Medical and Health Genomics PDF
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Medical and Health Genomics “Physician who fails to enter the body of a patient with the lamp of knowledge and understanding can never treat diseases” - Charaka, a noted Ayurveda practitioner, wrote the famous treatise “Charak Samhita” on Ayurvedic medicine in Ancient India c.1000 BC. The ancient Indian text refers to genetic factors determining the sex of the child and the origin of congenital blindness in the sperm or ovum rather than the mother or the father. “ …εἰ γὰρ ἐκ φλεγματώδεος φλεγματώδης, καὶ ἐκ χολώδεος χολώδης γίνεται, καὶ ἐκ φθινώδεος φθινώδης, καὶ ἐκ σπληνώδεος σπληνώδης, τί κωλύει ὅτῳ πατὴρ καὶ μήτηρ εἴχετο, τούτῳ τῷ νοσήματι καὶ τῶν ἐκγόνων ἔχεσθαί τινα; ὡς ὁ γόνος ἔρχεται πάντοθεν τοῦ σώματος, ἀπό τε τῶν ὑγιηρῶν ὑγιηρὸς, ἀπό τε τῶν νοσερῶν νοσερός…” Περὶ ἱερῆς νούσου “…For if a phlegmatic person be born of a phlegmatic, and a bilious of a bilious, and a phthisical of a phthisical, and one having spleen disease, of another having disease of the spleen, what is to hinder it from happening that where the father and mother were subject to this disease, certain of their offspring should be so affected also? As the semen comes from all parts of the body, healthy particles will come from healthy parts, and unhealthy from unhealthy parts…” “On the Sacred Disease” Hippocrates of Kos (Ἱπποκράτης; c.460–c.370 BC) Dedication To, The Late Shri Anand Swarup Kumar, Our Father and Shrimati Hardevi Kumar, Our Mother. Dhavendra, Anju, Ashish, Jaime, Jaya, Nikita and Mayank To, Grigoria, Emmanuel, Gregory, Alexander, Christina and their spouses Stylianos, Athena, Stylianos, Anne-Grigoria, Sophia, Raphael, Elisabeth Medical and Health Genomics Edited by Dhavendra Kumar Institute of Cancer & Genetics University Hospital of Wales Cardiff University School of Medicine Cardiff, UK Genomic Policy Unit Faculty of Life Sciences and Education University of South Wales Pontypridd, UK Stylianos Antonarakis Department of Medical Genetics University Hospitals of Geneva, Switzerland Institute of Genetics and Genomics of Geneva, Geneva, University of Switzerland 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 125 London Wall, London EC2Y 5AS, UK 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, USA The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK Copyright © 2016 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability 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. 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: 978-0-12-420196-5 For information on all Academic Press publications visit our website at https://www.elsevier.com/ Publisher: Mica Haley Acquisition Editor: Peter Linsley Editorial Project Manager: Lisa Eppich Production Project Manager: Edward Taylor Designer: Matthew Limbert Typeset by TNQ Books and Journals www.tnq.co.in List of Contributors A. Alfirevic University of Liverpool, Liverpool, United D. Kumar The University of South Wales, Pontypridd, Kingdom Wales, United Kingdom; Cardiff University School of Medicine, University Hospital of Wales, Cardiff, United S.E. Antonarakis University of Geneva Medical School, Kingdom Geneva, Switzerland; University Hospitals of Geneva, Geneva, Switzerland; iGE3 Institute of Genetics N. Lench Congenica Ltd., Hinxton, United Kingdom and Genomics of Geneva, Geneva, Switzerland; A. Lucassen University of Southampton Medical Centre, HUGO (Human Genome Organization), Geneva, Southampton, United Kingdom; University Medical Switzerland Centre Groningen and Rijksuniversiteit Groningen, A. Bhardwaj Institute of Microbial Technology, Council Groningen, The Netherlands of Scientific and Industrial Research, Chandigarh, I. Macciocca Victorian Clinical Genetics Service, India Melbourne, Australia P. Borry University of Leuven, Leuven, Belgium E. Maher University of Cambridge, Cambridge, United C. Børsting Section of Forensic Genetics, Department Kingdom of Forensic Medicine, Faculty of Health and Medical T.A. Manolio National Institutes of Health (NIH), Sciences, University of Copenhagen, Copenhagen, Bethesda, MD, United States Denmark D. McHale UCB, Braine L’Alleud, Belgium M.V. Busi Universidad Nacional de Rosario, Rosario, N. Morling Section of Forensic Genetics, Department of Argentina Forensic Medicine, Faculty of Health and Medical Sciences, V.H.W. Dissanayake University of Colombo, Colombo, University of Copenhagen, Copenhagen, Denmark Sri Lanka A. Mutreja MSD-Wellcome Trust Hilleman Laboratories, R. Festenstein Imperial College, London, United Kingdom New Delhi, India; Wellcome Trust Sanger Institute, C.L. Gaff Melbourne Genomics Health Alliance, Melbourne, Cambridge, United Kingdom Australia; The University of Melbourne, Melbourne, M. Penny Biogen, Cambridge, MA, United States Australia M. Pirmohamed University of Liverpool, Liverpool, D.F. Gomez-Casati Universidad Nacional de Rosario, United Kingdom Rosario, Argentina N.K. Rajput Institute of Microbial Technology, Council M. Grisolía Universidad Nacional de Rosario, Rosario, of Scientific and Industrial Research, Chandigarh, India Argentina Y.-H. Rogers The Jackson Laboratory for Genomic P. Gupta Institute of Microbial Technology, Council of Medicine, Farmington, CT, United States Scientific and Industrial Research, Chandigarh, India; H. Savage Congenica Ltd., Hinxton, United Kingdom Bhaskaracharya College of Applied Sciences, University of Delhi, New Delhi, India R. Saxena Indian Institute of Science Education and Research Bhopal, Madhya Pradesh, India A. Haworth Congenica Ltd., Hinxton, United Kingdom M. Shabani University of Leuven, Leuven, Belgium B. Kerr Manchester Academic Health Sciences Centre (MAHSC), Manchester, United Kingdom V.K. Sharma Indian Institute of Science Education and Research Bhopal, Madhya Pradesh, India B.M. Knoppers McGill University, Montreal, QC, Canada V. Singh Amity University, Noida, India B. Korf University of Alabama at Birmingham, Birmingham, AL, United States N. Sirisena University of Colombo, Colombo, Sri Lanka xi xii List of Contributors D. Sumathipala University of Colombo, Colombo, Sri J. Whitworth University of Cambridge, Cambridge, Lanka United Kingdom I. van Langen University Medical Centre Groningen A.L. Wise National Institutes of Health (NIH), Bethesda, and Rijksuniversiteit Groningen, Groningen, The MD, United States Netherlands C. Zhang The Jackson Laboratory for Genomic Medicine, K. Wettasinghe University of Colombo, Colombo, Sri Farmington, CT, United States Lanka Foreword Although inherited diseases in man have been known since sequence information would be. The technology was not biblical times, and the first clear scientific descriptions of confined to sequencing methodologies. The volume of data genetic disorders by Garrod and others date back to the early generated could not have been handled without commen- years of the 20th century, genetics was only introduced into surate improvements in computer hardware and software. regular medical practice with the advent of genetic counsel- Today it is arguable that the real block to understanding ing clinics in several countries, about 40 or 50 years ago. genetics and applying it clinically has more to do with our The discovery, in 1959, that Down syndrome was caused by inability to understand and manage the vast amounts of a chromosome abnormality was an enormous step toward data being generated, than to a need for better and cheaper recognition that laboratory-based genetics had a role to play sequencing. in medicine. In the early 1970s, few members of the public Despite this meteoric progress, there is still actually (or of the health professions) had heard of genetics and it rather little that modern genetics can do in the clinic, outside was considered pretty irrelevant to healthcare practice. of defining the molecular basis of rare inherited disorders. The change since then has been astonishing. Genetics But, particularly in cancer studies, that is changing rapidly. and genomics are now fully on the radar of most practic- It is now very likely indeed that, despite all the previous ing physicians, researchers, and health managers, as well overoptimistic statements that failed to materialize, genet- as journalists (who enjoy exaggerating the expected rate of ics will pay big health dividends within a modest period of progress) and politicians (who are commonly enthusiastic time. We can see it happening around us, eg, in new targeted and sometimes surprisingly well informed). There can no cancer therapies. It is very exciting indeed. longer be any doubt that the inherited components of dis- Since the completion of the human genome sequence ease are firmly embedded in medical practice and popular and rapid advances in genomic diagnostic methods, many culture. When I say at parties that I am a medical geneticist, avenues for diagnostic, therapeutic, and preventative inter- people more often look interested than mystified and bored. vention have emerged with promising medical and health Although it is true that much of this change has been applications. Those working in public and population health driven by advancing technology, that is an oversimplifica- are considering many aspects of genomics for improving tion. The single biggest event was the sequencing of the population health, particularly for the benefit of less devel- human genome. That achievement and the decision of those oped or developing nations. Many national and interna- involved to make their data freely available to all others, in tional genetic and genomic communities and organizations academia and in industry, at an early stage of the research are now actively engaged in furthering these objectives. process, were transformative. Its echoes have completely Against that background, this new book could not be changed not only medical research, but also anthropology, better timed. It reviews many aspects of the field, and agriculture, and even historical research—witness the use tries to help both professionals and interested observers to of mitochondrial sequencing to confirm the identity of King understand some of the core principles and complexities. Richard III several 100 years after his burial. Contributions from a distinguished group of authors, led by But the technology that we now enjoy was not there experienced and professional medical geneticists, provide when the Human Genome Project started, and arguably an excellent resource of information. I am confident it will would not be there today without that initiative. At the time, be of great value. the genome project was an act of scientific imagination; a few people with extraordinary vision were able to see, Martin Bobrow long before most others and against a significant amount Cambridge, England, August 2015 of scientific and public opposition, the immense value such xiii Preface diseases (chromosomal, single gene, and rare genetic syn- GENOMIC MEDICINE AND HEALTHCARE dromes) are now causally linked to pathogenic changes in In any sociocultural and geographic setting the provision many genes and molecules that operate in conjunction with of medical and healthcare are dependent upon several fac- many other biological systems. Some of these rare condi- tors, including societal, financial, and political denomina- tions result from specific mutations or pathogenic sequence tors. However, in the background of all these factors, the variation within one particular gene or loss of function fact remains that peoples for whom any medical and health- of other genes that belong to a multigene family encod- care system is aimed for are fundamentally different. The ing many peptides with overlapping structural similarity physical and psychological variation of the majority and and physiological functions. Examples include transcrip- minority population groups in any society or country deter- tion factors, nuclear envelope genes, RAS-MAPK genes, mine the outcomes of medical and healthcare provision, TBX genes, genes for many inherited metabolic disorders, however basic or sophisticated. Assessing human variation and a large number of gene–molecule families for sophis- solely for the purposes of assessing the outcomes of medi- ticated neuronal functions. Equipped with the knowledge cine and healthcare practices would require many different from genetic and molecular advances in uncommon and approaches. Many such approaches include conventional extremely rare diseases, researchers and clinicians are now anthropological and sociocultural variables. Since the dis- looking into solving the molecular complexities of com- covery of the ABO, Rhesus, and other blood group systems mon medical diseases with a considerable heritability. The in the early 20th century, the human variation has been scientific information from studying specific system and assessed using a number of different biomarkers. However, multisystem rare genetic disorders has given us insight to despite many years’ work and enormous data, a meaningful many fundamental molecular biological processes that are and scientific plausible correlation has not been possible. not only important for understanding the pathogenesis but Following the Human Genome Project and the subsequent also govern the outcomes of specific therapeutic interven- sequencing of thousands of individual human genomes, tions. Thus successful outcomes of genetic and genomic and the discovery of the extensive genomic variation and applications in medicine and healthcare practices would individuality, a major paradigm shift is taking place with be dependent upon understanding the molecular biology considerable impact on the nature and pattern of medicine of sequential diseases processes and their overall clinical and healthcare. The people and the society at large have impact governed by individual genomic variation. This is in high expectations from the genomic-led contemporary and essence the basis of medical and health genomics, rapidly future medical and healthcare practices. There are huge emerging along with the practice of specific genetic and expectations and hype surrounding the idea of genomic genomic medicine. medicine (also known as personalized/precision medicine), In keeping with the many dilemmas and predicaments which is based on the individual genomic variation. We are surrounding the genetic and genomic applications in medi- probably not fully prepared for this; there is a lot more to cine and healthcare, this new book sets out to collate basic be learned and accomplished before the society and medi- facts and information that could form the core of genomic cal/health professions could offer genomic healthcare with (personalized/precision) medicine and genomic healthcare. robust scientific confidence while making this efficient and A number of scientists, clinicians and healthcare profes- cost-effective. sionals have contributed to this high profile work under the Genetic and genomic variation among peoples and broad meaning title of Medical and Health Genomics. population groups are one of the many variables that influ- The core concepts of human genomics are presented ence the outcomes of any medical and healthcare practice. with emphasis on new emerging genomic technologies, This needs to be linked with the specific “gene–molecule” burgeoning genomic databases with enormous amount systems that operate at the cell and tissue levels. Follow- classified and unclassified data, genomic applications, and ing the successes of clinical genetics, along with related translations in clinical medicine and public health, particu- genetic laboratory techniques, a number of specific genetic larly the diagnostic genomics and clinical bioinformatics xv xvi Preface contributing to deciphering many complex phenotypes, cit- genomics in developing countries and emerging perspec- ing the specific example of the model of Victor McKusick’s tives of human and medical genomics in the context of pub- Online Mendelian Inheritance in Man (OMIM). lic and population health. Some additional areas of particular importance are The society and many people have high hopes and highlighted, including epigenetics modifications in human expectations from many recent new developments and health and disease; metabolomics with its many applications; progress in human (medical) genomics in the diagnosis and introduction to metagenomics and ecogenomics; wide-ranging management of both rare and common medical and health applications of microbial genomics in diagnosis, treatment, problems. These sentiments were echoed by Mr. Anthony and prevention of microbial diseases; and the personalized Charles Lynton (Tony) Blair, the British Prime Minister, on pharmacotherapy based on the genetic variation of each the occasion of the White House announcement of the com- individual (pharmacogenomics). pletion of the First Survey of the Entire Human Genome Medical and health aspects of genetics and genomics Project, broadcast (jointly with the United States President are discussed in detail with evidence on the relevance of Bill Clinton) on the day of the publication of the first draft of genome variation in human health and disease. This is fur- the human genome, “Ever so often in the history of human ther supported by critical information on multidisciplinary endeavor, there comes a breakthrough that takes humankind medical management using examples of systemic rare across a frontier into a new era. ... today’s announcement is genetic diseases, genetic and genomic testing and screen- such a breakthrough, a breakthrough that opens the way for ing, and genomic perspectives of genetic counseling. The massive advancement in the treatment of cancer and heredi- section on personalized and stratified medicine includes tary diseases. And that is only the beginning.” information on novel genomics-led drug discovery and We are delighted to present this book at a critical histori- development and discussion on novel genomics-led thera- cal phase of genome science, with the new global wave to peutic approaches. The organization, availability, and har- incorporate strengths and unlimited potential of genomics monization of genetic and genomic healthcare are reviewed for much needed advances in healthcare. This is reflected in with emphasis on medical and health burden of rare genetic President Obama’s State of the Union address on 30 January, diseases, multidisciplinary genetics and genomics-led 2015, launching the new United States Precision Medicine reproductive healthcare, and common and complex genetic initiative, “To enable a new era of medicine through research, cancer. This section includes a separate chapter on teaching technology, and policies that empower patients, researchers, and training genetics/genomics for medical and healthcare and providers to work together toward development of professionals. The detailed glossary lists a number of key individualized treatments.” phrases, definitions, abbreviations, and acronyms that the reader might find useful. Dhavendra Kumar, Cardiff, Wales, UK Editors and contributors hope that the book will convey Stylianos Antonarakis, Geneva, Switzerland the core concepts of medical and health genomics, high- Editors lighting the specialist genomic fields, emphasis on deliv- December 2015 ery of genetic/genomic medicine and healthcare, drawing attention to specific issues and requirements of human Chapter 1 The Human Genome D. Kumar1,2 1The University of South Wales, Pontypridd, Wales, United Kingdom; 2Cardiff University School of Medicine, University Hospital of Wales, Cardiff, United Kingdom Chapter Outline Introduction 1 The Mitochondrial Genome 8 Hereditary Factors, Genes, Genetics, and Genomics 1 Functional Genomics, Transcriptomics, and Proteomics 9 Structure and Organization of Nucleic Acids 2 Translational Human Genomics 10 Human Genome Variation and Human Disease 5 Human Genomics for Socioeconomic Development 11 Measuring Genetic and Genomic Variation 6 Conclusions 12 Genome Variation and Human Disease 7 References 12 INTRODUCTION to a better understanding of the principles governing hered- ity and the familial transmission of physical characteristics Toward the end of the last millennium, tremendous growth and diseases, better understanding of the pathophysiology in the sophistication of the biological sciences was har- of diseases, the development of new methods of clinical and nessed in medicine, the food industry, and related bioin- laboratory diagnosis, and innovative approaches to mak- dustries. New discoveries and innovations in biological ing early diagnoses (eg, prenatal diagnoses and newborn sciences during the five decades leading up to the 21st cen- screening) and offering reproductive choices, including tury have centered on genetics and genomics. It took just preimplantation genetic diagnoses. All these developments over 50 years after the unraveling of the structure of the are now accepted within the broad fields of human genetics, molecule of nucleic acids, the key unit of the biological life, medical genetics, clinical genetics, genetic medicine, and for scientists to embark on sequencing of major organisms’ the new emerging field of genomic medicine. Not surpris- entire genetic constitution or genome. The word genome ingly, the field remains wide open, encompassing the mas- includes gene and -ome, implying complete knowledge sive field of human genomics, broadly focusing on medical of all genes and related elements in any single organism. and health genomics [3]. Inevitably, this led to enthusiastic expansion of the whole This chapter leads the book, providing the basic factual science and thence to the emergence of genomics [1]. The information for grasping the concepts of heredity, genes, suffix -omic, derived from the ancient Greek, refers to in- genetics, and genomics. It is expected that the reader will pro- depth knowledge. Not surprisingly, genomics was followed ceed to subsequent chapters better equipped with the intro- by a plethora of related -omics; for example, proteomics, duction to genetic/genome sciences, genetic diseases, genetics metabolomics, transcriptomics, and so on [2]. Currently, we and genomics in medicine, applications in public health, and have over 30 such disciplines with the -omics suffix. specific issues related to society, ethics, and law [4]. The ultimate goal of any scientific discipline is its trans- lation for the benefit of all humans, crossing all possible bar- HEREDITARY FACTORS, GENES, GENETICS, riers and boundaries. Major advances in medicine and health AND GENOMICS were only possible through understanding basic principles and mechanisms underlying disease processes. This was The concepts of heredity and hereditary factors date back facilitated by rapid applications of physical and chemical several hundred and probably even thousands of years. sciences in medicine and health; for example, radiographi- The popular darwinian theory of natural selection rests cal diagnosis, ultrasound diagnosis, microbiology diagno- on the core concept of the transmission of hereditary fac- sis, immunohistochemical diagnosis, and finally, molecular tors[5]. For several thousand years, various descriptions diagnosis. Developments and advances in genetics have led and explanations have been put forward to define the Medical and Health Genomics. http://dx.doi.org/10.1016/B978-0-12-420196-5.00001-0 Copyright © 2016 Elsevier Inc. All rights reserved. 1
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