genetic Disease
Pharmacogenomics
Drug Metabolism
Genetic Variations Revealed by the Effects of Drugs
Precision Medicine
Treatment of Genetic Disease
Therapeutic Applications of Recombinant DNA Technology
Gene Therapy
RNA Modification
Targeted Gene Correction
Stem Cell Therapy
Further Reading
Section C: Clinical Genetics, Counseling, and

Ethics
16. Congenital Abnormalities, Dysmorphic Syndromes, and

Intellectual Disability
Abstract
Incidence
Definition and Classification of Birth Defects
Genetic Causes of Malformations
Environmental Agents (Teratogens)
Malformations of Unknown Cause
Counseling
Intellectual Disability
Further Reading
17. Chromosome Disorders
Abstract
Incidence of Chromosome Abnormalities
Disorders of the Sex Chromosomes
“Classic” Chromosome Deletion Syndromes
Chromosome Microarray/Microarray-Comparative Genomic

Hybridization
Chromosome Disorders and Behavioral Phenotypes
Chromosome Breakage Syndromes
Indications for Chromosome Microarray Analysis
Further Reading
18. Inborn Errors of Metabolism
Abstract
Disorders of Amino Acid and Peptide Metabolism
Disorders of Carbohydrate Metabolism
Disorders of Steroid Metabolism
Disorders of Lipid and Lipoprotein Metabolism
Lysosomal Storage Disorders

Disorders in the Metabolism of Purines, Pyrimidines, and
Nucleotides
Disorders of Porphyrin and Heme Metabolism
Disorders in the Metabolism of Trace Elements and Metals
Peroxisomal Disorders
Disorders of Fatty Acid and Ketone Body Metabolism
Disorders of Energy Metabolism
Prenatal Diagnosis of Inborn Errors of Metabolism
Further Reading
19. Mainstream Monogenic Disorders
Abstract
Neurological Disorders
CADASIL and Early-Onset Dementia
Inherited Peripheral Neuropathies
Motor Neurone Disease
Neurocutaneous Disorders
Muscular Dystrophies
Respiratory Disorders
Inherited Cardiac Conditions
Connective Tissue Disorders

Renal Disorders
Blood Disorders
Further Reading
20. Prenatal Testing and Reproductive Genetics
Abstract
Techniques Used in Prenatal Diagnosis
Antenatal and Prenatal Screening
Indications for Prenatal Testing
Special Problems in Prenatal Diagnosis
Termination of Pregnancy
Preimplantation Genetic Diagnosis
Assisted Conception and Implications for Genetic Disease
Prenatal Treatment
Further Reading
21. Genetic Counseling
Abstract
Definition
Establishing the Diagnosis
Calculating and Presenting the Risk

Discussing the Options
Communication and Support
Genetic Counseling—Directive or Non-directive?
Outcomes in Genetic Counseling
Special Issues in Genetic Counseling
Further Reading
22. Ethical and Legal Issues in Medical Genetics
Abstract
General Principles
Ethical Dilemmas in the Genetics Clinic
Ethical Dilemmas and the Public Interest
Conclusion
Further Reading
Glossary
Appendix: Websites and Clinical Databases
General Genetic Websites
Human Genome Websites
Molecular Genetics Websites

Cytogenetics Websites
Educational Human Genetics Websites
Human Genetics Societies
Clinical Databases
Other Resources
Multiple-Choice Questions
CHAPTER 2: The Cellular and Molecular Basis of Inheritance
CHAPTER 3: Chromosomes and Cell Division
CHAPTER 4: Finding the Cause of Monogenic Disorders by

Identifying Disease Genes
CHAPTER 5: Laboratory Techniques for Diagnosis of

Monogenic Disorders
CHAPTER 6: Patterns of Inheritance
CHAPTER 7: Population and Mathematical Genetics
CHAPTER 8: Risk Calculation
CHAPTER 9: Developmental Genetics
CHAPTER 10: Common Disease, Polygenic, and Multifactorial

Genetics
CHAPTER 11: Screening for Genetic Disease
CHAPTER 12: Hemoglobin and the Hemoglobinopathies
CHAPTER 13: Immunogenetics

CHAPTER 14: The Genetics of Cancer … and Cancer Genetics
CHAPTER 15: Pharmacogenomics, Precision Medicine, and the

CHAPTER 16: Congenital Abnormalities, Dysmorphic

Syndromes, and Learning Disability
CHAPTER 17: Chromosome Disorders
CHAPTER 18: Inborn Errors of Metabolism
CHAPTER 19: Mainstream Monogenic Disorders
CHAPTER 20: Prenatal Testing and Reproductive Genetics
CHAPTER 21: Genetic Counseling
Case-Based Questions

Genetics

Multiple-Choice Answers
CHAPTER 2: The Cellular and Molecular Basis of Inheritance
CHAPTER 3: Chromosomes and Cell Division
CHAPTER 4: Finding the Cause of Monogenic Disorders by

Identifying Disease Genes
CHAPTER 5: Laboratory Techniques for Diagnosis of

Monogenic Disorders

Genetics

CHAPTER 15: Pharmacogenomics, Precision Medicine, and the


Case-Based Answers and Discussion

Genetics


Clinical Scenario Answers and Discussion
Chapter 6
Chapter 8
Chapter 9
Chapter 11
Chapter 12
Chapter 13
Chapter 14
Chapter 16
Chapter 17
Chapter 18
Chapter 19
Chapter 20
Chapter 21
Chapter 22
Index
Copyright
EMERY'S ELEMENTS OF MEDICAL GENETICS AND GENOMICS,

EDITION: 16
ISBN: 978-0-702-079665
Copyright © 2022 by Elsevier, Ltd. All rights reserved.
No part of this publication may be reproduced or transmitted in any

form or by any means, electronic or mechanical, including
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This book and the individual contributions contained in it are

protected under copyright by the Publisher (other than as may be
noted herein).
Notice
Practitioners and researchers must always rely on their own
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Printed in Poland
Last digit is the print number: 9 8 7 6 5 4 3 2 1

Preface
Peter Turnpenny, Sian Ellard and Ruth Cleaver, Exeter, United
Kingdom
“Reading maketh a full man; conference a ready man; and writing an

exact man.”
Francis Bacon (1561–1626)
“To study the phenomena of disease without books is to sail an

uncharted sea, while to study books without patients is not to go to sea
at all.”
William Osler (1849–1919)
In the three years since we last updated Emery’s Elements the

applications of genetic technologies to all medical disciplines have
surged forward. Not only is the rich vein of gene discovery in rare
disease far from exhausted, but our understanding of broader
questions about the nature and function of the human genome have
advanced significantly, and there is far more hope for different forms
of treatment for genetic disease than ever before. The last few years
has seen the dramatic emergence of CRISPR/Cas9 gene editing, not
only as a research tool but also as demonstrating treatment potential;
cancer genomics is helping to elucidate and manage tumors and
malignancy; and non-invasive prenatal testing and diagnosis are
becoming embedded in routine fetal medicine practice. On top of
this, the often complex process of interpreting and classifying DNA
variants is now a well-established discipline, albeit one that is
destined to evolve.
All these developments pose huge challenges for clinical practice
in terms of the responsible application of the technologies to
diagnosis, patient care, and family management. Rolling out the new
technologies in healthcare systems and mainstream medicine varies
hugely worldwide, but universally relevant issues are those of
confidentiality, consent, disclosure, and non-disclosure, all in the
context of legal systems that are at best only beginning to
understand the implications of the vast amounts of personal data
being generated by the “genomics revolution.”
The other universally relevant issues relate to “capacity”—both
the capacity of healthcare systems to develop the infrastructure to
deliver the benefits of genetic knowledge and technologies, and the
capacity to inform and educate healthcare professionals. As such,
our hope is that this new edition will contribute to the much-needed
education and training in this expanding discipline, which has an
impact on all the others. We have sought to bring this edition up to
date with key developments while maintaining the same tried and
tested format. Many chapters have been enriched by case studies
that seek to take the reader to problem-solving clinical scenarios,
which, after all, are real life. As before, therefore, we hope this text
will prove useful to undergraduates and postgraduates alike and
help them swim rather than sink when faced with the depth and
extent of developments in medical genetics and genomics.
Acknowledgments
As always, we feel privileged to be working in an area of healthcare
science and service, and research and development, that continues to
be exciting and captivating as the technologies and knowledge move
forward so inexorably. We work within teams and networks of very
talented colleagues who are similarly inspired and, even though
unaware, contribute to this volume through their knowledge,
professional companionship, and encouragement. We have learned a
vast amount of clinical genetics from our patients and we thank
those who have agreed for their images to be added to this edition.
Particular thanks are due to Dr. Andrew Wood for his assistance
with the updating of Chapters 7 and 10 . We are grateful to Elsevier,
especially Kathleen Nahm, Deborah Poulson, and Alexandra
Mortimer, for their help, guidance, and patience throughout the
journey during 2019–2020.
Dedication
We again dedicate this edition to Alan Emery, a friend, mentor, and

constant source of inspiration and encouragement.
Alan E. H. Emery (c. 1983), Emeritus Professor of Human Genetics &

Honorary Fellow, University of Edinburgh, first established the
Elements of Medical Genetics in 1968.
“The book was first conceived and published by the University of

California Press in 1968 as Heredity, Disease, and Man: Genetics in
Medicine . However, when appointed Professor of Human Genetics at
Edinburgh in 1968, I decided I should prefer the book to be published
by Churchill Livingstone under the title Elements of Medical Genetics
, and made more accessible to UK students with a cheaper paperback
edition. This was all achieved and has retained this format ever since.
The current 16th edition illustrates very clearly how the subject has
advanced so much over the intervening years.”
Alan Emery
1
The History and Impact of Genetics in

Medicine
Abstract
This brief overview of the history of genetics, especially medical genetics, tells the story
of Gregor Mendel and his experiments with peas, followed by the key stages and
stepwise progress through the 20th century, together with the main scientists involved.
Discovery of the structure of DNA, and transcription and translation, led eventually to
the Human Genome Project, completed just over 100 years after the rediscovery of
Mendel’s experiments.
Keywords
Gregor Mendel; fruit fly; DNA; chromosomes; Watson and Crick; Victor McKusick; Fred
Sanger; Human Genome Project; Francis Collins; Craig Venter; John Sulston; Nobel Prize
winners
It’s just a little trick, but there is a long story connected with it which it would take too long to
tell.
Gregor Mendel, in Conversation With C.W. Eichling
It has not escaped our notice that the specific pairing we have postulated immediately suggests a
possible copying mechanism for the genetic material.
Watson & Crick (April 1953)
Presenting historical truth is at least as challenging as the pursuit of scientific truth, and our
view of human endeavors down the ages is heavily biased in favor of winners—those who
have conquered on military, political or, indeed, scientific fields of conflict. The history of
genetics in relation to medicine is one of breathtaking discovery from which patients and
families have benefitted hugely, and we are privileged to be witnessing such developments
at the beginning of what promises to be a dramatic and exciting era. However, success will
be measured by ongoing progress in translating discoveries into successful treatment and
prevention of disease, while at the same time causing no harm—for the Hippocratic
principle of primum non nocere applies to this field as any other. It is always inspiring to look
back with awe at what our forebears achieved with scarce resources and sheer
determination, sometimes aided by serendipity, to lay the foundations of this dynamic
science. This perspective can be compared with driving a car: without your eyes on the road
ahead, you will crash and make no progress; however, it is also essential to check the rear
and side mirrors regularly.
Gregor Mendel and the Laws of Inheritance
Early Beginnings
Developments in genetics during the 20th century have been truly spectacular. In 1900,
Mendel’s principles were awaiting rediscovery, chromosomes were barely visible, and the
science of molecular genetics did not exist. As we write this in 2020, the published sequence
of the entire human genome already feels like a piece of history, we are almost a decade into
a ‘gold rush’ era of disease gene discovery, and genomic science is revealing more about
humanity (and the entire living world) than most of us ever imagined.
Genetics is relevant and important to almost every medical discipline. Recent discoveries
impinge not just on rare genetic diseases and syndromes but increasingly on the common
disorders of adult life that may be predisposed by genetic variation, such as cardiovascular
disease, cancer, psychiatric illness, and behavior, not to mention influences on obesity,
athletic performance, musical ability, longevity, and a host of physiological variations and
tolerances. Clearly, a thorough grounding in genetics and genomics should be a
fundamental part of any undergraduate medical curriculum.
We start with an overview of some of the most notable milestones in the history of genetics
and medical genetics, followed by a review of the overall impact of genetic factors in causing
disease. Finally, we mention some new developments of major importance.
It is not known precisely when Homo sapiens first appeared on this planet. For a
considerable time, estimates based on the finding of fossilized human bones in Ethiopia
suggested man was roaming East Africa approximately 200,000 years ago. The finding of
skull bones in Morocco, however, suggests the possibility of man’s presence on Earth
stretching back 300,000 to 350,000 years. It is reasonable to suppose that our early ancestors
were as curious as ourselves about matters of inheritance and, just as today, they would have
experienced the birth of babies with all manner of physical defects. Engravings in Chaldea in
Babylonia (modern-day Iraq) dating back at least 6000 years show pedigrees documenting
the transmission of certain characteristics of the horse’s mane. However, any early attempts
to unravel the mysteries of genetics were severely hampered by a total lack of knowledge
and understanding of basic processes such as conception and reproduction, which was not
resolved to the satisfaction of modern science until 1875.
Early Greek philosophers and physicians such as Aristotle and Hippocrates concluded,
not without a little prejudice, that important human characteristics were determined by
semen, using menstrual blood as a culture medium and the uterus as an incubator. Semen
was thought to be produced by the whole body; hence, bald-headed fathers would beget
bald-headed sons. These ideas prevailed until the 17th century, when Dutch scientists such
as Leeuwenhoek and de Graaf recognized the existence of sperm and ova, thus explaining
how the female could also transmit characteristics to her offspring.
The blossoming scientific revolution of the 18th and 19th centuries saw a revival of interest
in heredity by scientists and physicians, among whom two names stand out. Pierre de
Maupertuis, a French naturalist, studied hereditary traits such as extra digits (polydactyly)
and lack of pigmentation (albinism) and showed from pedigree studies that these two
conditions were inherited in different ways. Joseph Adams (1756–1818), a British doctor, also
recognized that different mechanisms of inheritance existed and published A Treatise on the
Supposed Hereditary Properties of Diseases , which was intended as a basis for genetic
counseling. Also worthy of mention is the English physician Edward Meryon (1809–1880),
who in 1851 was the first to provide a systematic clinicopathological study of three boys with
the muscular disorder later eponymously attributed to the Frenchman Guillaume Duchenne
(1806–1875), who described a larger series in 1868.
The modern scientific era really begins with the work of the Austrian monk Gregor
Mendel (1822–1884; Fig. 1.1 ) who, in 1865, presented the results of his breeding experiments
on garden peas to the Natural History Society of Brünn in Bohemia (now Brno in the Czech
Republic). Shortly after, Mendel’s observations were published in the Transactions of the
Society , where they remained largely unnoticed until 1900, some 16 years after his death,
when their importance was first recognized. In essence, Mendel’s work can be considered as
the discovery of genes and how they are inherited. The term gene was first coined in 1909 by
a Danish botanist, Johannsen, and was derived from the term “pangen,” introduced by De
Vries. This term was itself a derivative of the word “pangenesis,” coined by Darwin in 1868.
In recognition of Mendel’s foundational work, the term mendelian is now part of scientific
vocabulary, applied both to the different patterns of inheritance and to disorders found to be
the result of defects in a single gene.
FIG. 1.1 Gregor Mendel. Reproduced with permission from BMJ Books.
In his breeding experiments, Mendel studied contrasting characters in the garden pea,
using for each experiment varieties that differed in only one characteristic. For example, he
noted that when strains bred for a feature such as tallness were crossed with plants bred to
be short, all of the offspring in the first filial, or F1, generation were tall. If plants in this F1
generation were interbred, this led to both tall and short plants in a ratio of 3:1 (Fig. 1.2 ).
Characteristics that were manifest in the F1 hybrids were referred to as dominant , whereas
those that reappeared in the F2 generation were described as being recessive . On reanalysis
it has been suggested that Mendel’s results were “too good to be true” in that the segregation
ratios he derived were suspiciously closer to the value of 3:1 than the laws of statistics would
predict. One possible explanation is that he may have published only those results that best
agreed with his preconceived single-gene hypothesis. Whatever the case, events have shown
that Mendel’s interpretation of his results was entirely correct.
FIG. 1.2 An illustration of one of Mendel’s breeding experiments and how he correctly
interpreted the results.
Mendel’s proposal was that the plant characteristics being studied were each controlled by
a pair of factors, one of which was inherited from each parent. The pure-bred plants with
two identical genes used in the initial cross would now be referred to as homozygous . The
hybrid F1 plants, each of which has one gene for tallness and one for shortness, would be
referred to as heterozygous . The genes responsible for these contrasting characteristics are
referred to as allelomorphs , or alleles for short.
An alternative method for determining genotypes in offspring involves the construction of
what is known as a Punnett square (Fig. 1.3 ). This is used further in Chapter 7 (Fig. 7.1 )
when considering how genes segregate in large populations, although in reality is seldom
referred to nowadays.
FIG. 1.3 A Punnett square showing the different ways in which genes can segregate and
combine in the second filial cross from Fig. 1.2 . Construction of a Punnett square
provides a simple method for showing the possible gamete combinations in different
matings.
On the basis of Mendel’s plant experiments, three main principles were established,
known as the laws of uniformity, segregation, and independent assortment.
The Law of Uniformity

The law of uniformity refers to the fact that, when two homozygotes with different alleles
are crossed, all of the offspring in the F1 generation are identical and heterozygous. In other
words, the characteristics do not blend, as had been believed previously, and can reappear in
later generations.
The Law of Segregation

The law of segregation refers to the observation that each person possesses two genes for a
particular characteristic, only one of which can be transmitted at any one time. Rare
exceptions to this rule can occur when two allelic genes fail to separate because of
chromosome nondisjunction at the first meiotic division (p. 32).
The Law of Independent Assortment
The law of independent assortment refers to the fact that members of different gene pairs
segregate to offspring independently of one another. In reality, this is not always true. Genes
that are close together on the same chromosome tend to be inherited together because they
are “linked” (p. 90). There are a number of other ways by which the laws of mendelian
inheritance are breached (see Chapter 6 ), but overall, they remain foundational to our
understanding of the science.
The Chromosomal Basis of Inheritance

As interest in mendelian inheritance grew, there was much speculation as to how it actually
occurred. At that time it was also known that each cell contains a nucleus within which there
are several threadlike structures known as chromosomes , so called because of their affinity
for certain stains (chroma = color, soma =body). Chromosomes had been observed since the
second half of the 19th century after development of cytologic staining techniques. Human
mitotic figures were observed from the late 1880s, and it was in 1902 that Walter Sutton, an
American medical student, and Theodour Boveri, a German biologist, independently
proposed that chromosomes could be the bearers of heredity (Fig. 1.4 ). Subsequently,
Thomas Hunt Morgan transformed Sutton’s chromosome theory into the theory of the gene
(1917), and Alfons Janssens observed the formation of chiasmata between homologous
chromosomes at meiosis. During the late 1920s and 1930s, Cyril Darlington helped to clarify
chromosome mechanics by the use of tulips collected on expeditions to Persia. It was during
the 1920s that the term genome entered the scientific vocabulary, being the fusion of genom
(German for “gene”) and ome from “chromosome.”
FIG. 1.4 Chromosomes dividing into two daughter cells at different stages of cell division.
(A) Metaphase; (B) anaphase; (C) telophase. The behavior of chromosomes in cell
division (mitosis) is described at length in Chapter 3 . Photographs courtesy Dr. K. Ocraft, City
Hospital, Nottingham.
When the connection between mendelian inheritance and chromosomes was first made,
the normal chromosome number in humans was thought to be 48, although various papers
had come up with a range of figures. Key to the number 48 was a paper in 1921 from
Theophilus Painter, an American cytologist who had been a student of Boveri. In fact, Painter
had some preparations clearly showing 46 chromosomes, even though he finally settled on
48. The discrepancies were probably from the poor quality of the material at that time; even
into the early 1950s cytologists were counting 48 chromosomes. It was not until 1956 that the
correct number of 46 was established by Tjio and Levan, 3 years after the correct structure of
DNA had been proposed. Within a few years, it was shown that some disorders in humans
could be caused by loss or gain of a whole chromosome, as well as by an abnormality in a
single gene. Chromosome disorders are discussed at length in Chapter 17 . Some
chromosome aberrations, such as translocations, can run in families (p. 37), and are
sometimes said to be segregating in a mendelian fashion.
DNA as the Basis of Inheritance

Although James Watson and Francis Crick are justifiably credited with discovering the
structure of DNA in 1953, they were attracted to working on it only because of its key role as
the genetic material, as established in the 1940s. Formerly, many believed that hereditary
characteristics were transmitted by proteins, until it was appreciated that their molecular
structure was far too cumbersome. Nucleic acids were actually discovered in 1849. In 1928,
Fred Griffith, working on two strains of Streptococcus , realized that characteristics of one
strain could be conferred on the other by something that he called the transforming
principle . In 1944, at the Rockefeller Institute in New York, Oswald Avery, Maclyn McCarty
and Colin MacLeod identified DNA as the genetic material while working on Streptococcus
pneumoniae . Even then, many in the scientific community were skeptical; DNA was only a
simple molecule with lots of repetition of four nucleic acids—very boring! The genius of
Watson and Crick, at Cambridge, was to hit on a structure for DNA, the elegant double helix
that would explain the very essence of biological reproduction. Crucial to their discovery
were the x-ray crystallography images captured by the often-overlooked graduate technician
Raymond Gosling, working under the supervision of Maurice Wilkins and Rosalind Franklin
in John Randall’s laboratory at King’s College, London.
This was merely the beginning, for it was necessary to discover the process whereby DNA,
in discrete units called genes, issues instructions for the precise assembly of proteins, the
building blocks of tissues. The sequence of bases in DNA, and the sequence of amino acids in
protein, the genetic code , was unraveled in some elegant biochemical experiments in the
1960s, and it became possible to predict the base change in DNA that led to the amino-acid
change in the protein. Further experiments involving Francis Crick, Paul Zamecnik, and
Mahlon Hoagland identified the molecule transfer RNA (tRNA) (p. 16), which directs genetic
instructions via amino acids to intracellular ribosomes, where protein chains are produced.
Confirmation of these discoveries came with DNA-sequencing methods and the advent of
recombinant DNA techniques. Interestingly, however, the first genetic trait to be
characterized at the molecular level had already been identified in 1957 by laborious
sequencing of the purified proteins. This was sickle-cell anemia, in which the mutation
affects the amino-acid sequence of the blood protein hemoglobin.
The Fruit Fly

It is worth a brief diversion to consider the merits of an unlikely creature that has proved to
be of immense value in genetic research. The fruit fly, Drosophila , possesses several distinct
advantages for the study of genetics:
1. It can be bred easily in a laboratory.

2. It reproduces rapidly and prolifically at a rate of 20 to 25 generations per annum.
3. It has a number of easily recognized characteristics, such as curly wings and a yellow
body , which follow mendelian inheritance.
4. Drosophila melanogaster , the species studied most frequently, has only four pairs of
chromosomes, each with a distinct appearance.
5. The chromosomes in the salivary glands of Drosophila larvae are among the largest
known in nature, being at least 100 times bigger than those in other body cells.
Thus fruit flies have been used extensively in early breeding experiments, contributing
enormously to developmental biology, where knowledge of gene homology throughout the
animal kingdom has enabled scientists to identify families of genes that are important in
human embryogenesis (see Chapter 9 ). Sequencing of the 180 million base pairs of the
Drosophila melanogaster genome was completed in late 1999.
The Origins of Medical Genetics

In addition to the previously mentioned Pierre de Maupertuis and Joseph Adams, whose
curiosity was aroused by polydactyly and albinism, there were other pioneers. John Dalton,
of atomic theory fame, observed that some conditions, notably color blindness and
hemophilia, show what is now referred to as sex- or X-linked inheritance—color blindness is
still occasionally referred to as daltonism .
In 1900, Mendel’s work resurfaced. His papers were quoted almost simultaneously by
three European botanists—De Vries (Holland), Correns (Germany), and Von Tschermak
(Austria)—and this marked the real beginning of medical genetics, providing an enormous
impetus for the study of inherited disease. Credit for the first recognition of a single-gene
trait is shared by William Bateson and Archibald Garrod, who in 1902 proposed that
alkaptonuria was a rare recessive disorder. In this relatively benign condition, urine turns
dark on standing or on exposure to alkali because of the patient’s inability to metabolize
homogentisic acid (p. 274). Young children show skin discoloration in the napkin (diaper)
area, and affected adults may develop arthritis in large joints. Realising that this was an
inherited disorder involving a chemical process, Garrod coined the term inborn error of
metabolism in 1908, although his work was largely ignored until the mid-20th century when
electrophoresis and chromatography revolutionized biochemistry. Hundreds of such
disorders have now been identified, giving rise to the field of biochemical genetics (see
Chapter 18 ).
During the course of the 20th century, it gradually became clear that hereditary factors
were implicated in many conditions and that different genetic mechanisms were involved.
Traditionally, hereditary conditions have been considered under the headings of single-gene
, chromosomal , and multifactorial . Increasingly, it is becoming clear that the interplay of
different genes (polygenic inheritance ) is important in disease, and that a further category
—acquired somatic genetic disease —should be included.
Single-Gene Disorders
In addition to alkaptonuria, Garrod suggested that albinism and cystinuria could also be
recessive. Other examples followed, leading to an explosion in knowledge and disease
delineation. By 1966, almost 1500 single-gene disorders or traits had been identified,
prompting the publication by an American physician, Victor McKusick (Fig. 1.5 ), of a
catalog of all known single-gene conditions. By 1998, when the 12th edition of the catalog
was published, it contained more than 8500 entries. The growth of “McKusick’s Catalog”
was exponential, and it became the electronic Online Mendelian Inheritance in Man (OMIM)
(see Appendix) in 1987. By late 2019, OMIM contained more than 25,000 entries, more than
5500 phenotypes with a known molecular basis, and more than 16,000 gene descriptions.
FIG. 1.5 Victor McKusick in 1994, whose studies and catalogues have been so important
to medical genetics.
Chromosome Abnormalities
Improved techniques for studying chromosomes led to the demonstration in 1959 that the
presence of an additional number 21 chromosome (trisomy 21) results in Down syndrome.
Other similar discoveries followed rapidly—Klinefelter and Turner syndromes—also in 1959.
Chromosome-banding techniques were developed by 1970 (p. 28), enabling reliable
identification of individual chromosomes and confirmation that loss or gain of even a very
small segment of a chromosome can have devastating effects on human development (see
Chapter 17 ).
Later it was shown that several rare conditions featuring learning difficulties and
abnormal physical features are caused by loss of such a tiny amount of chromosome material
that no abnormality can be detected using even the most high-powered light microscope.
These conditions are referred to as microdeletion syndromes (see Chapter 17 ) and can be
diagnosed using a technique known as fluorescence in situ hybridization (FISH) , which
combines conventional chromosome analysis (cytogenetics ) with newer DNA diagnostic
technology (molecular genetics ) (see Chapter 5 ). Today, the technique of microarray–
comparative genomic hybridization has revolutionized clinical investigation through the
detection of subtle genomic imbalances, that is, microdeletions and microduplications (p.
259), and, where available, is the first-line test of choice.
Multifactorial Disorders
Francis Galton, a cousin of Charles Darwin, had a long-standing interest in human
characteristics such as stature, physique, and intelligence. Much of his research was based on
the study of identical twins, in whom it was realized that differences in these parameters
must be largely the result of environmental influences. Galton introduced to genetics the
concept of the regression coefficient as a means of estimating the degree of resemblance
between various relatives. This concept was later extended to incorporate Mendel’s
discovery of genes, to try to explain how parameters such as height and skin color could be
determined by the interaction of many genes, each exerting a small additive effect. This is in
contrast to single-gene characteristics, in which the action of one gene is exerted largely
independently, in a non-additive fashion.
The model of quantitative inheritance is now widely accepted and has been adapted to
explain the pattern of inheritance observed for many relatively common conditions (see
Chapter 10 ). These include congenital malformations such as cleft lip and palate, and late-
onset conditions such as hypertension, diabetes mellitus, and Alzheimer disease. In this
view, genes at several loci interact to generate a susceptibility to the effects of adverse
environmental trigger factors. Recent research has confirmed that many genes are involved
in most of these adult-onset disorders, although progress in identifying specific
susceptibility loci has been slow. It has also emerged that in some conditions, such as type 1
diabetes mellitus, different genes can exert major or minor effects in determining
susceptibility (p. 136). Overall, multifactorial or polygenic conditions are now known to
make a major contribution to chronic illness in adult life (see Chapter 10 ).
Acquired Somatic Genetic Disease

Not all genetic errors are present from conception. Many billions of cell divisions (mitoses )
occur in the course of an average human lifetime. During each mitosis there is an
opportunity both for single-gene mutations to occur, because of DNA copy errors, and for
numerical chromosome abnormalities to arise as a result of errors in chromosome
separation. Accumulating somatic mutations and chromosome abnormalities are now
known to play a major role in causing cancer (see Chapter 14 ), and they probably also
explain the rising incidence with age of many other serious illnesses, as well as the aging
process itself. It is therefore necessary to appreciate that not all disease with a genetic basis is
hereditary.
Before considering the impact of hereditary disease, it is helpful to introduce a few
definitions.
Incidence
Incidence refers to the rate at which new cases occur. Thus, if the birth incidence of a
particular condition equals 1 in 1000, then on average 1 in every 1000 newborn infants is
affected.
Prevalence
This refers to the proportion of a population affected at any one time . The prevalence of a
genetic disease is usually less than its birth incidence, either because life expectancy is
reduced or because the condition shows a delayed age of onset.
Frequency
Frequency is a general term that lacks scientific specificity, although the word is often taken
as being synonymous with incidence when calculating gene “frequencies” (see Chapter 7 ).
Congenital
Congenital means that a condition is present at birth . Thus cleft palate represents an example
of a congenital malformation . Not all genetic disorders are congenital in terms of age of
onset (e.g., Huntington disease), nor are all congenital abnormalities genetic in origin (e.g.,
fetal disruptions, as discussed in Chapter 16 ).
DNA Sequencing
The ability to search for mutations in human DNA to identify the causes of genetic disease
clearly depended on being able to sequence DNA, which initially was very laborious. The
first really practical method was developed by Walter Gilbert, with sequencing based on a
cleavage at specific bases after chemical modification of DNA. But it was Frederick Sanger’s
(Fig. 1.6 ) ingenious technique (1975), based on dideoxynucleoside chain termination, that
proved efficient, reliable, and popular, not least because of low radioactivity. Both men were
awarded the Nobel Prize in 1980 for this achievement, which was Sanger’s second—he was
awarded the Chemistry Prize in 1958 for determining the amino acid sequence of insulin (he
remains the only British scientist to have won two Nobel Prizes). Sanger sequencing
remains central to human molecular genetics, and the term is as prominent in the language
of genetics as mendelian inheritance and McKusick’s Catalog.
FIG. 1.6 Frederick Sanger, inventor of the most widely used method of DNA sequencing,
and a double Nobel Laureate. With permission from Victor A McKusick: Mendelian Inheritance in
Man , 12th ed. 1998 Johns Hopkins University Press.
Sequencing techniques formed the basis for embarking on the Human Genome Project
(HGP) in the early 1990s. The first genome of a free-living organism to be sequenced was that
of Haemophilus influenzae in 1995 by Celera Genomics under Craig Venter. Venter’s
laboratory, together with the HGP under Francis Collins, jointly published the first draft of
the human genome in 2001 (Fig. 1.7 ).
FIG. 1.7 Francis Collins (left ) and Craig Venter (right ), who published the first draft of the
human genome in Science in 2001 (center).
The Impact of Genetic Disease

During the 20th century, huge changes in the patterns of disease have occurred, largely
through improvements in public health, programs of vaccination, improved housing and
sanitation, and therapeutics. This has resulted in increasing recognition of the role of genetic
factors at all ages. For some parameters, such as perinatal mortality, the actual numbers of
cases with exclusively genetic causes have probably remained constant, but their relative
contribution to overall figures has increased as other causes, such as infection, have declined.
For other conditions, such as the chronic diseases of adult life, the overall contribution of
genetics has almost certainly increased as greater life expectancy has provided more
opportunity for adverse genetic and environmental interaction to manifest itself, for example
in Alzheimer disease, macular degeneration, cardiomyopathy, diabetes mellitus, and obesity.
Consider the impact of genetic factors in disease at different ages from the following
observations.
Spontaneous Miscarriages
A chromosome abnormality is present in 40% to 50% of all recognized first-trimester
pregnancy loss. At least one in four pregnancies results in spontaneous miscarriage, so at
least 10% of all recognized conceptions are chromosomally abnormal (p. 250). This value
would be much higher if unrecognized pregnancies could also be included, and it is likely
that a significant proportion of miscarriages with normal chromosomes do in fact have
catastrophic submicroscopic or DNA sequence genetic errors.
Newborn Infants
Up to 3% of neonates have at least one major congenital abnormality, of which at least 50%
are caused exclusively or partially by genetic factors (see Chapter 16 ), with the incidences of
chromosome abnormalities and single-gene disorders in neonates being roughly 1 in 200 and
1 in 100, respectively.
Childhood
By school age, roughly 12% to 14% of children show problems of developmental origin.
Genetic disorders account for at least 50% of all childhood visual impairment, at least 50% of
all childhood hearing loss, and at least 50% of all cases of severe intellectual disability. In
developed countries, genetic disorders and congenital malformations together account for
30% of all childhood hospital admissions and 40% to 50% of all childhood deaths.
Adult Life
Approximately 1% of all malignancies are primarily caused by single-gene inheritance, and
between 5% and 10% of common cancers such as those of the breast, colon, and ovary have a
strong hereditary component. By the age of 25 years, 5% of the population will have a
disorder in which genetic factors play an important role. Taking into account the genetic
contribution to cancer and cardiovascular diseases, such as coronary artery occlusion and
hypertension, it has been estimated that more than 50% of the older adult population in
developed countries will have a genetically determined medical problem.
Major New Developments

The study of genetics and its role in causing human disease is now widely acknowledged as
being among the most exciting and influential areas of medical research. Since 1962 when
Francis Crick, James Watson, and Maurice Wilkins gained acclaim for their elucidation of the
structure of DNA, the Nobel Prize for Medicine and/or Physiology has been won on 28
occasions and the Chemistry Prize on 7 occasions by scientists working in human and
molecular genetics or related fields (Table 1.1 ). These pioneering studies have spawned a
thriving molecular technology industry with applications as diverse as the development of
genetically modified disease-resistant crops, the use of genetically engineered animals to
produce therapeutic drugs, and the possible introduction of DNA-based vaccines for
conditions such as malaria, not to mention the growing availability of affordable direct-to-
consumer testing for disease susceptibility. Pharmaceutical companies are investing heavily
in the DNA-based pharmacogenomics —drug therapy tailored to personal genetic makeup
(see Chapter 15 ).
Table 1.1 Genetic discoveries that have led to the award of the Nobel Prize for
Medicine or Physiology and/or Chemistry, 1962–2012
Prize
Year Discovery Year Prize Winners Discovery
Winners
1962 Francis The molecular 1999 Günter Blobel Protein transport
Crick structure of DNA signaling
James
Watson
Maurice
Wilkins
1965 François Genetic regulation 2000 Arvid Carlsson Signal transduction in
Jacob Paul Greengard the nervous system
Jacques Eric Kandel
Monod
André
Lwoff
1966 Peyton Oncogenic viruses 2001 Leland Hartwell Regulators of the cell
Rous Timothy Hunt cycle
Paul Nurse
1968 Robert Deciphering of the 2002 Sydney Brenner Genetic regulation in
Holley genetic code Robert Horvitz development and
Gobind John Sulston programmed cell
Khorana death (apoptosis)
Marshall
Nireberg
1972 Christian B. Ribonuclease 2006 Andrew Fire RNA interference
Anfisen Craig Mello (Medicine)
Stanford
Moore
William H.
Stein
1975 David Interaction between Roger D. Kornberg Eukaryotic
Baltimore tumour viruses and transcription
Renato nuclear DNA (Chemistry)
Dulbecco
Howard
Temin
1978 Werner Restriction 2007 Mario Capecchi Gene modification by
Arber endonucleases Martin Evans the use of embryonic
Daniel Oliver Smithies stem cells
Nathans
Hamilton
Smith
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CHAPTER XVI.
MRS. MASON'S OPINIONS.
TEN days had gone by, and Mrs. Stuart had her foot up
still on a chair, swathed in bandages. She was allowed to
hop downstairs once a day, with Archie's aid, but not to
stand yet.
Mrs. Stuart was by no means a patient invalid. It

seemed to her very hard indeed that she of all people
should be laid aside, very hard that she should have to
suffer pain, very hard that she should be indebted to
neighbours—above all, to the Dunns—for help. Other
people, of course, had their troubles, and must expect to
have them, as a matter of course, but why Mrs. Stuart
should have them was quite another question. She could
only count it "very hard." As for being patient and cheerful
under her trial, who could be so unreasonable as to expect
it of her!
Many a time Mrs. Stuart had heard in Church those

familiar words—"Whom the Lord loveth He chasteneth, and
scourgeth every son whom He receiveth." But it may very
much be doubted how far Mrs. Stuart really listened to the
reading of the Bible in Church; and it may be doubted still
more how far she really understood what she heard. Her
feeling towards God was in no sense the feeling of a child
towards a Father. She had no love for Him, and she knew
nothing of the deep Divine love which will rather send pain
and sorrow than suffer the wilful child to wander on in
courses of evil. Sometimes nothing less than great trouble
will bring the wayward soul to Christ.
Mrs. Stuart saw nothing of this, however. The love of
God was far away from her thoughts. She only considered
herself a much injured woman; and she felt sure that
nobody had ever had so much to bear as herself; while she
was vexed with the Dunns for their persistent kindness, and
yet more vexed with Archie for his growing friendship with
them.
Undoubtedly Mrs. Stuart was greatly indebted to the

Dunns. Mrs. Dunn had spent whole nights in the cottage,
and had taken turns with Nancy to run in and out by day.
Mrs. Dunn was looking quite fagged with all she had
undertaken, and Mrs. Stuart ought to have been extremely
grateful. But she was not grateful at all. She was only
annoyed with herself and the Dunns and Archie and
everybody—a most uncomfortable state of mind to be in.
Mrs. Mason, living opposite Woodbine Cottage, was

usually a very convenient person in time of illness. Being a
widow, with only one married daughter, and having
consequently no home-ties; being, moreover, a motherly
sort of body, with useful instincts, she liked to be called in
to help where help might be needed.
The very day, however, before Mrs. Stuart's accident,

Mrs. Mason was summoned to her married daughter by
telegram. Had it not been for this, she would as a matter of
course have shared with Mrs. Dunn the care of Mrs. Stuart.
After ten days, Mrs. Mason came home, leaving her

daughter recovered from a sharp little illness; and then she
was speedily made acquainted with events which had taken
place during her absence. The next thing that happened
was Mrs. Mason's appearance in Mrs. Stuart's kitchen, with
a half-knitted stocking, a short time before tea.
"Now, you didn't expect to see me, did you?" she asked,
in her round comfortable voice, which exactly suited her
stout and motherly figure. "But I'm come. I told Mrs. Dunn
I'd do it for her—get you your tea, I mean, and wash up.
Dear! I never thought I should find you like this—that I
didn't. There's never no knowing what'll happen next, and
that's a fact. Well—I'll put your kettle on to boil, first thing.
And so Mrs. Dunn's been looking after you all this while.
Just like her! She's got enough to do at home, though, and
I told her I'd come instead. But to think now of your
stealing a march on me, like that! To think of it!"
Mrs. Stuart failed to understand Mrs. Mason's meaning,

and she intimated the same in gloomy tones.
"What I mean! Why, I mean the Dunns, to be sure,"

said Mrs. Mason briskly. "The nicest family that's come to
Littleburgh for a year past. And as soon as ever I'm out of
the way, you've gone and stolen a march on me, and got as
intimate with 'em! No, I didn't expect it of you, I did not,
Mrs. Stuart!"
Mrs. Mason shook her head vigorously. But Mrs. Stuart

was in no humour for joking, and she intimated that fact
also in yet gloomier accents.
"A joke don't do nobody any harm," said Mrs. Mason,

"provided it's harmless. There's jokes and jokes. There's a
sort that's better avoided. But I'd sooner laugh than cry
over a worry any day. You wouldn't be half such a skinny
scarecrow of a woman, if you was to laugh oftener, and
glower seldomer over your frets. That you wouldn't."
Mrs. Mason was too useful a woman to be quarrelled

with for her plain-spokenness; but certainly, her remarks
did not lessen Mrs. Stuart's moodiness.
"That Nancy Dunn is the best and prettiest girl ever I
see!" remarked Mrs. Mason.
Mrs. Stuart grunted.
"Isn't she now?" asked Mrs. Mason.
"I've got nothing to say against her," declared Mrs.

Stuart, with the air of one suppressing truths.
"Shouldn't think you had, nor anybody else neither.

Don't Archie like her?" demanded Mrs. Mason, rising to get
the teapot.
No answer to this.
"Well, if I was you, I'd encourage it in every way I

could. That's what I'd do," said Mrs. Mason emphatically,
rinsing out the teapot. "She's a pretty girl, and a good girl,
and she'll make a good wife to somebody some day. That
girl's had a training that it isn't many girls get now-a-days.
She'll clean up a room in next to no time; and she's first-
rate at washing and ironing; and she's a good cook in a
plain way. Yes; Mrs. Dunn's a wise mother. She's trained up
Nancy to follow in her footsteps. And that isn't all neither;
for she's trained up Nannie to live for God, and to think of
the world that's to come, and not only of just how to eat
and drink and get along."
Mrs. Stuart found something to say at last. She opened

her lips with a resolute, "I don't hold with being so mighty
religious."
"No?" said Mrs. Mason. "How much religion do you hold

with?"
"I'm not one as likes shams," said Mrs. Stuart.

"Nor me neither," responded Mrs. Mason. "But there's
no sort of shamming about the Dunns. It's real honest
hearty living to God, and trying to do His will. I can tell you,
Mrs. Stuart, I've learnt a thing or two from them already,
though it's so short a time they've been here; and I'm not
ashamed to own it. And I hope I'll be the better for knowing
them. And as for being 'mighty religious'—if fighting against
wrong, and struggling to do right, and helping those that's
in need, and serving God in every bit of daily life—if that's
what you mean by 'mighty religious,' why, I wish there was
a lot more of it in the world. I do, and that's a fact. For it
would be a deal better sort of world."
"I don't like talk," said Mrs. Stuart.
"Nor me neither," assented Mrs. Mason again. "That's to

say, I don't like talk that's not carried out in action. Folks
must talk. It's natural to human nature. And folks 'll talk
mostly of what comes nearest to 'em. There's some cares
most for eating, and they'll talk of their eating. And there's
some cares most for politics, and they'll talk of politics. And
there's some cares most for their children, and they'll talk
of their children. And, dear me, there's some cares only for
themselves, and won't they talk a lot about themselves?
But that's all natural. It's all human nature.
"And when a man cares for religion, and loves God from
his heart—why, don't it stand to reason that he'll speak
sometimes of the things he cares for most? That's not
shamming, Mrs. Stuart. It's shamming if a man talks
religion, and don't let it come into his daily life. And it's
shamming when folks keep all their religion for Sunday, and
make believe to pray to Him in Church, and then never
think of Him at all from Monday morning till Saturday night.
That's shamming, as much as you like. But as for talk—why,
talk's natural—in moderation. And you'll never find Mrs.
Dunn talk too much. No, never."
Perhaps the same could not be said of good-humoured

voluble Mrs. Mason. She brought the teapot from the hob,
and set it on the table.
"There—that's all right," she said, in a different tone,

possibly feeling that she had said enough on one subject.
"I've had my tea before coming, so I don't want any; but I'll
stay to wash up. I've got my knitting. And by-and-by I'll
come in again. So Archie's out with friends to-night? Well,
he's a likely young fellow—sure to make friends. I hope
they'll all be as good friends as the Dunns. And you've had
Mr. Wilmot here, paying you visits? Kind sort of man, isn't
he?—and as good! No sort of sham there neither! But he
don't look as he should. What is come over him?"
Mrs. Stuart did not know that anything had.
"He's not himself," said Mrs. Mason. "Lost all his colour,
and don't walk with half his spirit. He'd ought to take care
of himself. Good people ain't too common in this world. It's
my belief, he works a deal too hard. Yes—there's something
wrong. I'm sure I don't know what."
CHAPTER XVII.
PEOPLE AND THINGS.
MANY weeks had gone by, and Mrs. Stuart was pretty
well recovered from her accident. She limped a little, it is
true, and was unable to walk any distance; still, on the
whole, she might be counted convalescent.
Archie had been a good son to her through those

weeks. Nobody could question it. Even Mrs. Stuart did not
deny the fact.
It may seem an odd thing to say, considering the

mother's love for her boy, but, undoubtedly, Mrs. Stuart had
not quite forgiven Archie for being in some sort the cause of
her accident. If Archie had not left her all those hours alone,
she would not have gone searching after him in the brick-
fields. Mrs. Stuart was wont to dilate on this very self-
evident truth; while she forgot to mention the equally self-
evident truth that if she had not given way to ill-temper,
Archie would not have left her. Archie had been to blame,
no question as to that. But Mrs. Stuart herself could
scarcely be reckoned blameless.
And Mrs. Stuart was not of a generous nature. When

her foot was at its worst, she seemed to find a particular
gratification in reminding Archie that it was "all his doing." A
generous nature would have shrunk from allowing Archie to
see how much she suffered, for fear he should blame
himself too far.
Archie bore his mother's reproaches patiently—so

patiently that Mrs. Dunn often wondered, looking on. For
she knew the young fellow to be of a quick and hasty
disposition; and she did not know yet how a strong new
principle was taking root in Archie Stuart's heart, and
beginning already to show in his life.
One result of Mrs. Stuart's accident was a great
pleasure to Archie. His friendship with the Dunns was no
longer a thing forbidden. Mrs. Stuart hardly could prevent
it, after Susan Dunn's kind care of her. But she still did not
care to see more of the Dunns than was necessary; and if
Archie spoke of Nannie, Mrs. Stuart was sure to spend some
sulky hours in consequence.
It was very difficult for him to abstain from speaking of

Nancy; for by this time he thought of her more than of any
other human being. Nancy's pretty face was before his
mind's eye perpetually. When he looked forward to the
future, it was always a future with Nancy Dunn—not always
as Nancy Dunn. But he had not spoken out to anybody yet
of his wish. He wanted his mother to learn to like Nancy
first.
"Why don't you come to see my mother oftener?" he

asked one day, and Nancy answered frankly—
"I don't think she cares to have me come. She always

seems so busy."
This was true, and Archie could not deny it. The thought
troubled him much, but he tried to wait quietly. Meanwhile
he was very often in and out at Woodbine Cottage; and the
more he saw of the Dunns, the more thoroughly he
respected and wished to be like them.
For there was nothing half-hearted, nothing

inconsistent, about these Dunns. They were not great
talkers, but neither did they hide their religion. In Richard
Dunn's life, the leading aim was to serve that dear Lord and
Master who had died for him on the Cross, and this aim was
followed out with steady persistence. If need arose, he
could speak of his heart's desire; if required to do aught
which he believed to be contrary to God's will, he could
refuse quietly, and without bluster. Lesser aims were
included in the one great aim. He was a steady workman;
he sought to keep his wife and children in comfort; he loved
to have a tasteful and well-furnished little house. These
things were right. It was well that he should be the better
workman, because he served first a Heavenly Master; and it
was well that while striving to do God's will, he should seek
to please his wife, and make his children happy.
Things were much the same with Susan Dunn and with
Nancy. Setting first before them the desire to please in all
things a Heavenly Master and Friend, they did, as a matter
of course, their best in all things.
But there was nothing sombre, nothing gloomy, in the

atmosphere of Woodbine Cottage. How should there be?
Richard Dunn was a man of cheerful spirit. You need not
suppose for a moment that he or his family were the less
cheerful because of their religion. Why, how should they be?
Real religion—the religion of Christ—is rest, and joy, and
safety now, and the looking forward to a glorious by-and-
by. That doesn't make people gloomy. No doubt a great
many true servants of God are gloomy, but they find their
gloom in themselves, not in their religion, if it is indeed
according to the teaching of Christ.
You would not have heard merrier children's voices

anywhere in the neighbourhood than in Woodbine Cottage,
or a sweeter laugh than Nancy's; nor would you have seen
a sunnier face than Susan's, or a busier and happier life
than Richard Dunn's. He was always at work upon
something, even in leisure hours; reading a book, or doing
a bit of carpentering, or tending his plants, or having a
game with his little ones. There was no time in his life for
idle lounging, any more than there was in Susan's or
Nancy's for gossiping.
Some people may count it odd to talk of a man being

"at work" when he reads a book or plays with his children.
But there are many different kinds of work. Reading may be
very hard work indeed—not of course just looking at a
shallow article in a paper, or glancing through a worthless
novel, but real steady mastering of facts worth knowing in a
volume of history or science. And though playing with a
child is not hard work, yet it may really be in one sense
work for God, if the father is lovingly trying to win his little
one's heart in every possible way, and to please God in so
doing.
Archie Stuart being much in and out of Woodbine

Cottage, noticed all these items of the way in which his
friends lived and acted, and gradually, he seemed to catch
something of the same spirit. He began to feel that for a
man to live only to himself is not grand; that to please one's
self always is very easy, but not beautiful. He saw slowly,
more and more, how grand and beautiful, aye, and how
manly a thing it is, to be permitted to fight on God's side in
the mighty world-wide battle between good and evil.
No namby-pamby matter this, as Archie soon

discovered. For with all his young vigour and his strong will,
he found soon how little he could do, how strong were the
powers of evil; and then it was that his friends could speak
to him of One "mighty to save," in whose great strength
Archie should, if he willed, be "more than conqueror." And
then, Archie learned to pray.
That was how Archie grew more kind and patient during
the weeks of his mother's illness. He did not think it himself.
He had never found self-restraint harder, or the temptation
to sharp self-defence more keen. But others looking on saw
the difference in him already.
This learning to pray is a great step in anybody's life.

Archie no longer went to Church merely as a dull duty, to
listen to words which had as yet no meaning for him,
because his eyes were not open to their meaning. He went
now to ask God, in common with others, for things which he
and they needed, to offer thanks for things already given.
Both in Church, and in his own little room, he had begun to
draw nearer to the footstool of Christ the King, to know Him
as the Crucified, to trust Him as the Saviour, to be taught of
His Spirit, to bow before Him as Lord.
For all this Archie lost no whit of his growing manliness.

Was it likely? Does any one lose in force or manliness
through daily intercourse with a mind infinitely greater and
wiser than his own? Besides, what is more manly than self-
control, than conquests over one's evil tempers, than a
spirit of kindness and generosity to those weaker than one's
self? Archie was growing in these things more manly, not
less manly, day by day, and many remarked that it was so.
The Dunns saw it especially.
CHAPTER XVIII.
THE GARDINERS.
THINGS were widely different, next door to the Dunns,

from what Archie had found in Woodbine Cottage. It is
astonishing what a change comes over the scene, if one just
passes from one little cottage home into a second, the two
being separated by only a slender wall.
There was not too much religion in the Gardiner

household by any means, neither was there too much of
happy children's laughter, or too much wifely affection, or
too much manliness in the head of the household.
John Gardiner had probably no intention of being

unmanly. Probably, also, he was what people call "a well-
meaning man," that is, he meant to do well, so long as
doing well didn't happen to cross his own inclinations. He
was a man of very strong principle too, after a fashion, his
one leading principle being always, and on all occasions, to
do exactly what he chose, without consulting the
inclinations or wishes of anybody else.
In the workshop, this principle had of course to be in a

measure subordinate to the will of his employers. But at
home it had full swing.
John Gardiner at home counted himself absolute

master, and he insisted on being so too. A wife was, in his
estimation, a useful sort of creature, fit to scour and wash
and cook, fit also to be the victim of harsh words when he
pleased to bestow them. If words failed to bring submission,
he would not object to try the effect of a blow. After which,
no one could rightly speak of John Gardiner as a "manly
Englishman," much as he might desire the term. For a man
who can stoop to strike a woman has forfeited utterly all
claim to "manliness."
But of course Gardiner did not see this. A coward nature

seldom knows its own cowardice. A bully is always a
coward; and there was a good deal of the bully in Gardiner's
nature.
His children shrank away from him habitually, with a

mixture of dread and cunning. Not that they saw much of
their father. He allowed his wife a certain amount out of his
wages for household expenses—expecting a goodly amount
of the same to be spent upon food for himself—and he
came home to eat and to sleep. That was about all.
His evenings were spent elsewhere, always. If his wife

knew where he went, it was by accident, since he rarely
condescended to tell her. Perhaps it is not too much to say
that neither his wife nor his children craved more of
Gardiner's presence in the little home.
If Betsy Gardiner knew little of her husband's doings, he

was not much better acquainted with those of his wife and
children. The eldest girl, Bess, was at sixteen practically
independent. She chose her own friends, followed her own
devices, and was at once blamed and sheltered by the weak
and hasty yet indulgent mother. Betsy Gardiner might slap
her children roughly, under sudden provocation; but to see
them feel the weight of their father's heavy hand was
another matter. She shrank from that; and she shrank from
what might drive the elder girl permanently from home.
The state of things could hardly be wondered at. John

Gardiner was a man who lived distinctly and solely for
himself. He expected everybody and everything in the
household to bend to his pleasure. He gave no love and he
received none. The example of abject self-pleasing—for
such slavery to self is abject and contemptible—was
naturally followed by his children. How should it not be?
There were no softening influences; none of an opposite
kind. The spirit of the household was a reflection of the
father's spirit—how in every way to please and indulge self,
coupled in the case of the children with a constant effort to
shirk blame at any cost.
The Gardiners and the Dunns were not disposed to be

intimate. Naturally two families of such different minds and
views did not suit. Had the Gardiners been in trouble, Susan
Dunn would have been ready at once to help them. But she
did not care for the friendship of Mrs. Gardiner for herself,
or of Bess for Nancy, or of the quarrelsome shrieking
children for her own Dick and Susie.
Two girls could scarcely have been found in the place

more unlike than Nancy Dunn and Bess Gardiner: Nancy,
with her sweet blue eyes, and pretty smile, and modest
dress, and gentle manner; and Bess, with her rough
bearing, her coarse laugh, her conspicuous fringe, her
gaudy dress. They were girls utterly unsuited to one
another. Their bringing-up had been different, their tastes
were different, their pursuits were different, their rules of
action were different.
Yet these two girls were alike in one thing, and that was
in the possession of a naturally warm heart.
Only, with Nannie the warmth had been fostered, the

tenderness had been cherished, till it was as natural to her
to give out love as for a sunbeam to give out warmth. Bess,
on the other hand, had been checked and snubbed, fretted,
neglected, and scolded, till she had grown-up seemingly
hard, and ready to fight the whole world, with all her
natural warmth hidden away beneath a tough outside crust.
The warmth was there still, however. It only needed to

be set free. And nobody would have guessed that gentle
Nancy Dunn would be the one to win her way in through
this crust. Yet so it was.
At first when the Dunns came, Bess laughed at them,

and said scornful words about Nancy's "prim ways." But
whenever the two girls met, Nanny always had a little smile,
and a kind passing word for Bess. And gradually Bess
ceased to sneer. The winning manner and the soft
straightforward eyes were unconsciously gaining possession
of poor Bess Gardiner's frozen-up heart.
Nancy did not know it. She guessed nothing of it yet.

She only thought it rather odd that she should so often
lately have met Bess. Somehow Bess seemed to be always
coming across her path. Bess would say nothing when they
met. She only hung about sheepishly till she had had a
word of greeting, and then rushed away. And Nancy never
gave more than the passing word; for she knew that Bess'
companionship would not be liked by her mother. Nannie
did not know how Bess craved for more, how Bess watched
for her coming, and feasted on the passing word, and would
have run a mile for a second word. If any one had
suggested such a state of things, Nancy would have
laughed and thought the idea absurd.
Yet things had actually come to this pass, one August

evening, when Nancy Dunn had been to speak to Miss
Wilmot at the Rectory, and was walking home—things had
come to such a pass that poor rough-mannered Bess might
almost be said to worship the ground on which Nancy Dunn
walked.
The evening was a lovely one, and Nancy was tempted

to stroll a short distance round on her way home. She chose
a quiet lane, with a hedge on either side, more country-like
than most of the roads round Littleburgh. And halfway
through this lane, she found Bess Gardiner standing alone
doing nothing, only watching her approach.
CHAPTER XIX.
THAT GIRL BESS!
"GOOD evening," Nancy said pleasantly, as she reached

Bess, and was about to pass her.
But Bess, with a sudden movement, placed herself in

front of Nancy.
"You don't never say one word more!" she burst out.
"And I wish you would."
Nancy looked at her in surprise. "Why—what do you

want me to say?" she asked. "I don't understand."
Bess hung her head and was silent. She had spoken
under a momentary impulse, and now shyness seized upon
her. Rough-mannered Bess was by no means wont to suffer
from shyness, and the sensation came as a novelty.
"I'd like to walk along the lane with you," she muttered
at length.
Nancy was perplexed, knowing well that her mother

would strongly disapprove of any intercourse beyond the
exchange of bare civilities between Bess and herself. She
stood still, thinking.
"I ain't good enough for you. But I'd like a talk with you
sometimes. Don't see why I shouldn't. Might make me
better, you know," continued Bess awkwardly.
"I should like to help anybody," Nancy said, speaking

slowly. "Anybody that wants help. I should like to help you—
if I could," and she hesitated, "but—"
"But you don't choose to be seen walking along of me,"

cried Bess, in loud tones.
"It isn't choosing—indeed it is not," said Nancy,

distressed at the other's look. "Bess, please believe me. It
is only—I always tell mother first—and then—"
But Bess flung herself away, and rushed off, hurt and
angry. Nancy felt sorrowful, fearing that she might have
acted unwisely, and done harm.
When, however, she reached the end of the lane, and

turned into a broader road, there stood Bess.
"I say," the strange girl burst out, "you aren't angered?"
"No," Nancy answered, with a little smile; "I'm only

sorry."
"I say," repeated the other, "d'you mean to say you do

just as your mother tells you?"
"I hope so," Nancy said gravely. "Why, Bess, doesn't the
Bible tell us to obey our parents? And she's such a dear
good mother, I couldn't bear to make her unhappy."
"Oh, well; mine's a different sort from that," said Bess.

"But if she is—if she were—that wouldn't make any
difference about what's right for you," urged Nancy.
"Oh, I think it does! I've had pretty near enough of my

home," said Bess recklessly. "I'll go and live with somebody
else."
"O no, Bess, you won't," said Nancy seriously.
"But I mean to," responded Bess. "So there! I did think

I'd have a talk with you—and you won't."
Nancy's eyes looked into those of Bess.
"Don't be vexed," the gentle girl urged. "I'll have a talk

with mother, and she'll let me see you, I'm sure."
"She don't like girls as wears hair like mine. I know,"

said Bess, with a careless shake of the unkempt mass which
descended low on her freckled forehead. "I've seen her look
me over. I know."
"Mother doesn't think that sort of thing respectable for

girls in our position, Bess," said Nancy quietly.
"Nor you don't neither," said Bess.
"No," said Nancy.
Bess shoved back the loose mass, stared at Nancy and

suddenly burst into tears.
"I'd be respectable if I could," she sobbed. "Nobody's

never taught me; and I don't know how. I'd learn from you,
that I would—and you won't help me! I'd best give up,
that's what I'd best do! I'll give up, and I'll never speak one
word to you again, that I won't."
But Nancy's hand was on Bess' arm, detaining her,
when she would have rushed away.
"No, Bess," Nancy said, "you won't give up. You'll try
harder. And you'll come home with me now and see mother,
and she'll tell you what to do."
"Come home! With you!" gasped Bess.
"Yes; come straight home with me now."
Bess said not another word. She gave herself up to

Nancy's guidance, and followed her meekly into Woodbine
Cottage. The two girls hardly spoke by the way; and indeed
the distance was very short.
Susan Dunn happened to be alone indoors, her husband

having taken out the two children for a short walk. Susan
was busy over some mending. She looked up with a smile
on Nancy's entrance, but the smile passed into an
expression of doubtful welcome, as her eyes fell on Nancy's
companion.
"Mother, I've brought Bess Gardiner to you," said Nancy

simply. "She isn't happy at home, and she wants some one
to help her to be better. And I didn't know what you'd like
me to do, so I've brought her to you. I knew you'd be glad."
Was Susan glad? With all her kind-heartedness, she had

very particular notions about proper acquaintances for
herself and her children, more especially for Nancy. And she
had taken such pains to avoid any kind of intimacy with
those Gardiners. For a moment Susan really did feel quite
provoked, and the only answer she made to Nancy's appeal
was a slow, "Well—sit down."
Bess stood doggedly upright.

"I told you so!" she muttered to Nancy. "And I'm not a-
going to stay where I'm not wanted."
"Mother, Bess isn't happy, and she wants help," pleaded

Nancy.
"Not likely to be happy with their sort of way of going

on," said Susan. "But if there's anything I can do—Sit
down," she repeated.
No, Bess declined to obey. She came a step forward,

with glowering eyes.
"It wasn't my wish to come," she declared. "I'm not one

of them who'll go where they're not wanted. And she'd
ought to have known better than to bring me. I don't say
I'm fit company for her, neither. Only, she's always got a
kind word for me—and I did think—maybe—but it don't
matter! I'll go my own way, and I'll never trouble nobody
again—never It don't matter. Folks are born to be
miserable, I suppose. And there's nobody to care. It don't
matter. So, good-bye."
"O mother!" cried Nancy in distress, tears filling her

eyes, as Bess turned away.
But it was not Nancy's cry which made Susan Dunn

stand up and move swiftly between Bess and the door, with
a face which had softened all at once into motherly pity.
Another thought had come to Susan—the thought of One
who did care, who cared so much for poor rough Bess as to
have given up His life for her on Calvary. How would it be in
His eyes, if Susan let this poor untaught girl wander away
without the help which she craved?
"Good-bye; I'm going," repeated Bess hoarsely. "Let me

go."

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Emery's Elements of Medical Genetics

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Peter D. Turnpenny, BSc MB ChB

Sian Ellard, OBE BSc PhD FRCPath

Ruth Cleaver, BSc MB ChB PGCert

1. The History and Impact of Genetics in Medicine

Gregor Mendel and the Laws of Inheritance

DNA as the Basis of Inheritance

The Fruit Fly

The Origins of Medical Genetics

Major New Developments

The Societal Impact of Advances in Genetics

Section A: The Scientific Basis of Human Genetics

2. The Cellular and Molecular Basis of Inheritance

DNA: The Hereditary Material

Types of DNA Sequence

The Genetic Code

Regulation of Gene Expression

RNA-Directed DNA Synthesis

Mutations and Mutagenesis

3. Chromosomes and Cell Division

Methods of Chromosome Analysis

4. Finding the Cause of Monogenic Disorders by Identifying Disease

Position-Independent Identification of Human Disease Genes

The Human Genome Project

Identifying the Genetic Etiology of Monogenic Disorders by

5. Laboratory Techniques for Diagnosis of Monogenic Disorders

Polymerase Chain Reaction

Nucleic Acid Hybridization Techniques

Genome Sequencing as a Clinical Diagnostic Test

Multiple Alleles and Complex Traits

7. Population and Mathematical Genetics

Allele Frequencies in Populations

Medical and Societal Intervention

Autosomal Dominant Inheritance

Autosomal Recessive Inheritance

X-Linked Recessive Inheritance

The Use of Linked Markers

Bayes’ Theorem and Prenatal Screening

Fertilization and Gastrulation

Developmental Gene Families

The Pharyngeal Arches

The Role of Cilia in Developmental Abnormalities

The Limb as a Developmental Model

Developmental Genes and Cancer

Positional Effects and Developmental Genes

Epigenetics and Development

Sex Determination and Disorders of Sex Development

Section B: Genetics in Medicine and Genomic

10. Common Disease, Polygenic, and Multifactorial Genetics

Types and Mechanisms of Genetic Susceptibility

Approaches to Demonstrating Genetic Susceptibility to Common

Multifactorial Inheritance—the Liability/Threshold Model

Identifying Genes That Cause Multifactorial Disorders

Polygenic Risk Scores

Disease Models for Multifactorial Inheritance