MOLECULAR MEDICINE Genomics to Personalized Healthcare MOLECULAR MEDICINE Genomics to Personalized Healthcare
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MOLECULAR MEDICINE Genomics to Personalized Healthcare MOLECULAR MEDICINE Genomics to Personalized Healthcare FOURTH EDITION Ronald J Trent PhD, BSc(Med), MBBS (Sydney), DPhil (Oxon), FRACP, FRCPA, FFSc, FTSE Professor of Medical Molecular Genetics, Sydney Medical School, University of Sydney and Director, Department of Molecular & Clinical Genetics, Royal Prince Alfred Hospital, NSW 2050, Australia AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier Academic Press is an imprint of Elsevier 32 Jamestown Road, London NW1 7BY, UK 225 Wyman Street, Waltham, MA 02451, USA 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA First edition 1993 Second edition 1997 Third edition 2005 Fourth edition 2012 Copyright © 2012 Elsevier Inc. All rights reserved No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the publisher Permissions may be sought directly from Elsevier’s Science & Technology Rights Department in Oxford, UK: phone (44) (0) 1865 843830; fax (44) (0) 1865 853333; email: [email protected]. Alternatively, visit the Science and Technology Books website at www.elsevierdirect.com/rights for further information Notice No responsibility is assumed by the publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN: 0-443-04635-2 (First ed) ISBN: 0-443-05366-9 (Second ed) ISBN: 978-0-12-699057-7 (Third ed) ISBN: 978-0-12-381451-7 For information on all Academic Press publications visit our website at www.elsevierdirect.com Typeset by MPS Limited, Chennai, India www.adi-mps.com Printed and bound in China 12 13 14 15 10 9 8 7 6 5 4 3 2 1 Acknowledgments and Dedications I would like to thank members of the Mary Preap and Julia Haynes from Elsevier Molecular Genetics Laboratory at RPA Hospital. have been very supportive. Their skills and dedication made molecu- I dedicate the 4th Edition to my family – Pit, lar medicine a lot more interesting. Prof. John Charlotte and Timothy. They have constantly Buchanan in Auckland understood early on provided support and understanding when I that Molecular Medicine was important for needed to do “home work” for this book. Also patient care and steered me towards the educa- my Executive Assistant Carol Yeung, who has tional aspects. My mother Ninette and my sister drawn the illustrations for all four editions and Lynette have always been there when needed. still remains enthusiastic. vii Preface There have been six major developments professionals are suitably engaged. The first edi- since the third edition of Molecular Medicine: tion was subtitled: An introductory text for stu- dents. This was left out in subsequent editions 1. Growth of omics particularly genomics; on the assumption that the clinical applications 2. The start of whole genome sequencing for of DNA-based medicine were being taught in patient care; the universities. However, new developments 3. Broader acceptance of personalized medicine in in omics are occurring rapidly, and there is some selecting the right drug or its dose based on concern that their educational aspects are not molecular typing of patient DNA; being addressed in many of the modern cur- 4. A shift to somatic cell genetics particularly ricula. Governments and major research funders solid cancers; are attempting to fast track the translational 5. Expansion in the Direct-to-Consumer DNA aspects of molecular medicine but this will not testing market, and be enough without linking their initiatives to the 6. Recognition of a roadblock to the effective education of tomorrow’s health practitioners. translation of molecular medicine research This edition no longer has a Glossary or including the need for better bioinformatics to Methodology because this material can be found understand the significance of DNA variants on the Internet. Nevertheless, Methodology and the many changes in DNA, RNA or even remains important, since patients and fami- chromosomes now detectable through omics lies are interested and will go to the Internet, strategies. so the health professional may be asked techni- The title to this edition has subtly changed cal questions. In the era of open yet personal- to include reference to personalized medi- ized medicine, there is no reason why the health cine, which, as explained in Chapter 1, is not professional and the patient or family can- new with some taking it as another example of not sit down and work through the technical inappropriate hype. Nevertheless, it attracts issues using the computer as a component of the attention and so is useful if it helps to push the consultation. translational components of molecular medi- Ronald J Trent cine and ensures the next generation of health Sydney, December 2011 ix CHAPTER 1 Genes to Personalized Medicine OUTLINE Introduction 1 10 Years On 28 Genome Anatomy 2 Genome Variation 31 DNA 2 1 000 Genome Project 31 Protein-Coding Genes 9 Encyclopedia of DNA Elements Junk DNA 11 (ENCODE) Project 32 RNA 14 Personalized Medicine 32 ncRNA 15 Education and Resources 33 Chromosomes 18 Roadmap 34 Human Genome Project 22 References 36 Goals 24 The 10 Year Project 25 INTRODUCTION l Molecular genetics – the discipline within genetics that deals with the structure and There are many definitions of molecular function of DNA and RNA. medicine. In this book the term predominantly The common thread in these names is describes the effect that knowledge of DNA the way in which an understanding of DNA (and increasingly RNA) is having on medical and the ability to manipulate it in vitro or practice. Some other terms which overlap with in vivo – and increasingly now to interrogate it molecular medicine include: in silico – has greatly expanded the options that l Molecular biology – the application of DNA or are available in clinical practice, public health, RNA knowledge in research or industry. research and industry. l Genetic engineering or recombinant DNA Single gene Mendelian disorders are relatively (rDNA) technology – the manipulation of an uncommon and are traditionally considered organism’s DNA using DNA or RNA-based under genetics. Examples include cystic fibro- techniques. sis, hemophilia, Huntington disease and genetic Molecular Medicine. DOI: http://dx.doi.org/10.1016/B978-0-12-381451-7.00001-3 1 © 2012 Elsevier Inc. All rights reserved. 2 1. GENES TO PERSONALIZED MEDICINE forms of cancer. Complex genetic disorders are com- Today, medical research and clinical prac- mon and comprise important public health chal- tice underpinned by molecular medicine lenges both in the developed and the developing continue to provide novel insights into our world. Included here are diabetes, heart disease understanding of disease pathogenesis. From and dementia. The emerging health issues related these concepts, new therapies to prevent or to aging and obesity also have a complex genetic treat important and common human disorders component underlying their pathogenesis. are starting to emerge. The consequences of the The understanding of complex genetic dis- Human Genome Project (described later in this orders requires a new level of sophistication chapter) are many. One of the significant but now possible through omics which describes less publicized outcomes has been the increas- an approach that characterizes all or many mol- ing trend to form large multi-centered interna- ecules within a cell, tissue or organism. The catalyst tional research collaborations that can ask very for omics has been the Human Genome Project ambitious research questions. which has rewritten the way research is con- ducted, and has enabled impressive technological developments. While genomics (all or many GENOME ANATOMY genes) will be the predominant theme of this book, it is important to acknowledge that other Most of what was considered the core com- omics particularly transcriptomics (all or many ponent of the human genome actually occu- RNA transcripts), metabolomics (all or many pies a relatively small portion of it. Only about metabolites), proteomics (all or many proteins), 1–2% contains protein-coding genes. The func- epigenomics (the complete epigenetic profile) tion of the remaining 98% is now starting to be and phenomics (the composite of the phenotypes) explored. This includes: contribute to molecular medicine. Thus genomic medicine overlaps with molecular medicine but 1. Intronic sequences; has a narrower brief. 2. Copy number variations; To store and analyze the large data sets gen- 3. Non-coding (nc) RNA genes; erated by omics requires sophisticated compu- 4. Regulatory elements, and ter power and software. This is bioinformatics 5. Repetitive DNA. (also called informatics, or computational biol- ogy). Related to bioinformatics is the concept of For convenience the term gene will gener- systems biology which attempts to join the dots ally describe segments of DNA that code for between the seemingly unrelated data that are proteins (these are also called structural genes), emerging (Chapter 4). although this does not distinguish other genes The emergence of molecular medicine may particularly the ncRNA genes described later. broadly be considered over three time periods: (1) The discovery of DNA structure in 1953 fol- lowed by developments in recombinant DNA DNA (rDNA) technologies; (2) The Human Genome Project 1990–2000, and (3) The launch of omics Many discoveries led to the uncovering of (Figure 1.1).