Table Of ContentIntroduction to Genomics
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INTRODUCTION TO
GENOMICS
SECOND EDITION
Arthur M. Lesk
The Pennsylvania State University
Immured the whole of Life
Within a magic Prison
– Emily Dickinson
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For Victor and Valerie
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PREFACE TO THE FIRST EDITION
Of all the claims on our curiosity, we want most sources of our differences from our closest extant
to understand ourselves. What are we? What lies in non-human relatives, the chimpanzees? What do we
our future? Many features of our lives depend on have in common and how do we diverge from other
accidents of history. The time and place of our birth species of primates? of mammals? of vertebrates? of
largely determine what language we fi rst learn to eukaryotes? of all other living things?
speak and whether we are likely to be well-fed and The complete sequences of human and other
well-educated and receive adequate medical care. genomes give us complete information about the
Many aspects of our future depend on events outside underlying text of this story. We are beginning to
ourselves and beyond our control. understand how our lives shape themselves under the
Within ourselves, also, there are constraints on our infl uence of our genes plus our surroundings.
lives that brook relatively little argument. In some We are also beginning to intervene. Genetic engineer-
respects, we are at the mercy of our genomes. Under ing of microorganisms is an established technique.
normal circumstances, all of our basic anatomy and Genetically modifi ed plants and animals exist and
physiology, and eye colour, height, intelligence and are the subjects of lively debate. To override the genes
basic personality traits, are ingrained in our DNA for hair colour is trivial. Changes in lifestyle or
sequences. This is not to say that our genomes dictate behaviour can – to some extent – avoid or postpone
our lives. Some of the constraints are tight – eye development of diseases to which we are genetically
colour, for instance – but our genetic endowment prone. Gene therapy offers the promise of rectifying
also confers on us a remarkable robustness. some inborn defects.
This robustness also is a product of evolution. In this book, we shall explore this new knowledge,
When Shakespeare wrote of ‘the thousand natural what it tells us about ourselves and how we can apply
shocks that fl esh is heir to’, he coupled the challenges it. With power derived from knowledge goes com-
of life to heredity. Within the last century, lifestyles mitment to act wisely. We have responsibilities, to
have changed with a rapidity hitherto unknown ourselves, to other people, to other species and to
(except for the instants of asteroid impacts). Our tal- ecosystems ranging in size up to the entire biosphere.
ents have many opportunities to nurture themselves Ethical, legal and social issues have been a promin-
and develop in novel ways, and we can meet and sur- ent component of the human genome project. Most
vive brutal stresses. These are gifts of our genomic technical questions in genomics, as in other scientifi c
endowment: What genes control is the response of an subjects, have objectively correct answers. We do not
organism to its environment. know all the answers, but they are out there for us to
The human genome is only one of the many com- discover. Ethical, legal and social issues are different.
plete genome sequences known. Taken together, Many choices are possible. Their selection is not the
genome sequences from organisms distributed widely privilege of scientists in individual laboratories, but
among the branches of the tree of life give us a sense, of society as a whole. Scientists do have a responsibil-
only hinted at before, of the very great unity in detail ity to contribute to the informed public discussion
of all life on Earth. This recognition has changed our that is essential for wise decisions.
perceptions, much as the fi rst pictures of the Earth One problem encountered in writing about gen-
from space engendered a unifi ed view of our planet. omics is the need to pick and choose from the many
Of course, superimposed on this basic unity is riches of the subject. The list of subjects that cannot
great variety. We ask: What is special about us? What be left out is too long and threatens to reduce the
do we share with our parents and siblings and how treatment of each to superfi ciality. There is also a
do we differ from them? What do we share with all serious organizational challenge: many phenomena
other human beings and what makes us different must be approached from several different points of
from the other members of our species? What are the view. A reader may be relieved to conclude that a
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viii Preface to the first edition
topic has been beaten thoroughly into submission at least in part, to all of them. However, the central
in one chapter, only to encounter it again, alive and point of view remains focused on the biology.
kicking, in a different context. More specifi cally, the focus is on human biology.
The speed at which the fi eld is moving causes other In fact, on the biology of humans who are curious
problems. One is often pleased with a draft of a sec- about other species, albeit primarily for what the
tion only to fi nd the carefully described conclusions other species tell us about ourselves. This choice
modifi ed in next week’s journals. Yet, there is a great naturally refl ects the potential readership of this
pleasure in seeing Nature’s secrets emerging before book. (If bacteria or fruit fl ies could read, genomics
one’s eyes. textbooks would look very different.)
Another casualty of rapid progress is a loss of This book assumes that the reader already has
interest in history and biography. We are fantastically some acquaintance with modern molecular biology,
interested in the development of the sea urchin and and builds on and develops this background, as a
the fruit fl y, but not at all in the development of self-contained presentation. It is suitable as a text-
molecular genomics. Intellectual struggles that occu- book for undergraduates or starting postgraduate
pied entire careers leave behind only terse conclusions, students.
often without any appreciation of the experiments Exercises, problems and ‘weblems’ at ends of chap-
that established the facts, much less of the alternative ters test and consolidate understanding and provide
hypothesis tested and rejected. The force of the scien- opportunities to practise skills and explore additional
tists’ personalities, and their foibles, are forgotten. subjects. Exercises are short and straightforward
This is too bad: those who do not learn from the suc- applications of material in the text. Answers to exer-
cesses of history will fi nd it harder to emulate them. cises appear on the web site associated with the book.
Genomics is an interdisciplinary subject. The phe- Problems, also, make use of no information not
nomena we want to explain are biological. But many contained in the text, but require lengthier answers
fi elds contribute to the methods and the intellectual or in some cases calculations. The third category,
approaches that we bring to bear on the data. Physi- ‘weblems’, require access to the World Wide Web.
cists, mathematicians, computer scientists, engineers, Weblems are designed to give readers practice with
chemists, clinical practitioners and researchers, have the tools required for further study and research in
all joined in the enterprise. This book will appeal, the fi eld.
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PREFACE TO THE SECOND EDITION
Fast, inexpensive sequencing has transformed genom- support of conservation efforts dedicated to preserv-
ics. The landmark goal, the $US1000 human genome, ing endangered species. Development of alternative
will likely soon be achieved. At the time of writing, energy sources is a challenge to both physics and
thousands of human individuals have had their full biology.
genomes sequenced, and many more are on the way. Underlying these applications, genomics offers us
A very large number of people have had sequences a profound understanding of fundamental principles
determined for individual genes. For example, muta- of biology. On the personal level, genome exegesis
tions in BRCA1 suggest an increased likelihood of will fundamentally alter our perception of ourselves:
developing breast or ovarian cancer. what does it mean to be human? The answer lies
Genetic testing for disease is one of many possible somewhere in the complex interplay of our genes
fi elds of application of genomics. Clinical medicine and life histories. For some characteristics, there is a
heads the list; no one doubts that it was the promise simple answer. Your eye colour, and whether or not
of improvements in health that motivated support for you suffer from sickle-cell anaemia, depend exclu-
the original human genome project. Understanding sively on the sequences of particular genes. For most
the relationships between genes and disease will allow of your phenotypic traits, however, the assignment
more precise diagnosis and warnings of increased risk of contributions to their origin from genome, epi-
of disease in patients and their offspring. It will allow genetics, and life history is a severe challenge.
design of treatment tailored to the biochemical char- In this book, I have tried to present a balanced
acteristics of the patient, called pharmacogenomics. view of the background of the subject, the technical
Genomes of other organisms also have implications developments that have so greatly increased the data
for human health, especially those of pathogenic fl ow, the current state of our knowledge and under-
organisms that have developed, or are threatening to standing of the data, and applications to medicine
develop, antibiotic resistance. Other applications of and other fi elds. One aspect of the fi rst edition that
genomics include improvement of crops and domes- I liked was its concision. Unfortunately, this has had
ticated animals, enhancing food production, and to be sacrifi ced to the stampeding progress of the fi eld.
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