Genetics and Genomics in Medicine

546 Pages·2015·28.53 MB·English

by  Tom Strachan, Judith Goodship and Patrick Chinnery

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Genetics and Genomics in Medicine is a new textbook written for undergraduate I
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students, graduate students, and medical researchers that explains the science
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behind the uses of genetics and genomics in medicine today. It is a comprehensive

and integrated account of how genetics and genomics affect the whole spectrum of a
human health and disease. DNA technologies are explained, with emphasis on the n
modern techniques that have revolutionized the use of genetic information in d
medicine and are indicating the role of genetics in common diseases. Epigenetics
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and non-coding RNA are covered in-depth as are genetic approaches to treatment
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and prevention, including pharmacogenomics, genetic testing, personalized medicine,
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clinical genomics, and public health genomics. Cancers are essentially genetic
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diseases and are given a dedicated chapter that includes new insights into its
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molecular basis and approaches to its detection gained from cancer genomics.
Specific topics such as clinical disorders, molecular mechanisms, and technological I
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advances are discussed in boxes throughout the text.
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Tom Strachan is Emeritus Professor of Human Molecular Genetics at h
Newcastle University, UK and co-author of Human Molecular Genetics ip (cid:127)
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Judith Goodship is Professor of Medical Genetics and a in
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Consultant Clinical Geneticist at Newcastle University, UK e
ry Tom Strachan
Patrick Chinnery is Professor of Neurogenetics and a
Consultant Clinical Neurologist at Newcastle University, UK
ISBN 978-0-8153-4480-3
Judith Goodship (cid:127) Patrick Chinnery
99 778800881155 334444880033
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Tom Strachan
Judith Goodship • Patrick Chinnery
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Garland Science
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Editor: Elizabeth Owen
Assistant Editor: Dave Borrowdale
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©2015 by Garland Science, Taylor & Francis Group, LLC
This book contains information obtained from authentic and highly regarded Tom Strachan is Emeritus Professor of Human Molecular
sources. Every effort has been made to trace copyright holders and to Genetics at Newcastle University, UK. He was the founding
obtain their permission for the use of copyright material. Reprinted material Head of Institute at Newcastle University’s Institute of
is quoted with permission, and sources are indicated. A wide variety of Human Genetics (now the Institute of Genetic Medicine)
references are listed. Reasonable efforts have been made to publish reliable and is a Fellow of the Royal Society of Edinburgh and
data and information, but the author and the publisher cannot assume a Fellow of the Academy of Medical Sciences. Tom has
responsibility for the validity of all materials or for the consequences of their made many important research contributions in medical,
use. All rights reserved. No part of this publication may be reproduced, stored evolutionary and developmental genetics. After publishing
in a retrieval system or transmitted in any form or by any means—graphic, a short textbook on the Human Genome in 1992 he
electronic, or mechanical, including photocopying, recording, taping, or conceived the idea of a larger, follow-up textbook, Human
information storage and retrieval systems—without permission of the Molecular Genetics, currently in its fourth edition and
copyright holder. co-written with a former colleague, Andrew Read. Their
achievement was recognized by the award of the European
Society of Human Genetics’s Education Prize in 2007.
ISBN 978-0-8153-4480-3
Patrick Chinnery is Director of the Institute of Genetic
Medicine at Newcastle University, where he is Professor
Library of Congress Cataloging-in-Publication Data of Neurogenetics and a Clinical Neurologist. He has
Strachan, T., author. been a Wellcome Trust Senior Fellow in Clinical Science
Genetics and genomics in medicine / Tom Strachan, Judith Goodship, for over ten years, and is a Fellow of the Academy of
Patrick Chinnery. Medical Sciences. His laboratory and clinical research
p. ; cm. has focussed on understanding the molecular basis of
Includes bibliographical references. inherited neurological diseases, with a particular interest in
ISBN 978-0-8153-4480-3 (paperback : alk. paper) mitochondrial disorders. In addition to defining several new
I. Goodship, J. (Judith), author. II. Chinnery, Patrick F., author. mitochondrial disease genes, he has defined the molecular
III. Title. mechanisms underpinning the mtDNA genetic bottleneck,
[DNLM: 1. Genetic Phenomena. 2. Genetic Diseases, Inborn--therapy. 3. and carried out clinical trials developing new treatments
Genomics. 4. Individualized Medicine. QU 450] for mitochondrial disorders.
RB155.5
616’.042--dc23 Judith Goodship is Professor of Medical Genetics at
2014010769 Newcastle University and a Clinical Geneticist. She has
identified the molecular basis of a number of Mendelian
disorders including Seckel syndrome and Ellis-van Creveld
Published by Garland Science, Taylor & Francis Group, LLC, syndrome. Her main research is on development of the
an informa business, heart and congenital heart disease. As a practicing clinician
711 Third Avenue, New York, NY, 10017, USA, her aim is to improve management of inherited disorders;
and 3 Park Square, Milton Park, Abingdon, OX14 4RN, UK. she particularly wants to improve support and information
for those with genetic disorders around the transition from
Printed in the United States of America childhood to adulthood.
15 14 13 12 11 10 9 8 7 6 5 4 3 2 1
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PREFACE
Enduring high hopes that genetics might transform medicine have been
tempered by technical challenges that initially restricted the pace of devel-
opments. Even until quite recently, the geneticist’s view of our genome
was typically limited to small regions of interest, a gene-centered vista.
The Human Genome Project and subsequent technological develop-
ments—notably, genomewide microarray technologies and massively
parallel DNA sequencing—changed all that. Now, genome-centered
perspectives are readily attained and are transforming the research land-
scape and clinical applications. In January 2014, the long-sought $1000
genome became a reality at last, genomewide screening and diagnosis
are becoming routine, and ambitious sequencing projects are underway
to decode the genomes of very large numbers of affected individuals.
Might we soon live in societies in which genome sequencing of citizens
becomes the norm?
It’s a time of transition: the era of medical genetics—with a focus on
chromo somal abnormalities, monogenic disorders, and genes—is giving
way to the era of clinical and public health genomics; genomewide
analyses of genetic variation are beginning to link genome to phenome
in a comprehensive way. Genetic and genomic technologies are being
deployed in a wide range of medical disciplines, and debate has begun as
to what conditions might make it appropriate to begin routine genome
sequencing of newborns. That, inevitably, raises many ethical questions.
In this book we try to summarize pertinent knowledge, and to structure
it in the form of principles, rather than seek to compartmentalize inform-
ation into chapters on topics such as genetic variation, epigenetics,
population genetics, evolutionary genetics, immunogenetics, and
pharma cogenetics. To help readers find broad topics that might be dealt
with in two or more chapters we provide a road map on the inside front
cover that charts how some of the broad themes are distributed between
different chapters.
We start with three introductory chapters that provide basic back-
ground details. Chapters 1 and 2 cover the fundamentals of DNA,
chromosomes, the cell cycle, human genome organization, and gene
expression. Chapter 3 introduces the basics of three core molecular
genetic approaches used to manipulate DNA: DNA amplification (by DNA
cloning or PCR), nucleic acid hybridization, and DNA sequencing, but we
delay bringing in applica tions of these fundamental methods until later
chapters, setting them against appropriate contexts that directly explain
their relevance.
The next three chapters provide some background principles at a
higher level. In Chapter 4 we take a broad look at general principles of
genetic variation, including DNA repair mechanisms and some detail on
functional variation (but we consider how genetic variation contributes
to disease in later chapters, notably chapters 7, 8, and 10). Chapter 5
takes a look at how genes are transmitted in families and at allele
frequencies in populations. Chapter 6 moves from the basic principles
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vi PREFACE
of gene expression covered in Chapter 2 to explaining how genes are
regulated by a wide range of protein and noncoding RNA regulators, and
the central role of regulatory sequences in both DNA and RNA. In this
chapter, too, we outline the principles of chromatin modification and
epigenetic regulation, and explain how aberrant chromatin structure
underlies many single-gene disorders.
The remainder of the book is devoted to clinical applications. We explain in
Chapter 7 how chromosome abnormalities arise and their consequences,
and how mutations and large-scale DNA changes can directly cause
disease. In Chapter 8 we look at how genes underlying single-gene
disorders are identified, and how genetic variants that confer susceptibil-
ity to complex diseases are identified. Then we consider the ways in
which genetic variants, epigenetic dysregulation, and environmental
factors all make important contributions to complex diseases. Chapter 9
briefly covers the wide range of approaches for treating genetic disorders,
before examining in detail how genetic approaches are used directly and
indirectly in treating disease. In this chapter, too, we examine how genetic
variation affects how we respond to drug treatment. Chapter 10 deals with
cancer genetics and genomics, and explains how cancers arise from a
combination of abnormal genetic variants and epigenetic dysregulation.
Finally, Chapter 11 takes a broad look at diagnostic applications (and the
exciting applications offered by new genomewide technologies), plus
ethical considerations in diagnosis and gene therapies.
As genetic and genomic technologies have an increasing impact on
mainstream medicine, and huge numbers of people have their genomes
decoded for medical reasons, we really are moving into a new era. How
far will we move from the commonplace one-size-fits-all approach to
disease treatment toward an era of personalized or precision medicine?
At the very least, we can expect an era of stratified medicine in which,
according to the genetic variants exhibited by patients with specific dis-
eases, different medical actions are taken.
We have tried to convey the excitement of fast-moving research in genet-
ics and genomics and their clinical applications, while explaining how
the progress has been achieved. There is a long way to go, notably in fully
understanding complex disease and in developing effective treatments
for many disorders, despite some impressive recent advances in gene
therapy. But the new technological developments have engendered an
undeniable sense of excitement and optimism.
We would like to thank the staff at Garland Science, Elizabeth Owen,
David Borrowdale and Ioana Moldovan, who have undertaken the job
of converting our drafts into the finished product. We are also grateful to
the support of family members: to Meryl Lusher and James Strachan for
help on proofreading and choice of questions, and to Alex Strachan for
assistance on various text issues.
Tom Strachan, Judith Goodship, and Patrick Chinnery
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PREFACE vii
Literature access
We live in a digital age and, accordingly, we have sought to provide elec-
tronic access to information. To help readers find references cited under
Further Reading we provide the relevant PubMed identification (PMID)
numbers for the individual articles – see also the PMID glossary item.
We would like to take this opportunity to thank the US National Center
for Biotechnology Information (NCBI) for their invaluable PubMed data-
base that is freely available at: http://www.ncbi.nlm.nih.gov/pubmed/.
Readers who are interested in new research articles that have emerged
since publication of this book, or who might want to study certain areas
in depth, may wish to take advantage of literature citation databases such
as the freely available Google Scholar database (scholar.google.com).
For background information on single gene disorders we often provide
reference numbers to access OMIM, the Online Mendelian Inheritance
in Man database (http://www.omim.org). For the more well-studied of
these disorders, individual chapters in the University of Washington’s
GeneReviews series are highly recommended. They are electronically
available at the NCBI’s Bookshelf at (http://www.ncbi.nlm.nih.gov/
books/NBK138602/) and within its PubMed database. For convenience
we have given the PubMed Identifier (PMID) for individual articles in the
GeneReviews series (which are also collected as an alphabetic listing of
all disorders at PMID 20301295).
Online resources
Accessible from www.garlandscience.com, the Student and Instructor
Resource Websites provide learning and teaching tools created for
Genetics and Genomics in Medicine. The Student Resource Site is open
to everyone, and users have the option to register in order to use book-
marking and note-taking tools. The Instructor Resource Site requires
registration and access is available only to qualified instructors. To access
the Instructor Resource Site, please contact your local sales representa-
tive or email [email protected]. Below is an overview of the resources
available for this book. On the Website, the resources may be browsed by
individual chapters and there is a search engine. You can also access the
resources available for other Garland Science titles.
For students
(available directly at www.garlandscience.com/ggm-students)
Quiz A multiple-choice quiz is given with answers and guidance for
self-testing.
Answers and Explanations The answers and explanations to the end of
chapter questions are provided for further analysis of student knowledge
and understanding.
Flashcards Each chapter contains a set of flashcards that allow students
to review key terms from the text.
Glossary The complete glossary from the book can be searched and
browsed as a whole or sorted by chapter.
For instructors
Figures The images from the book are available in two convenient
formats: PowerPoint® and JPEG. They have been optimized for display
on a computer.
Question Bank A further set of questions and answers are provided for
instructors to use as homework, tests, and examinations.
PowerPoint is a registered trademark of Microsoft Corporation in the United States and/
or other countries.
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ACKNOWLEDGMENTS
In writing this book we have benefited greatly from the advice of many
geneticists, biologists and clinicians. We are greatful to many col-
leagues at Newcastle University and the NHS Northern Genetic Service
at Newcastle upon Tyne who advised on the contents of the chapters
and/or commented on some aspects of the text, notably: Lyle Armstrong,
David Bourn, Nick Bown, Gareth Breese, Steven Clifford, Heather Cordell,
Ann Daly, David Elliott, Jerome Evans, Fiona Harding, Michael Jackson,
Majlinda Lako, Herbie Newell, Caroline Relton, Miranda Splitt, Louise
Stanley, Josef Vormoor and Simon Zwolinski.
We would also like to thank the external reviewers for their suggestions
and advice in preparing the text and figures.
Sayeda Abu-Amero (University College London Institute of Child Health,
UK); S.S. Agarwal (Sanjay Gandhi Postgraduate Institute of Medical
Sciences, India); Robin Allshire (Edinburgh University); Barbara Birshtein
(Albert Einstein College of Medicine, USA); Daniel Brazeau (University at
New England, USA); Hsiao Chang Chan (Chinese University of Hong Kong,
Hong Kong); Frederic Chedin (University of California, USA); Ken-Shiung
Chen (Nanyang Technological University, Singapore); David N. Cooper
(Cardiff University, UK); Ashwin B. Dalal (Centre for DNA Fingerprinting
and Diagnostics, India); Caroline Dalton (Sheffield Hallam University,
UK); Shoumita Dasgupta (Boston University School of Medicine, USA);
Josh Deignan (University of California, Los Angeles, USA); Donna
Dixon (New York Institute of Technology, USA); Diane Dorsett (Georgia
Gwinnett College, USA); George Edick (Rensselaer Polytechnic Institute,
USA); Mark S. Elliot (George Washington University, USA); David Elliott
(Newcastle University, UK); Robert Fowler (San Jose State University,
USA); Mary Fujiwara (McGill University, Canada); K.M. Girisha [Q1]
(Kasturba Medical College, India); Jack R. Girton (Iowa State University,
USA); Neerja Gupta (All India Institute of Medical Sciences, India);
Adrian Hall (Sheffield Hallam University, UK); Lise Lotte Hansen (Aarhus
University, Denmark); Sankar V. Hariharan (Government Medical College,
India); Graham Heap (Queen Mary, University of London, UK); Chew-
Kiat Heng (National University of Singapore, Singapore); Simon Hettle
(University of the West of Scotland, UK); Matthew Hurles (Wellcome Trust
Sanger Institute, Hinxton, UK); Mary O. Huff (Bellarmine University, USA);
Howard N. Hughes (Manchester Metropolitan University, UK); Daniela
Iacoboni (Michigan State University, USA); David Iles (University of Leeds,
UK); Miho Ishida (University College London Institute of Child Health,
UK); Leigh Jackson (Plymouth University, UK); Maria Jackson (University
of Glasgow, UK); Suman Kapur (Birla Institute of Medical Sciences, India);
Susan Karcher (Purdue University, USA); Robert Koeleman (University
Medical Center Utrecht, Netherlands); Michael Ladomery (University of
the West of England, UK); Zhi-Chun Lai (Pennsylvania State University,
USA); Janine Lamb (University of Manchester, UK); Alan Lehmann
(University of Sussex, UK); Cathy W. Levenson (Florida State University
College of Medicine, USA); Qintong Li (Sichuan University, China); Dick
Lindhout (University Medical Center Utrecht, Netherlands); Anneke
Lucassen (Southampton University, UK); Alasdair MacKenzie (University
of Aberdeen, UK); Khadijah Makky (Marquette University, USA); Elvira
Mambetisaeva (University College London Genetics Institute, UK);
Elaine Mardis (Washington University School of Medicine, USA); Sarabijt
Mastana (Loughborough University, UK); Cynthia J. Moore (Illinois State
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