E xploring Personal Genomics J o el T . D u dley A ssistant Professor of Genetics and Genomic Sciences & D irector of Biomedical Informatics, Mount Sinai School of Medicine, USA K onrad J. Karczewski B iomedical Informatics, Stanford University School of Medicine, USA 1 Exploring Personal Genomics. First Edition. Joel T. Dudley and Konrad J. Karczewski. © Joel T. Dudley and Konrad J. Karczewski 2013. Published 2013 by Oxford University Press. 1 Great Clarendon Street, Oxford, OX2 6DP, United Kingdom Oxford University Press is a department of the University of Oxford. It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide. Oxford is a registered trade mark of Oxford University Press in the UK and in certain other countries © Joel T. Dudley and Konrad J. Karczewski 2013 The moral rights of the authors have been asserted First published 2013 Impression: 1 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, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, by licence or under terms agreed with the appropriate reprographics rights organization. Enquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above You must not circulate this work in any other form and you must impose the same condition on any acquirer British Library Cataloguing in Publication Data Data available ISBN 978–0–19–964448–3 (hbk.) ISBN 978–0–19–964449–0 (pbk.) Printed and bound by CPI Group (UK) Ltd, Croydon, CR0 4YY Links to third party websites are provided by Oxford in good faith and for information only. Oxford disclaims any responsibility for the materials contained in any third party website referenced in this work. C ontents Foreword vii G eorge M. Church Introduction i x A cknowledgments x i Part I 1. A gentle introduction to genomics 3 1 .1 I ntroduction 3 1 .2 W hat is a genome? 3 1 .3 H ow does a genome work? 8 1 .4 G ene regulation: when and where a gene is expressed 1 1 1 .5 T he human epigenome 1 3 1 .6 R eplication and reproduction 1 4 1 .7 G enetic variation 1 6 2. P ractical and ethical considerations in personal genomics 24 2 .1 C onsiderations when obtaining personal genomic information 2 4 2 .2 L imitations of personal genomics 2 5 2 .3 R isks of personal genomics 3 0 2 .4 S ummary 3 3 3. G etting started with personal genomics 3 4 3 .1 O btaining personal genomic information 3 4 3 .2 F rom DNA to “raw” data 3 6 3 .3 W orking with personal genomic data 4 7 3 .4 C onclusion 5 0 4. V isualizing personal genomics 5 2 4 .1 I ntroduction 5 2 4 .2 T abular views 5 3 4 .3 I deograms 5 7 iii iv C O N T E N T S 4 .4 G enome browsers 6 1 4 .5 V isual quantitative assessment 6 7 4 .6 I ntegrative visualizations 7 1 4 .7 C onclusion 7 4 5. A ncestry and genealogy 7 6 5 .1 T he genetics of human ancestry 7 6 5 .2 G lobal genetic similarity 7 8 5 .3 G enetic similarity between individuals 8 6 5 .4 I dentity by descent 8 9 5 .5 F amilial lineages 92 5 .6 G enetic anthropology and ancient human DNA 9 5 5 .7 C onclusions 9 8 6. G enetic trait associations 1 00 6 .1 I ntroduction 1 00 6 .2 D iscovery of genetic trait associations 1 00 6 .3 G enetic disease associations 111 6 .4 A pplication and interpretation of genetic associations 1 17 6 .5 Q uantitative trait inference 1 35 6 .6 S ummary 1 37 7. P harmacogenomics 1 39 7 .1 W hat is pharmacogenomics? 1 39 7 .2 M apping common pharmacogenomic variants 1 42 7 .3 M ajor applications of pharmacogenomics 1 46 7 .4 A ssessment of rare variants in PD/PK genes 1 49 7 .5 V ariation in pharmacogenomic pathways 1 55 7 .6 C onclusion 1 58 Part II 8. P ersonal genomics and the environment 1 63 8 .1 I ntroduction 1 63 8 .2 N utritional genomics 1 64 8 .3 E nvironmental toxins 1 67 8 .4 M etagenomics and infectious disease 1 74 8 .5 I dentifying personal genetic risk modif ers 1 74 8 .6 S ummary 1 78 9. F rom DNA to physiology 1 81 9 .1 I ntroduction 1 81 9 .2 B ridging DNA and physiology through gene regulation 1 82 9 .3 C reating personal genomic eQTL prof les 1 84 C O N T E N T S v 9 .4 P ersonal genomic eQTL enrichment analysis 1 87 9 .5 F unctional assessment of personal genomic regulatory variants 1 93 9 .6 L inking to further aspects of physiology 1 95 9 .7 S ummary 1 97 1 0. R are and novel variants 199 1 0.1 G eneral challenges 2 00 1 0.2 C ompound heterozygosity 2 02 1 0.3 E volutionary conservation 2 04 1 0.4 R are variants in coding regions 2 08 1 0.5 R are variants in non-coding regions 2 11 1 0.6 P ractical application of rare variant assessment tools 2 13 1 0.7 F urther challenges 2 18 11. S tructural variation 2 21 1 1.1 C opy number variation 2 23 1 1.2 M ore complex events (insertions, inversions, translocations) 2 25 1 1.3 C hallenges 2 28 C onclusion 232 Glossary 2 33 I ndex 2 41 This page intentionally left blank F oreword G e orge M . C h urch W hat a timely book! Rarely (never, maybe) has tech- and inexpensive electronic means. Do we want to nology changed so quickly (a millionfold in six share our genome, environment, and trait data with years) nor hit so close to the core of our human family, social networks, prof t-motivated compa- nature. The Copernican revolution merely impacted nies, closed medical research, or open-access par- our perception of our place in the sky, but the ticipatory research like PersonalGenomes.org? Will genome revolution changes our contract with our the breakthroughs come from obvious experts, or body as well as our past, present and future family. from unexpected geniuses collaborating world- We are moving from a $3 billion price tag to a $1000 wide. Do the keys to progress lie in common delete- (or free) genome—from 15 years in giant factories rious variations or rare ones? Or rare protective per genome to 15 minutes on a hand-held device. variations? As we get interpretations back from We are moving beyond merely inherited genomes, such studies, how will we react? to environmental genomes and epi-genomes; from W ith the plummeting genome costs, we have a rarely testing for even a single microbe in a clinic, to chance to level the playing f eld—to decrease rather testing all microbes and allergens wherever we than increase health disparities between rich and walk. We might not have enough genetic counsel- poor nations and individuals. But this will require lors to handle this exponentially growing f ood of getting the word out to everyone. To minimize personal genome data coming our way; the few that risks—of monoculture, stigmatization, misclassif - we do have need to be trained swiftly and their cation, and dehumanization, as well as to maximize numbers increased. They and all of us will turn to benef ts—of the economics of fewer missed days books like the one in your hands now. We need to and missed vocations, and more healthy years per inject this knowledge into early education in life. People should be motivated and excited to learn national and international efforts, like PGEd.org, from this book as never before. The world now has not just in advanced biology classes, but also basic six billion mobile phones—in principle, giving health classes. Not just in school, but in the streets, access to computing and diverse knowledge—liter- in the games, videos, and media feeds that swirl ally expanding minds. Genetics is not destiny. We around us and programme us. This book will light can change our environments and we can even our path—it is highly supportive (and even required) change the genes in our bodies. We are given an reading for so many of us. increasingly large say about the genes of our I n one year (1993) we went from zero web pages descendants—moving us from accepting the genetic to millions, with very few “web counsellors” per lottery to orchestrating it. We need no longer wan- capita to guide us. Like the internet, our new genetic der blindly through a fog of deadly microbes and resources are only useful if we share and under- other environmental threats—but we can gain stand them. What is a web with no connections? We vision and navigate paths around such hazards. We each are the best experts on our own body history can replace fear of and discrimination against the and idiosyncrasies. We can monitor our environ- neuro-atypical with understanding that enables ment and physiology with increasingly convenient greater neuro-diversity. vii viii F O R E W O R D S o, the time is NOW for people of all ages and revolution, progress in the health revolution all walks of life to become educated and engaged depends on participation, from lay individuals— in personal genomics through this book and other from all of us. sources. All of us, not just computer experts, have G eorge M. Church mastered electronics. Now all of us, not just health experts, will master knowledge of our own per- P rofessor of Genetics sonalized health. Even more than in the internet H arvard Medical School I ntroduction A t the time of this book’s writing, the world is sit- comes from our experiences participating in some ting on the cusp of the next major revolution in per- of the earliest academic efforts in genome inter- sonal genomics: whole genome sequences measured pretation, and a desire to assemble all the relevant quickly, accurately, and economically for any indi- information for anyone interested in exploring vidual. As the cost of whole genome sequencing personal genomics. Whether you are a clinician (WGS) rapidly approaches the symbolic $1000 USD interested in incorporating personal genomics cost mark (the cost of sequencing a personal genome into clinical practice, or a student who wants to at high resolution is about US$2000 at the time of explore their personal genomic information this writing), more clinical studies are incorporating obtained from a direct-to-consumer genomics WGS into their designs, and many private individu- company, the aim of this book is to provide the als are now obtaining complete personal genomes reader with clear and concise information on prac- for didactic and clinical purposes. Considering that tical and specif c understanding of approaches for the International Human Genome Sequencing Con- genome interpretation. Although much can be sortium announced the f rst completed sequence of learned from this book by simply understanding the human genome less than 10 years ago in April the concepts presented in the book, we strongly 2003, it is apparent that advances in genome encourage readers to obtain a personal genome sequencing represent an astounding technical sequence (their own or a publicly available achievement similar to—or even greater than—the sequence), and to attempt the approaches pre- personal computing technology revolution of the sented in this book f rst-hand. last three decades. If we extrapolate forward just a T his book does not assume that the reader is well- few years on the trajectory of genome sequencing versed in biology or genomics and so, we provide a technology development, it is clear that genome basic introduction to genomic concepts in C hapter 1 . sequencing will soon become ubiquitous not only If the reader has not yet obtained their genetic infor- inside the clinic, but also in research labs, class- mation, we provide some background on the ethical rooms, and in the homes of genomics hobbyists and and legal implications behind personal genomics enthusiasts. (C hapter 2 ) , practical matters in obtaining personal F rom this point forward, the major challenge in genomic information (C hapter 3 ) , as well as tech- personal genomics lies in making sense of billions niques and resources for visualization (C hapter 4 ) . of base pairs that comprise each genome. A per- C hapters 5 – 7 describe the current main focus of per- sonal genome can answer many questions about sonal genomics, or ancestry, disease risk, and indi- an individual: questions about ancestral origins, vidual response to drugs (pharmacogenomics). In disease risk, drug response, physiological traits, P art 2 , we describe advanced topics in personal and more. However, the means for answering genomics, intended for readers interested in look- these questions from personal genomic informa- ing further into their genetic data and the future tion have only recently been developed, and their of personal genomics. These include the role of descriptions are often hidden away in academic environment (C hapter 8 ) , the effect of DNA variants research journals. The motivation from this book on molecular physiology (C hapter 9 ) , as well as ix