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Preface
Of all the claims on our curiosity, we want most to
understand ourselves. What are we? How have we
come to be what we are? What lies in our future?
Many features of our lives depend on accidents of
history. The time and place of our birth largely deter-
mine what language we first learn to speak, whether
we are likely to be well fed and well educated, and
receive adequate medical care. Many aspects of
our future depend on events outside ourselves and
beyond our control.
Yet, within us, there are constraints on our
lives that brook relatively little argument. In some
respects, we are at the mercy of our genomes. Under
normal circumstances, all of our basic anatomy and
physiology, and eye colour, height, intelligence, and
basic personality traits, are ingrained in our DNA
sequences. This is not to say that our genomes dictate
our lives. Some constraints are tight—for instance,
eye colour—but our genetic endowment also confers
on us a remarkable robustness.
This robustness also is a product of evolution.
Within the last century, lifestyles have changed with
a rapidity hitherto unknown (except for the instants
of asteroid impacts). We can meet and survive brutal
stresses. Our talents have many opportunities to
nurture themselves and to develop in novel ways.
These are gifts of our genomic endowment: What
genes control is the response of an organism to its
environment.
The human genome is only one of the many com-
plete genome sequences known. Taken together,
genome sequences from organisms distributed widely
among the branches of the tree of life give us a sense,
only hinted at before, of the very great unity in detail
of all life on Earth. This recognition has changed our
perceptions, much as the first pictures of the Earth
from space engendered a unified view of our planet.
Superimposed on this underlying unity is great
variety. We ask: What is special about us? What do
we share with our parents and siblings and how do
we differ from them? What do we share with all
other human beings and what makes us different
from the other members of our species? What are
the sources of our differences from our closest extant
non-human relatives, the chimpanzees? What do we
have in common and how do we diverge from other
species of primates? Of mammals? Of vertebrates?
Of eukaryotes? Of all other living things?
The complete sequences of human and other
genomes reveal the underlying text of this story. We
are beginning to understand how our lives shape
themselves under the influence of our genes, epigen-
etic modifications, and our surroundings and life
histories.
We are also beginning to be able to intervene.
Genetic engineering of microorganisms is an estab-
lished technique. Genetically-modified plants and
animals exist, and are the subjects of lively debate. To
override the genes for hair colour is trivial. Changes
in lifestyle or behaviour can—to some extent—avoid
or postpone development of diseases to which we are
genetically at risk. Gene therapy offers the promise
of rectifying some inborn defects. Novel gene editing
techniques based on the CRISPR/Cas system offer
revolutionary power in reshaping individuals, whole
species, and ecosystems.
Fast, inexpensive sequencing has transformed
genomics. The landmark goal, the $US1000 human
genome, has been achieved. It is very likely that within
the lifetime of many readers, human genome sequenc-
ing will be nearly universal. Already, hundreds of
thousands of human individuals have had their full
genomes sequenced, and many more are on the way.
Many people have had sequences determined for
individual genes. For example, mutations in BRCA1,
BRCA2, and PALB2 suggest an increased likelihood
of developing breast or ovarian cancer. Many people
have had these regions sequenced to provide informa-
tion about their personal risk. This can be more than
informative: some individuals—most famously the
actress Angelina Jolie—have opted for prophylactic
surgery.
The spectacular progress in high-throughput
sequencing, and the resulting explosive growth of the
data produced—in quality, quantity, and type—have
altered the entire landscape of genomics itself, and its
influence has invaded surrounding fields. No area of
biology has been left unscathed.
viii Preface
Study of human disease through sequencing con-
tinues to be a major effort. The possibility of appli-
cations to improve human health were the major
motivation for support of the Human Genome
Project, and continue to be the major elicitor of lar-
gesse for pursuing its consequences. Identification
of genes responsible for particular diseases permits
testing, genetic counselling, and risk assessment and
avoidance. Cancer genomics—the comparison of
sequences from normal and tumour cells from single
patients—has become a heavy industry.
Understanding the relationships between genes
and disease will allow more precise diagnosis and
warnings of increased risk of disease in patients
and their offspring. For many important diseases,
a patient can expect more precise diagnosis and
prognosis, and more precise recommendations for
treatment. Design of treatment based on a patient’s
genome, called pharmacogenomics, is already part
of clinical practice. Genomes of other organisms
also have implications for human health, especially
those of pathogenic organisms that have developed,
or are threatening to develop, antibiotic resistance.
We study the biology of viruses and bacteria to take
advantage of their vulnerabilities, and the biology of
humans to ward off the consequences of our own.
This century will see a revolution in healthcare
development and delivery. Walls between ‘blue sky’
research and clinical practice are tumbling down. It is
possible that a reader of this book will discover a cure
for a disease that would otherwise kill him or her. It
is extremely likely that Szent-Györgyi’s quip, ‘Cancer
supports more people than it kills’, will come true.
One hopes that this will happen because the research
establishment succeeds in developing therapeutic or
preventative measures against tumours, rather than
by merely imitating their uncontrolled growth.
Other applications of genomics include improve-
ment of crops and domesticated animals, enhanc-
ing food production, and support of conservation
efforts dedicated to preserving endangered species.
Development of alternative energy sources is a chal-
lenge to both physics and biology.
Beyond these applications, genomics offers us a
profound understanding of fundamental principles of
biology. The history of life is a pageant for which we
are beginning to delineate the choreography. On the
personal level, within this history, genome exegesis
will fundamentally alter our perception of ourselves:
what it means to be human.
In this book, I have tried to present a balanced
view of the background of the subject, the technical
developments that have so greatly increased the data
flow, the current state of our knowledge and under-
standing of the data, and applications to medicine
and other fields. With power derived from knowledge
goes commitment to act wisely. We have responsibili-
ties, to ourselves, to other people, to other species,
and to ecosystems ranging up to the entire biosphere.
Ethical, legal, and social issues have been a promi-
nent component of the human genome project. Most
technical questions in genomics, as in other scientific
subjects, have objectively correct answers. We do not
know all the answers, but they are out there for us to
discover. Ethical, legal, and social issues are different.
Many choices are possible. Their selection is not the
privilege of scientists in individual laboratories, but
of society as a whole. Scientists do have a responsi-
bility to contribute to the informed public discussion
that is essential for wise decisions.
One aspect of the first edition that I liked was its
concision. Unfortunately, this has had to be sacri-
ficed to the stampeding progress of the field. A major
problem encountered in writing about genomics is
the need to pick and choose from the many riches
of the subject. The list of subjects that cannot be left
out is too long and threatens to reduce the treat-
ment of each to superficiality. There is also a serious
organizational challenge: many phenomena must be
approached from several different points of view. A
reader may be relieved to conclude that a topic has
been beaten thoroughly into submission in one chap-
ter, only to encounter it again, alive and kicking, in a
later section, in a different context.
The speed at which the field is moving causes other
problems. An author is often pleased with a draft of
a section only to find the carefully described conclu-
sions overturned in next week’s journals. Yet, there
is a great pleasure in seeing nature’s secrets emerging
before one’s eyes.
Another casualty of rapid progress is the frequent
dismissal of attention to history and biography. We
are fantastically interested in the development of the
sea urchin and the fruit fly, but not in the development
of molecular genomics. This is too bad: those who
do not learn from the successes of history will find
 Preface ix

it harder to emulate them. Intellectual struggles that
occupied entire careers leave behind only the terse
conclusions, often without any appreciation of the
experiments that established the facts, much less of
the alternative hypotheses tested and rejected. We
remember the breakthroughs, but not the frustra-
tions that their achievement required. The force of
the scientists’ personalities, and their foibles, are for-
gotten. Making use of other people’s results isn’t the
same thing as creating new ones: ‘To imitate the Iliad
is not to imitate Homer’.
Genomics is an interdisciplinary subject. The phe-
nomena we want to explain are biological. But many
fields contribute to the methods and the intellec-
tual approaches that we bring to bear on the data.
Physicists, mathematicians, computer scientists, engi-
neers, chemists, clinical practitioners and research-
ers have all joined in the enterprise. This book will
appeal, at least in part, to all of them. However, the
central point of view remains focused on the biology.
More specifically, the focus is on human biology.
In fact, on the biology of humans who are curious
about other species, albeit primarily for what the
other species tell us about ourselves. This choice nat-
urally reflects the potential readership of this book.
(If bacteria or fruit flies could read, genomics text-
books would look very different.)
In the new edition, extended coverage is given both
to clinical applications to humans and to the applica-
tions of genome sequences to working out of evolu-
tionary relationships in microorganisms, plants, and
animals. Non-clinical applications to human biology
and history are sufficient to justify a chapter of their
own. The genomics of plant and animal domestica-
tions not only shed light on human—as well as plant
and animal—history, but emphasize the reciprocal
interactions between humans and the rest of the
biosphere.
This book assumes that the reader already has
some acquaintance with modern molecular biology,
and builds on and develops this background, as a self-
contained presentation. It is suitable as a textbook for
undergraduates or starting postgraduate students.
Progress is happening so fast as to make unavoid-
able a feeling of frustration in aiming at a moving
target. The hope is that the third edition has erected
for the reader a sound framework, both intellectual
and factual, that will make it possible, when encoun-
tering subsequent developments, to see where and
how they fit in.

Exercises and problems at the end of each chapter, and ‘weblems’ on the Online
Resource Centre, test and consolidate understanding, and provide opportunities to
practise skills and explore additional subjects. Exercises are short and straightforward
applications of material in the text. Answers to exercises appear on the website associ-
ated with the book. Problems, also, make use of no information not contained in the
text, but require lengthier answers or, in some cases, calculations. The third category,
‘weblems’, requires access to the Internet. Weblems are designed to give readers prac-
tice with the tools required for further study and research in the field. Some of these are
suitable for use as practical or laboratory assignments, or even as class projects.

Key terms are highlighted in the text, and are defined in the Glossary at the end of
the book.
PLAN OF THE THIRD EDITION
Chapter 1, Introduction and Background, sets the
scene, and introduces all of the major players: DNA
and protein sequences and structures, genomes and
proteomes, databases and information retrieval, and
bioinformatics and the Internet. Subsequent chapters
develop these topics in detail. Chapter 1 sketches the
framework in which the pieces fit together and sets
genomics in its context among the biomedical, physi-
cal, and computational sciences.
The message is clear: genomics is the hub of biol-
ogy. Whereas genome sequences are determined from
individuals, to appreciate life as a whole requires
extending our point of view spatially, to populations
and interacting populations; and temporally, to con-
sider life as a phenomenon with a history. We can
study the characteristics of life in the present, we can
determine what came before, and we can—at least
to some extent—extrapolate to the future. The ‘cen-
tral dogma’ and the genetic code underlie the imple-
mentation of the genome, in terms of the synthesis
of RNAs and proteins. Absent from Crick’s original
statement of the central dogma is the crucial role of
regulation in making cells stable and robust, two
characteristics essential for survival.
Chapter 2, The Human Genome Project:
Achievements and Applications, focuses on the human
genome and the applications of human genome
sequences. It reports the current state of the data,
although that gives an inadequate sense of their explo-
sive growth. Clinical applications are maturing from
hype to serious promise to actual clinical practice.
Putting our species in context involves, most nar-
rowly, comparing our genomes with those of our
closest relatives, including Neanderthal man and the
chimpanzee, our nearest extant relative. More general
applications to anthropology appear in Chapter 9.
Applications of genome sequences in personal
identification are well known. These include determi-
nations of paternity, and, less frequently, maternity.
Crime-scene investigation has proved the guilt or
innocence of many suspects. It is the stuff of popular
entertainment.
Although much genome sequence investigation is car-
ried out under clinical or forensic organization, sequenc-
ing has gone public with ‘pop’ applications provided by
personal genealogy companies. There are even ‘dating
sites’ that use the correlation between major histocom-
patibility complex haplotype and mate selection to offer
to identify mutually attractive individuals.
Many of these applications involve ethical, legal,
and social issues. Different jurisdictions have estab-
lished different guidelines or regulations.
Chapter 3, Mapping, Sequencing, Annotation, and
Databases, describes how genomics has emerged from
classical genetics and molecular biology. The first
nucleic acid sequencing, by groups led by F. Sanger
and W. Gilbert, in the 1970s, was a breakthrough
comparable to the discovery of the double helix of
DNA. The challenges of sequencing stimulated spec-
tacular improvements in technology. First came auto-
mation of the Sanger method. The original sequences
of the human genome were accomplished by batter-
ies of automated Sanger sequencers. Subsequently, a
series of ‘new generations’ of novel approaches have
achieved the landmark goal, the $US1000 human
genome. Sequencing power is very widely distrib-
uted. There are major specialized institutions, such
as the Beijing Genomics Institute (now in Shenzhen).
BGI sequencers generate 10 terabytes of raw data per
day. (You do the math: that’s over 2 human genomes
per minute!) Smaller installations are common in
universities, hospitals, and companies.
Where do all the publicly available data go?
Chapter 3 also introduces the databanks that archive,
curate, and distribute the data, and some of the infor-
mation-retrieval tools that make them accessible to
scientific enquiry.
Chapter 4, Evolution and Genomic Change,
treats relationships. Life has been shaped by evo-
lution, primarily acting through natural selection.
T. Dobzhansky famously said, ‘Nothing in biology
makes sense except in the light of evolution’.1
Genomics allows us to trace many aspects of this
process, if not always to make sense of them.
Of course, most of evolution took place in the
past. We cannot observe it directly. However, we can
observe and draw inferences from its products. These
1
I would add thermodynamics to the list of things
except in the light of which nothing in biology makes
sense.

products are, for the most part, the genomes—and
phenotypes—of extant organisms, plus sporadic data
from recently extinct species. In addition, many evo-
lutionary events have left their traces in contempo-
rary genomes.
Chapter 4 explores some of the tools that scientists
have developed to analyse sequence data for what it
can reveal about evolution. Prominent among these
are methods for sequence alignment and calibration
of the results, and the computation of phylogenetic
trees.
We are entering an era when evolution, even in
natural populations, may be under the direct con-
trol of molecular biologists wielding tools based on
CRISPR/Cas and gene drive. Because most of the
material in Chapter 4 is decades or even centuries
old, one might think that these sections might be the
least-likely parts of this book to need significant revi-
sion during the coming decade or so. This may be a
dangerous assumption. We shall see.
Chapter 5, Genomes of Prokaryotes and Viruses,
surveys the genomes of viruses, bacteria, and archaea
in more detail. Taxonomy and phylogeny pres-
ent problems because of extensive horizontal gene
transfer. Indeed, horizontal gene transfer challenges
the whole idea of a hierarchy of biological classifi-
cation. In the past, many bacteria have been cloned
and studied in isolation, especially those responsible
for disease. However, a new field, metagenomics,
deals with the entire complement of living things
in an environmental sample, allowing us to address
questions about interspecies interaction in the ‘real
world’. Sources include ocean water, soil, and the
human body.
Chapter 6 surveys Genomes of Eukaryotes. It starts
with yeast, which is about as simple as a eukaryote
can get. Selected plant, invertebrate, and chordate
genomes illuminate the many profound common fea-
tures of eukaryotic genomes; and the very great vari-
ety of structures, biochemistry, and lifestyles that are
compatible with the underlying similarities. There
are examples of recovery and sequencing of DNA
from extinct organisms.
The goal of Chapter 7, Comparative Genomics,
is to harvest some conclusions from the surveys
of viral, prokaryotic, and eukaryotic genomes
presented in the preceding chapters. We begin
by comparing the different modes of genome
Plan of the third edition xi
organization with which living things have experi-
mented. If the great variety of living things has
arisen through evolution by natural selection—the
change in allele frequency in a population through
differential reproductive success among different
variants—how does the variation arise? We must
consider the nature and extent of the variability in
the genomes within individual populations, and the
mechanisms that generate this variability. It will
emerge that, especially in prokaryotes, horizontal
gene transfer is a very important component of the
mechanism.
Chapter 8, The Impact of Genome Sequences on
Health and Disease, describes clinical applications
of genome sequencing. Sometimes, when particular
genes are known to correlate with disease or risk
of disease, specific regions in a patient’s genome are
sequenced. More and more, we will see complete
genome sequencing in clinical contexts.
Applications include improved diagnosis and prog-
nosis of the causes of presenting syndromes, genetic
counselling of parents with family histories of a dan-
gerous genetic condition, and ‘pharmacogenomics’: the
tailoring of treatment to the individual patient, based
on DNA sequence information. ‘Gene therapy’, the
replacement of defective genes with correct ones, has
already had some successes and, with the development
of CRISPR/Cas technology of genome editing, will
undoubtedly grow in applicability. (Guidelines emerg-
ing from a 2015 Washington conference urged a mora-
torium on application of CRISPR to humans. In 2017,
the US National Academies of Sciences and Medicine
recommended allowing human germline editing under
certain stringent conditions. But the pressure is too
great for deterrence to survive, even in the US.)
Chapter 9, Genomics and Anthropology, devel-
ops additional applications to the study of our own
species. Although clinical applications are undoubt-
edly the most important, genomics has important
contributions to make to human palaeontology and
anthropology. The ability to extract DNA from
extinct species, including Neanderthals, sheds light
on our early evolution. Events in our history, includ-
ing migrations and domestication of crops and ani-
mals, have left their traces in DNA sequences.
With Chapter 10, Transcriptomics, we move on
from the (relatively) static genome to the selectivity
and dynamics of expression patterns. Following the
 xii Plan of the third edition
central dogma, there are at least two stages: transcrip-
tion, in which DNA makes RNA (Chapter 10); and
translation, in which RNA makes protein (Chapter
11).
Measurements of cellular RNAs describe the tran-
scription patterns of regions of the genome. These
patterns vary in response to changes in the environ-
ment: the lac operon of Escherichia coli is a classic
example. Expression patterns vary among different
tissues, different physiological states, and different
developmental stages. Thus, the human embryo and
neonate synthesizes embryonic and then foetal hae-
moglobin, switching to expression of adult haemo-
globin at about 6 months post-birth.
The inventory of mRNAs in the cell—a component
of the transcriptome—is naturally of interest for what
it can tell us about the distribution of cellular proteins.
Certainly protein synthesis does involve many RNAs,
including messenger RNAs, the RNA of the ribosome,
transfer RNAs, and the RNAs of the spliceosome, that
removes introns from pre-messenger RNAs. However,
other RNAs have a variety of roles, including catalytic
activity. Catalytically active RNAs are called ribo-
zymes. (In both the ribosome and the spliceosome,
the catalytic activity is in the RNA, not the protein
component.) Other RNAs, such as microRNAs, short
interfering RNAs, and silencing RNAs, control gene
expression by interacting with messenger RNAs. The
RNA transcripts of CRISPR sequences, bound to
CRISPR-associated nucleases, identify viral invaders.
There is good reason to believe that many other RNA
functions remain to be discovered.
Chapter 11, Proteomics, describes briefly the prin-
ciples of protein structure and the high-throughput
data streams that provide information about sets
of proteins in cells, including methods for predict-
ing protein structure from amino-acid sequence.2
Proteomics is an essential complement to genomics.
(A colleague once entitled a keynote lecture: ‘Genes
are from Venus, proteins are from Mars.’) In fact, one
2
For a more thorough treatment of proteins see Liljas, A., Liljas, L., Piskur, J., Lindblom, G., Nissen, P., & Kjeldgaard,
M. (2009). Textbook of Structural Biology. World Scientific, Singapore; or Lesk, A. (2016). Introduction to Protein
Architecture: Structure, Function, and Genomics, 3rd ed. Oxford University Press, Oxford.
of the major messages of Chapters 10 and 11 is how
much the genome doesn’t tell us about cellular pro-
teins. Nevertheless, the interactions and relationships
between the genome and proteome are intimate,
both during cellular activity and in the longer term
in evolution.
Chapters 12 and 13 introduce systems biology,
a relatively new field that presents a description of
biological organization based on networks. Systems
biology deals with the connectivity of biological net-
works, and analyses and models the mechanisms that
control traffic patterns through them.
A reasonable definition of life would include
the criterion that a living thing executes controlled
manipulations of matter, energy, and information.
Chapters 12 and 13 treat the cellular networks that
carry out and regulate these tasks.
Chapter 12, Metabolomics, deals with the meta-
bolic networks that manipulate matter and energy.
Cells require a source of energy, from nutrients or
from light, and use it to drive metabolites through
series of metabolic pathways. The flows through the
paths in this network must be kept under control. To
achieve this, another network, a logical one, keeps
cellular activities organized. Cells contain parallel
sets of networks based on physical and logical inter-
actions among molecules. Each network also has
static and dynamic aspects.
Components present in a cell at any instant are
subject to direct controls, for instance feedback inhi-
bition by an end product to shut down a metabolic
pathway. But transcription is subject to very exten-
sive oversight: turning genes on and off. Chapter
13, Systems Biology, treats the logical component
of cellular networks that controls transcription and
metabolism.
The genius of classical biochemistry was to take
cells apart and show that the components could func-
tion in isolation. Now our job now is to put things
back together.
RECOMMENDED READING
Where else might the interested reader turn? This
book is designed as a companion volume to three
others: Introduction to Protein Architecture:
The Structural Biology of Proteins; Introduction
to Protein Science: Architecture, Function, and
Genomics; and Introduction to Bioinformatics (all
published by Oxford University Press). Of course,
there are many fine books and articles by many
authors, some of which are listed as recommended
reading at the ends of the chapters. The goal is that
each reader will come to recognize his or her own
interests, and be equipped to follow them up.
For the recommendations for additional reading at
the ends of chapters, I have limited myself to books,
and to articles in the scientific literature. However, if
one wants an introduction to a topic, there are many
quite good lectures on the Internet, which might well
be useful. Or, if one wants up-to-date details about a
topic, there are blogs. Indeed, blog entries are often
more useful than a full scientific paper. With a full
INTRODUCTION TO GENOMICS ON THE WEB
Results and research in genomics make use of the
Internet, both for storage and distribution of data,
and for methods of analysis. Readers will need to
become familiar with websites in genomics, and to
develop skills in using them. Many useful sites are
mentioned in the book. The author’s Introduction
to Bioinformatics offers a pedagogical approach to
computational aspects of genomics. However, clearly,
paper there is the problem of extracting a take-home
message from a mass of detail, whereas the blog
entries often contain one or two concise and ‘to-the-
point’ paragraphs.
Nevertheless, I am reluctant to include these in
the recommendations. This is partly out of a com-
mitment to the refereed scientific literature. But
also: (1) there is no control over whether a recom-
mended website will remain available. The scien-
tific literature at least has a permanent presence. (2)
Blogs can contain a mixture of some contributions
that are very useful and others that are not; and
it may be difficult to distinguish. But it is unde-
niable that the Internet contains very many useful
sources of information outside of the printed scien-
tific literature.
Many applications of genomics to healthcare are
discussed in the book. However, nothing here should
be taken as offering medical advice to anyone about
any condition.
the place to learn about the Internet is on the Internet
itself.
To this end, an Online Resource Centre at www.
oxfordtextbooks.co.uk/orc/leskgenomics3e/ accom-
panies this book. This contains web-based problems
(‘weblems’) and material from the book—figures and
‘movies’ of the pictures of structures, answers to exercises,
hints for solving problems, and guides to useful websites.
ACKNOWLEDGEMENTS
I thank S. Ades, G.F. Anderson, E. Axelsson, M.M.
Babu, S.L. Baldauf, P. Berman, B. de Bono, D.A.
Bryant, C. Cirelli, A. Cornish-Bowden, R. Diskin,
R.B. Eckhardt, N.V. Fedoroff, J.G. Ferry, R. Flegg,
J.R. Fresco, S. Girirajan, N. Goldman, J. Gough,
D. Grove, D.J. Halitsky, R. Hardison, E. Holmes,
H. Klein, E. Koc, A.S. Konagurthu, T. Kouzarides,
H.A. Lawson, E.L. Lesk, M.E. Lesk, V.E. Lesk, V.I.
Lesk, D.A. Lomas, B. Luisi, J.A. Lumadue, P. Maas,
K. Makova, W.B. Miller, C. Mitchell, J. Moult, E.
Nacheva, A. Nekrutenko, G. Otto, A. Pastore, D.
Perry, C. Praul, K. Reed, G.D. Rose, J. Rossjohn, S.
Schuster, R.L. Serrano, B. Shapiro, J. Shi, J. Tamames,
A. Tramontano, A.A. Travers, A. Valencia, G. Vriend,
L. Waits, R. Wayne, J.C. Whisstock, A.S. Wilkins and
V.E. Womble, and E.B. Ziff for helpful advice.
I thank the staff of Oxford University Press for
their essential and superb contributions to this book.
The author and publisher would also like to thank
those who gave their time and expertise to review the
book throughout the writing process. Your help was
invaluable:
• Richard Bingham, Department of Biological Sciences,
University of Huddersfield, UK
• Joanna Kelley, School of Biological Sciences,
Washington State University, USA
• Hans Michael Kohn, Institute of Biosciences and
Bioengineering, Rice University, USA
• Emma Laing, Department of Microbial and Cellular
Sciences, University of Surrey, UK
• Frances Pearl, School of Life Sciences, University of
Sussex, UK
• Michael Shiaris, College of Science and Mathematics,
University of Massachusetts Boston, USA
• Adrian Slater, Faculty of Health and Life Sciences,
De Montfort University, UK
• David Studholme, College of Life and Environmental
Sciences, University of Exeter, UK
CONTENTS

Prefacevii
Plan of the third edition x
Recommended reading xiii
Introduction to genomics on the web xiii
Acknowledgementsxiv
List of abbreviations xxv

1 Introduction and Background 1

Learning goals 1
Genomics: the hub of biology 2
Phenotype = genotype + environment + life history + epigenetics 2
Varieties of genome organization 4
Chromosomes, organelles, and plasmids 4
Genes 6
The scope and applications of genome sequencing projects 9
Variations in genome sequences within species 10
Mutations and disease 10
Single-nucleotide polymorphisms 10
Haplotypes 13
A clinically important haplotype: the major histocompatibility complex 14
Populations 15
Species 17
The biosphere 18
Extinctions 19
The future? 22
Genome projects and our current library of genome information 25
High-throughput sequencing 25
De novo sequencing 26
Resequencing 26
Exome sequencing 26
What’s in a genome? 27
Some regions of the genome encode non-protein-coding RNA molecules 28
Some regions of the genome contain pseudogenes 28
Other regions contain binding sites for ligands responsible for regulation
of transcription 29
Repetitive elements of unknown function account for surprisingly large
fractions of our genomes 29
Dynamic components of genomes 30
Genomics and developmental biology 32
Genes and minds: neurogenomics 35
Genetics of behaviour 36
xvi Contents

Proteomics 37
Protein evolution: divergence of sequences and structures
within and among species 39
Mechanisms of protein evolution 39
Organization and regulation 42
Some mechanisms of regulation act at the level of transcription 45
Some mechanisms of regulation act at the level of translation 45
Some regulatory mechanisms affect protein activity 47
On the web: genome browsers 47
Genomics and computing 52
Archiving and analysis of genome sequences and related data 52
Databanks in molecular biology 53
Programming 54
Looking forward 55
Recommended reading 55
Exercises and problems 57

2 The Human Genome Project: Achievements and Applications 62

Learning goals 62
‘… the end of the beginning’ 63
Human genome sequencing 66
What makes us human? 67
Comparative genomics 68
Genomics and language 68
The human genome and medicine 71
Prevention of disease 71
Detection and precise diagnosis 72
Genetic counselling—carrier status 72
Discovery and implementation of effective treatment 72
Tunable healthcare delivery: pharmacogenomics 74
‘Pop’ applications of genome sequencing 76
Genomics in personal identification 76
DNA ‘fingerprinting’ 77
Personal identification by amplification of specific regions has
superseded the RFLP approach 79
Mitochondrial DNA 79
Analysis of non-human DNA sequences 82
Parentage testing 82
Inference of physical features, and even family name 83
Ethical, legal, and social issues 85
Databases containing human DNA sequence information 85
Use of DNA sequencing in research on human subjects 88
Looking forward 88
Recommended reading 88
Exercises and problems 90
 Contents xvii

3 Mapping, Sequencing, Annotation, and Databases 97

Learning goals 97
Classical genetics as background 98
What is a gene? 99
Maps and tour guides 99
Genetic maps 100
Linkage 101
Linkage disequilibrium 102
Chromosome banding pattern maps 103
Restriction maps 106
Discovery of the structure of DNA 107
DNA sequencing 110
Frederick Sanger and the development of DNA sequencing 111
DNA sequencing by termination of chain replication 111
The Maxam–Gilbert chemical cleavage method 114
Automation of DNA sequencing 114
Organizing a large-scale sequencing project 116
Bring on the clones: hierarchical—or ‘BAC-to-BAC’—genome
sequencing 116
Whole-genome shotgun sequencing 116
Next-generation sequencing 118
Roche 454 Life Sciences 120
Illumina 121
Ion Torrent/Personal Genome Machine (PGM) 124
PacBio 124
Oxford Nanopore 124
10X Genomics 125
The Bionano Irys system 125
Life in the fast lane 126
How much sequencing power is there in the world? 126
Databanks in molecular biology 128
Nucleic acid sequence databases 130
Protein sequence databases 130
Databases of genetic diseases—OMIM and OMIA 130
Databases of structures 131
Specialized or ‘boutique’ databases 132
Expression and proteomics databases 132
Databases of metabolic pathways 133
Bibliographic databases 133
Surveys of molecular biology databases and servers 134
Computer programming in genomics 134
Programming languages 135
How to compute effectively 136
Looking forward 137
Recommended reading 137
Exercises and problems 138
xviii Contents

4. Evolution and Genomic Change 143

Learning goals 143

Evolution is exploration 144
Biological systematics 146
Biological nomenclature 146
Measurement of biological similarities and differences 148
Homologues and families 150
Pattern matching—the basic tool of bioinformatics 151
Sequence alignment 151
Defining the optimum alignment 153
Scoring schemes 155
Varieties and extensions 157
Approximate methods for quick screening of databases 158
Pattern matching in three-dimensional structures 160
Evolution of protein sequences, structures, and functions 161
Evolution of protein structure and function 164
Phylogeny 165
Calculation of phylogenetic trees 169
Short-circuiting evolution: genetic engineering 173
Looking forward 175
Recommended reading 176
Exercises and problems 177

5 Genomes of Prokaryotes and Viruses 179

Learning goals 179

Evolution and phylogenetic relationships in prokaryotes 180
Major types of prokaryotes 180
Do we know the root of the tree of life? 182
Genome organization in prokaryotes 183
Replication and transcription 184
Gene transfer 184
Archaea 184
The genome of Methanococcus jannaschii 186
Life at extreme temperatures 188
Comparative genomics of hyperthermophilic archaea:
Thermococcus kodakarensis and pyrococci 189
Bacteria 194
Genomes of pathogenic bacteria 195
Genomics and the development of vaccines 197
Viruses 198
Nucleocytoplasmic large DNA viruses (or giant viruses) 199
Viral genomes 199
Recombinant viruses 199
Viruses and evolution 201
Influenza: a past and current threat 201
 Contents xix

’Ome, ’ome, on the range: metagenomics, the genomes in a

coherent environmental sample 204
Marine cyanobacteria—an in-depth study 205
Looking forward 208
Recommended reading 208
Exercises and problems 210

6 Genomes of Eukaryotes 211

Learning goals 211

The origin and evolution of eukaryotes 212
Evolution and phylogenetic relationships in eukaryotes 212
The yeast genome 212
The evolution of plants 214
The Arabidopsis thaliana genome 214
Genomes of animals 216
The genome of the sea squirt (Ciona intestinalis) 216
The genome of the pufferfish (Tetraodon nigroviridis) 217
The genome of the chicken (Gallus gallus domesticus) 220
The genome of the platypus (Ornithorhynchus anatinus) 221
The genome of the dog 223
Palaeosequencing—ancient DNA 225
Recovery of DNA from ancient samples 225
DNA from extinct birds 226
High-throughput sequencing of mammoth DNA 227
The phylogeny of elephants 230
Looking forward 230
Recommended reading 231
Exercises and problems 231

7 Comparative Genomics 233

Learning goals 233

Introduction 234
Unity and diversity of life 234
Taxonomy based on sequences 235
Sizes and organization of genomes 238
Genome sizes 238
Genome organization in eukaryotes 241
Photosynthetic sea slugs: endosymbiosis of chloroplasts 242
How genomes differ 243
Variation at the level of individual nucleotides 243
Duplications 243
Duplication of genes 244
xx Contents

Family expansion: G protein-coupled receptors 247

Comparisons at the chromosome level: synteny 252
What makes us human? 252
Comparative genomics 252
Genomes of chimpanzees and humans 252
Genomes of mice and rats 254
Model organisms for study of human diseases 255
The genome of Caenorhabditis elegans 256
The genome of Drosophila melanogaster 256
Homologous genes in humans, worms, and flies 257
Looking forward 258
Recommended reading 260
Exercises and problems 261

8 The Impact of Genome Sequences on Human

Health and Disease 264

Learning goals 264

Introduction 265
Some diseases are associated with mutations in specific genes 265
Haemoglobinopathies—molecular diseases caused by abnormal
haemoglobins 265
Phenylketonuria 266
Alzheimer’s disease 268
Identification of genes associated with inherited diseases 268
Genome-wide association studies 271
GWAS of sickle-cell disease 274
GWAS of type 2 diabetes 275
GWAS of schizophrenia 276
The human microbiome 278
Treatment of abnormal microbiome composition 281
Cancer genomics 281
SNPs and cancer 284
Whole-genome sequencing association studies of breast cancer 285
Copy-number alterations in cancer 286
Chromosomal aberrations 288
Epigenetics and cancer 289
microRNAs and cancer 290
Immunotherapy for cancer 291
Looking forward 292
Recommended reading 292
Exercises and problems 294
 Contents xxi

9 Genomics and Anthropology: Human Evolution,

Migration, and Domestication of Plants and Animals 295

Learning goals 295

Ancestry of Homo sapiens 296
The Neanderthal genome 297
The Denisovan genome 298
What do these data tell us? 299
What have Neanderthals and Denisovans done for us lately? 300
Ancient populations and migrations 300
Western civilization? ‘I think it would be a good idea’ 308
Domestication of the dog 310
Domestication of the horse 311
Domestication of crops 313
Maize (Zea mays) 315
Rice (Oryza sativa) 317
Control of flowering time 318
History of rice domestication 320
Chocolate (Theobroma cacao) 321
The Theobroma cacao genome 322
Looking forward 324
Recommended reading 326
Exercises and problems 327

10 Transcriptomics 329

Learning goals 329

Introduction 330
Microarrays 331
Microarray data are semiquantitative 332
Applications of DNA microarrays 332
Analysis of microarray data 333
RNAseq 336
RNAseq versus microarrays 337
Expression patterns in different physiological states 339
Sleep in rats and fruit flies 340
Expression pattern changes in development 342
Variation of expression patterns during the life cycle of
Drosophila melanogaster 342
Flower formation in roses 344
Expression patterns in learning and memory: long-term potentiation 347
Conserved clusters of co-expressing genes 350
xxii Contents

Evolutionary changes in expression patterns 351

Applications of transcriptomics in medicine 353
Development of antibiotic resistance in bacteria 353
Childhood leukaemias 357
The Encyclopedia of DNA Elements (ENCODE) 359
Looking forward 359
Recommended reading 360
Exercises and problems 361

11 Proteomics 363

Learning goals 363

Introduction 364
Protein nature and types of proteins 364
Protein structure 365
The chemical structure of proteins 365
Conformation of the polypeptide chain 367
Protein folding patterns 367
Domains 370
Disorder in proteins 370
Post-translational modifications 372
Why is there a common genetic code with 20 canonical amino acids? 374
Separation and analysis of proteins 375
Polyacrylamide gel electrophoresis (PAGE) 375
Two-dimensional PAGE 375
Mass spectrometry 376
Identification of components of a complex mixture 377
Protein sequencing by mass spectrometry 378
Quantitative analysis of relative abundance 378
Measuring deuterium exchange in proteins 379
Experimental methods of protein structure determination 381
X-ray crystallography of proteins 381
Interpretation of the electron density: model building and improvement 383
How accurate are the structures? 384
NMR spectroscopy in structural biology 386
Protein structure determination by NMR 386
Low-temperature electron microscopy (cryoEM) 387
Classifications of protein structures 388
SCOP 389
SCOP2 391
Protein complexes and aggregates 391
Protein aggregation diseases 392
Properties of protein–protein complexes 393
Stoichiometry—what is the composition of the complex? 393
Affinity—how stable is the complex? 394
 Contents xxiii

How are complexes organized in three dimensions? 395

Multisubunit proteins 396
Many proteins change conformation as part of the mechanism
of their function 396
Conformational change during enzymatic catalysis 397
Motor proteins 399
Allosteric regulation of protein function 401
Allosteric changes in haemoglobin 402
Conformational states of serine protease inhibitors (serpins) 404
Protein structure prediction and modelling 405
Homology modelling 406
Secondary structure prediction 408
Prediction of novel folds: ROSETTA 408
Available protocols for protein structure prediction 409
Structural genomics 411
Directed evolution and protein design 412
Directed evolution of subtilisin E 412
Looking forward 414
Recommended reading 414
Exercises and problems 415

12 Metabolomics 419

Learning goals 419

Introduction 419
Classification and assignment of protein function 420
The Enzyme Commission 420
The Gene Ontology™ Consortium protein function classification 421
Comparison of EC and GO classifications 423
Metabolic networks 424
Databases of metabolic pathways 425
EcoCyc 425
The Kyoto Encyclopedia of Genes and Genomes 427
The Human Metabolome Database 428
Evolution and phylogeny of metabolic pathways 429
Alignment and comparison of metabolic pathways 431
Comparing linear metabolic pathways 432
Reconstruction of metabolic networks 432
Comparing non-linear metabolic pathways: the pentose phosphate
pathway and the Calvin–Benson cycle 434
Metabolomics in ecology 435
Dynamic modelling of metabolic pathways 437
Looking forward 439
Recommended reading 439
Exercises and problems 441
xxiv Contents

13 Systems Biology 443

Learning goals 443

Introduction 444
Regulatory mechanisms 444
Two parallel networks: physical and logical 445
Networks and graphs 446
Robustness and redundancy 447
Connectivity in networks 448
Dynamics, stability, and robustness 449
Protein complexes and aggregates 451
Protein interaction networks 451
Protein–DNA interactions 456
DNA–protein complexes 456
Structural themes in protein–DNA binding and sequence recognition 457
Bacteriophage T7 DNA polymerase 458
Some protein–DNA complexes that regulate gene transcription 459
Regulatory networks 463
Structures of regulatory networks 464
Structural biology of regulatory networks 465
Gene regulation 466
The transcriptional regulatory network of Escherichia coli 466
The genetic switch of bacteriophage λ 469
Regulation of the lactose operon in Escherichia coli 472
The genetic regulatory network of Saccharomyces cerevisiae 474
Adaptability of the yeast regulatory network 476
Looking forward 479
Recommended reading 479
Exercises and problems 480

Epilogue 483
Glossary 484
Index 493
Another random document with
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 WRENS AND NEST. [Page 8.
“It is amusing,” he continues, “to watch the motions
of a young family of wrens just come abroad. A Builder of Many
Nests.
Walking among furze, broom, or juniper, you are
attracted to some bush by hearing issue from it the frequent
repetition of a sound resembling the syllable chit. On going up you
perceive an old wren flitting about the twigs, and presently a young
one flies off, uttering a stifled chirr, to conceal itself among the
bushes. Several follow, whilst the parents continue to flutter about in
great alarm, uttering their chit, chit, with various degrees of
excitement.”
The nest of the wren is a wonderful structure, of which I shall have a
good deal to say. It begins building in April, and is not by any means
particular in situation. Sometimes it builds in the hole of a wall or
tree; sometimes, as in this lovely little picture of ours, in the mossy
hollow of a primrose-covered bank; and because it was formerly
supposed to live only in holes or little caves, it received the name of
Troglodytes, or cave-dweller. But it builds equally willingly in the
thatch of out-buildings, in barn-lofts, or tree-branches, either when
growing apart or nailed against a wall, amongst ivy or other climbing
plants; in fact, it seems to be of such a happy disposition as to adapt
itself to a great variety of situations. It is a singular fact that it will
often build several nests in one season—not that it needs so many
separate dwellings, or that it finishes them when built; but it builds as
if for the very pleasure of the work. Our naturalist says, speaking of
this odd propensity, “that, whilst the hen is sitting, the he-bird, as if
from a desire to be doing something, will construct as many as half-
a-dozen nests near the first, none of which, however, are lined with
feathers; and that whilst the true nest, on which the mother-bird is
sitting, will be carefully concealed, these sham nests are open to
view. Some say that as the wrens, during the cold weather, sleep in
some snug, warm hole, they frequently occupy these extra nests as
winter-bedchambers, four or five, or even more, huddling together, to
keep one another warm.”
Mr. Weir, a friend of the author I have just quoted, says this was the
case in his own garden; and that, during the winter, when the ground
was covered with snow, two of the extra nests were occupied at
night by a little family of seven, which had hatched in the garden. He
was very observant of their ways, and says it was amusing to see
one of the old wrens, coming a little before sunset and standing a
few inches from the nest, utter his little cry till the whole number of
them had arrived. Nor were they long about it; they very soon
answered the call, flying from all quarters—the seven young ones
and the other parent-bird—and then at once nestled into their snug
little dormitory. It was also remarkable that when the wind blew from
the east they occupied a nest which had its opening to the west, and
when it blew from the west, then one that opened to the east, so that
it was evident they knew how to make themselves comfortable.
And now as regards the building of these little homes. I will, as far as
I am able, give you the details of the whole business from the diary
of the same gentleman, which is as accurate as if the little wren had
kept it himself, and which will just as well refer to the little nest in the
primrose bank as to the nest in the Spanish juniper-tree, where, in
fact, it was built.
“On the 30th of May, therefore, you must imagine a
little pair of wrens, having, after a great deal of How a Nest was
built.
consultation, made up their minds to build
themselves a home in the branches of a Spanish juniper. The
female, at about seven o’clock in the morning, laid the foundation
with the decayed leaf of a lime-tree. Some men were at work cutting
a drain not far off, but she took no notice of them, and worked away
industriously, carrying to her work bundles of dead leaves as big as
herself, her mate, seeming the while to be delighted with her
industry, seated not far off in a Portugal laurel, where he watched
her, singing to her, and so doing, making her labour, no doubt, light
and pleasant. From eight o’clock to nine she worked like a little
slave, carrying in leaves, and then selecting from them such as
suited her purpose and putting aside the rest. This was the
foundation of the nest, which she rendered compact by pressing it
down with her breast, and turning herself round in it: then she began
to rear the sides. And now the delicate and difficult part of the work
began, and she was often away for eight or ten minutes together.
From the inside she built the underpart of the aperture with the stalks
of leaves, which she fitted together very ingeniously with moss. The
upper part of it was constructed solely with the last-mentioned
material. To round it and give it the requisite solidity, she pressed it
with her breast and wings, turning the body round in various
directions. Most wonderful to tell, about seven o’clock in the evening
the whole outside workmanship of this snug little erection was almost
complete.
“Being very anxious to examine the interior of it, I went out for that
purpose at half-past two the next morning. I introduced my finger, the
birds not being there, and found its structure so close, that though it
had rained in the night, yet that it was quite dry. The birds at this
early hour were singing as if in ecstasy, and at about three o’clock
the little he-wren came and surveyed his domicile with evident
satisfaction; then, flying to the top of a tree, began singing most
merrily. In half-an-hour’s time the hen-bird made her appearance,
and, going into the nest, remained there about five minutes, rounding
the entrance by pressing it with her breast and the shoulders of her
wings. For the next hour she went out and came back five times with
fine moss in her bill, with which she adjusted a small depression in
the fore-part of it; then, after twenty minutes’ absence, returned with
a bundle of leaves to fill up a vacancy which she had discovered in
the back of the structure. Although it was a cold morning, with wind
and rain, the male bird sang delightfully; but between seven and
eight o’clock, either having received a reproof from his wife for his
indolence, or being himself seized with an impulse to work, he began
to help her, and for the next ten minutes brought in moss, and
worked at the inside of the nest. At eleven o’clock both of them flew
off, either for a little recreation, or for their dinners, and were away till
a little after one. From this time till four o’clock both worked
industriously, bringing in fine moss; then, during another hour, the
hen-bird brought in a feather three times. So that day came to an
end.
“The next morning, June 1st, they did not begin their work early, as
was evident to Mr. Weir, because having placed a slender leaf-stalk
at the entrance, there it remained till half-past eight o’clock, when the
two began to work as the day before with fine moss, the he-bird
leaving off, however, every now and then to express his satisfaction
on a near tree-top. Again, this day, they went off either for dinner or
amusement; then came back and worked for another hour, bringing
in fine moss and feathers.
“The next morning the little he-wren seemed in a
regular ecstasy, and sang incessantly till half-past The Patient
Industry of this
nine, when they both brought in moss and feathers, Bird.
working on for about two hours, and again they went off, remaining
away an hour later than usual. Their work was now nearly over, and
they seemed to be taking their leisure, when all at once the hen-bird,
who was sitting in her nest and looking out at her door, espied a man
half-hidden by an arbor vitæ. It was no other than her good friend,
but that she did not know; all men were terrible, as enemies to her
race, and at once she set up her cry of alarm. The he-bird, on
hearing this, appeared in a great state of agitation, and though the
frightful monster immediately ran off, the little creatures pursued him,
scolding vehemently.
“The next day they worked again with feathers and fine moss, and
again went off after having brought in a few more feathers. So they
did for the next five days; working leisurely, and latterly only with
feathers. On the tenth day the nest was finished, and the little
mother-bird laid her first egg in it.”
Where is the boy, let him be as ruthless a bird-nester as he may, who
could have the heart to take a wren’s nest, only to tear it to pieces,
after reading the history of this patient labour of love?
The wren, like various other small birds, cannot bear that their nests
or eggs should be touched; they are always disturbed and distressed
by it, and sometimes even will desert their nest and eggs in
consequence. On one occasion, therefore, this good, kind-hearted
friend of every bird that builds, carefully put his finger into a wren’s
nest, during the mother’s absence, to ascertain whether the young
were hatched; on her return, perceiving that the entrance had been
touched, she set up a doleful lamentation, carefully rounded it again
with her breast and wings, so as to bring everything into proper
order, after which she and her mate attended to their young. These
particular young ones, only six in number, were fed by their parents
278 times in the course of a day. This was a small wren-family; and if
there had been twelve, or even sixteen, as is often the case, what an
amount of labour and care the birds must have had! But they would
have been equal to it, and merry all the time.
For all these little creatures, which so lightly we regard,
They love to do their duty, and they never think it hard.
 CHAPTER II.
THE GOLDFINCH.
The Goldfinch, which is cousin to the Linnet, is wonderfully clever
and docile, as I shall show you presently. In the first place, however,
let me say a word or two about bird cleverness in general, which I
copy from Jules Michelet’s interesting work, “The Bird.” Speaking of
the great, cruel, and rapacious family of the Raptores, or Birds of
Prey, he expresses satisfaction in the idea that this race of
destroyers is decreasing, and that there may come a time when they
no longer exist on the earth. He has no admiration for them, though
they may be the swiftest of the swift, and the strongest of the strong,
because they put forth none of the higher qualities of courage,
address, or patient endurance in taking their prey, which are all weak
and powerless in comparison with themselves; their poor
unoffending victims. “All these cruel tyrants of the air,” he says, “like
the serpents, have flattened skulls, which show the want of intellect
and intelligence. These birds of prey, with their small brains, offer a
striking contrast to the amiable and intelligent species which we find
amongst the smaller birds. The head of the former is only a beak,
that of the latter is a face.” Afterwards, to prove this more strongly,
he gives a table to show the proportion of brain to the size of the
body in these different species of birds. Thus the chaffinch, the
sparrow, and the goldfinch, have more than six times as much brain
as the eagle in proportion to the size of the body. We may look,
therefore, for no less than six times his intelligence and docile ability.
Whilst in the case of the little tomtit it is thirteen times as much.
But now for the goldfinch, of which our cut—which is both faithful and
beautiful—shows us a pair, evidently contemplating with much
satisfaction the nest which they have just finished on one of the
topmost boughs of a blossomy apple-tree. This nest is a wonderful
little fabric, built of moss, dry grass, and slender roots, lined with hair,
wool, and thistle-down; but the true wonder of the nest is the exact
manner in which the outside is made to imitate the bough upon
which it is placed. All its little ruggednesses and lichen growths are
represented, whilst the colouring is so exactly that of the old apple-
tree that it is almost impossible to know it from the branch itself.
Wonderful ingenuity of instinct, which human skill would find it almost
impossible to imitate!
The bird lays mostly five eggs, which are of a bluish-grey, spotted
with greyish-purple or brown, and sometimes with a dark streak or
two.
The goldfinch is one of the most beautiful of our English birds, with
its scarlet forehead, and quaint little black velvet-like cap brought
down over its white cheeks; its back is cinnamon brown, and its
breast white; its wings are beautifully varied in black and white, as
are also its tail feathers. In the midland counties it is known as “The
Proud Tailor,” probably because its attire looks so bright and fresh,
and it has a lively air as if conscious of being well dressed.
 GOLDFINCHES AND NEST. [Page 16.
Like its relation, the linnet, it congregates in flocks
as soon as its young can take wing, when they may Daily Life of this
be seen wheeling round in the pleasant late Bird.
summer and autumn fields, full of life, and in the enjoyment of the
plenty that surrounds them, in the ripened thistle-down, and all such
winged seeds as are then floating in the air.
How often have I said it is worth while to go out into the woods and
fields, and, bringing yourself into a state of quietness, watch the little
birds in their life’s employment, building their nests, feeding their
young, or pursuing their innocent diversions! So now, on this
pleasant, still autumn afternoon, if you will go into the old pasture
fields where the thistles have not been stubbed up for generations,
or on the margin of the old lane where ragwort, and groundsel, and
burdock flourish abundantly, “let us,” as the author of “British Birds”
says, “stand still to observe a flock of goldfinches. They flutter over
the plants, cling to the stalks, bend in various attitudes, disperse the
down, already dry and winged, like themselves, for flight, pick them
out one by one and swallow them. Then comes a stray cow followed
by a herd boy. At once the birds cease their labour, pause for a
moment, and fly off in succession. You observe how lightly and
buoyantly they cleave the air, each fluttering its little wings,
descending in a curved line, mounting again, and speeding along.
Anon they alight in a little thicket of dried weeds, and, in settling,
display to the delighted eye the beautiful tints of their plumage, as
with fluttering wings and expanded tail, they hover for a moment to
select a landing place amid the prickly points of the stout thistles
whose heads are now bursting with downy-winged seeds.”
The song of the goldfinch, which begins about the
end of March, is very sweet, unassuming, and low The Goldfinch.
—similar to that of the linnet, but singularly varied
and pleasant.
Now, however, we must give a few instances of this bird’s teachable
sagacity, which, indeed, are so numerous that it is difficult to make a
selection.
Mr. Syme, in his “British Song Birds,” says, “The goldfinch is easily
tamed and taught, and its capacity for learning the notes of other
birds is well known. A few years ago the Sieur Roman exhibited a
number of trained birds: they were goldfinches, linnets, and canaries.
One appeared dead, and was held up by the tail or claw without
exhibiting any signs of life; a second stood on its head with its claws
in the air; a third imitated a Dutch milkmaid going to market with pails
on its shoulders; a fourth mimicked a Venetian girl looking out at a
window; a fifth appeared as a soldier, and mounted guard as a
sentinel; whilst a sixth acted as a cannonier, with a cap on its head, a
firelock on its shoulder, and a match in its claw, and discharged a
small cannon. The same bird also acted as if it had been wounded. It
was wheeled in a barrow as if to convey it to the hospital, after which
it flew away before the whole company. The seventh turned a kind of
windmill; and the last bird stood in the midst of some fireworks which
were discharged all round it, and this without showing the least sign
of fear.”
Others, as I have said, may be taught to draw up their food and
water, as from a well, in little buckets. All this is very wonderful, and
shows great docility in the bird; but I cannot greatly admire it, from
the secret fear that cruelty or harshness may have been used to
teach them these arts so contrary to their nature. At all events it
proves what teachable and clever little creatures they are, how
readily they may be made to understand the will of their master, and
how obediently and faithfully they act according to it.
Man, however, should always stand as a human Providence to the
animal world. In him the creatures should ever find their friend and
protector; and were it so we should then see many an astonishing
faculty displayed; and birds would then, instead of being the most
timid of animals, gladden and beautify our daily life by their sweet
songs, their affectionate regard, and their amusing and imitative little
arts.
The early Italian and German painters introduce a
goldfinch into their beautiful sacred pictures— Introduced into
generally on the ground—hopping at the feet of Pictures.
some martyred saint or love-commissioned angel, perhaps from an
old legend of the bird’s sympathy with the suffering Saviour, or from
an intuitive sense that the divine spirit of Christianity extends to bird
and beast as well as to man.
 CHAPTER III.
THE SONG THRUSH.
We have here a charming picture of one of the finest and noblest of
our song-birds—the thrush, throstle, or mavis. The trees are yet
leafless, but the bird is in the act of building, whilst her mate, on the
tree-top, pours forth his exquisite melody. The almost completed
nest, like a richly ornamented bowl, is before us.
This bird belongs to a grandly musical family, being own cousin to
the missel-thrush and the blackbird, each one having a kindred song,
but all, at the same time, distinctly characteristic.
The colouring of the thrush is soft and very pleasing; the upper parts
of a yellowish-brown; the chin, white; the under part of the body,
grayish white; the throat, breast, and sides of the neck, yellowish,
thickly spotted with dark brown.
 SONG THRUSH AND NEST. [Page 20.
The thrush remains with us the whole year, and may occasionally be
heard singing even in the winter, though April, May, and June are the
months when he is in fullest song. They pair in March, and by the
end of that month, or early in April, begin to build. They have several
broods in the year. The nest, which, as we see, is commodious, is
placed at no great height from the ground, in a thick bush or hedge,
and sometimes, also, in a rough bank, amongst bushes and
undergrowth. They are particularly fond of spruce-fir plantations,
building on one of the low, spreading branches, close to the stem.
Though the structure is so solid and substantial, yet it is built very
rapidly; indeed, the thrush seems to be wide awake in all its
movements; he is no loiterer, and does his work well. As a proof of
his expedition I will mention that a pair of these birds began to build
a second, perhaps, indeed, it might be a third nest, on a Thursday,
June 15; on Friday afternoon the nest was finished, and on Saturday
morning the first egg was laid, though the interior plastering was not
then dry. On the 21st the hen began to sit, and on the 17th of July
the young birds were hatched.
The frame-work, so to speak, of the nest is composed of twigs, roots,
grasses, and moss, the two latter being brought to the outside.
Inside it is lined with a thin plastering of mud, cow-dung, and rotten
wood, which is laid on quite smoothly, almost like the glaze on
earthenware; nor is there an internal covering between this and the
eggs. The circular form of the nest is as perfect as a bowl shaped
upon a lathe, and often contracts inwards at the top. The eggs,
which are generally five in number, are of a bright blue-green,
spotted over with brownish-black, these spots being more numerous
at the larger end.
The food of the thrush is mostly of an animal character, as worms,
slugs, and snails; and, by seasides, small molluscs, as whelks and
periwinkles. On all such as are enclosed in shells he exercises his
ingenuity in a remarkable way. We ourselves lived at one time in an
old house standing in an old garden where were many ancient trees
and out-buildings, in the old ivied roots and walls of which
congregated great quantities of shell-snails. One portion of this
garden, which enclosed an old, disused dairy, was a great resort of
thrushes, where they had, so to speak, their stones of sacrifice,
around which lay heaps of the broken shells of snails, their victims. I
have repeatedly watched them at work: hither they brought their
snails, and, taking their stand by the stone with the snail in their
beak, struck it repeatedly against the stone, till, the shell being
smashed, they picked it out as easily as the oyster is taken from its
opened shell. This may seem easy work with the slender-shelled
snail, but the labour is considerably greater with hard shell-fish. On
this subject the intelligent author of “British Birds” says, that many
years ago, when in the Isle of Harris, he frequently heard a sharp
sound as of one small stone being struck upon another, the cause of
which he, for a considerable time, sought for in vain. At length, one
day, being in search of birds when the tide was out, he heard the
well-known click, and saw a bird standing between two flat stones,
moving its head and body alternately up and down, each downward
motion being accompanied by the sound which had hitherto been so
mysterious. Running up to the spot, he found a thrush, which, flying
off, left a whelk, newly-broken, lying amongst fragments of shells
lying around the stone.
Thrushes are remarkably clean and neat with regard to their nests,
suffering no litter or impurity to lie about, and in this way are a great
example to many untidy people. Their domestic character, too, is
excellent, the he-bird now and then taking the place of the hen on
the eggs, and, when not doing so, feeding her as she sits. When the
young are hatched, the parents may be seen, by those who will
watch them silently and patiently, frequently stretching out the wings
of the young as if to exercise them, and pruning and trimming their
feathers. To put their love of cleanliness to the proof, a gentleman, a
great friend of all birds, had some sticky mud rubbed upon the backs
of two of the young ones whilst the parents were absent. On their
return, either by their own keen sense of propriety, or, perhaps, the
complaint of the young ones, they saw what had happened, and
were not only greatly disconcerted, but very angry, and instantly set
to work to clean the little unfortunates, which, strange to say, they
managed to do by making use of dry earth, which they brought to the
nest for that purpose. Human intellect could not have suggested a
better mode.
This same gentleman determined to spend a whole
day in discovering how the thrushes spent it. Hiding How a Day was
himself, therefore, in a little hut of fir boughs, he spent.
began his observations in the early morning of the 8th of June. At
half-past two o’clock, the birds began to feed their brood, and in two
hours had fed them thirty-six times. It was now half-past five, the little
birds were all wide awake, and one of them, whilst pruning its
feathers, lost its balance and fell out of the nest to the ground. On
this the old ones set up the most doleful lamentations, and the
gentleman, coming out of his retreat, put the little one back into the
nest. This kind action, however, wholly disconcerted the parents, nor
did they again venture to feed their young till an artifice of the
gentleman led them to suppose that he was gone from their
neighbourhood. No other event happened to them through the day,
and by half-past nine o’clock at night, when all went to rest, the
young ones had been fed two hundred and six times.
Thrushes, however, become occasionally so extremely tame that the
female will remain upon her eggs and feed her young, without any
symptom of alarm, in the close neighbourhood of man. Of this I will
give an instance from Bishop Stanley’s “History of Birds”—
“A short time ago, in Scotland, some carpenters working in a shed
adjacent to the house observed a thrush flying in and out, which
induced them to direct their attention to the cause, when, to their
surprise, they found a nest commenced amongst the teeth of a
harrow, which, with other farming tools and implements, was placed
upon the joists of the shed, just over their heads. The carpenters had
arrived soon after six o’clock, and at seven, when they found the
nest, it was in a great state of forwardness, and had evidently been
the morning’s work of a pair of these indefatigable birds. Their
activity throughout the day was incessant; and, when the workmen
came the next morning, they found the female seated in her half-
finished mansion, and, when she flew off for a short time, it was
found that she had laid an egg. When all was finished, the he-bird
took his share of the labour, and, in thirteen days, the young birds
were out of their shells, the refuse of which the old ones carried
away from the spot. All this seems to have been carefully observed
by the workmen; and it is much to their credit that they were so quiet
and friendly as to win the confidence of the birds.”
The song of the thrush is remarkable for its rich, mellow intonation,
and for the great variety of its notes.
Unfortunately for the thrush, its exquisite power as
a songster makes it by no means an unusual Wordsworth’s
prisoner. You are often startled by hearing, from the Verses
Thrush.
on the

doleful upper window of some dreary court or alley

of London, or some other large town, an outpouring of joyous, full-
souled melody from an imprisoned thrush, which, perfect as it is,
saddens you, as being so wholly out of place. Yet who can say how
the song of that bird may speak to the soul of many a town-
imprisoned passer-by? Wordsworth thus touchingly describes an
incident of this kind:—
At the corner of Wood Street, when daylight appears,
Hangs a thrush that sings loud; it has sung for three years:
Poor Susan has passed by the spot, and has heard,
In the silence of morning, the song of the bird.

Green pastures she views in the midst of the dale,

Down which she so often has tripped with her pail,
And a single small cottage, a nest like a dove’s,
The one only dwelling on earth which she loves.

’Tis a note of enchantment; what ails her? she sees

A mountain ascending, a vision of trees;
Bright volumes of vapour through Lothbury glide,
And a river flows on through the vale of Cheapside.

She looks, and her heart is in heaven: but they fade—

The mist and the river, the hill, sun, and shade;
The stream will not flow, and the hill will not rise,
And the colours have all passed away from her eyes.
 CHAPTER IV.
THE BLACKBIRD.
The Blackbird is familiar to us all. It is a thoroughly English bird, and,
with its cousin the thrush, is not only one of the pleasantest features
in our English spring and summer landscape, but both figure in our
old poetry and ballads, as the “merle and the mavis,” “the blackbird
and the throstle-cock;” for those old poets loved the country, and
could not speak of the greenwood without the bird.
When shaws are sheen and fields are fair,
And leaves both large and long,
’Tis merry walk’ng in the green forest
To hear the wild birds’ song;

The wood merle sings, and will not cease,

Sitting upon a spray;
The merle and the mavis shout their fill,
From morn till the set of day.
 BLACKBIRD AND NEST. [Page 26.
The blackbird takes its name from a very intelligible cause—its
perfectly black plumage, which, however, is agreeably relieved by
the bright orange of its bill, the orange circles round its eyes, and its
yellow feet; though this is peculiar only to the male, nor does he
assume this distinguishing colour till his second year. The female is
of a dusky-brown colour.