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MAPPING AND SEQUENCING THE H U M A N G E N O M E Committee on Mapping and Sequencing the Human Genome Board on Basic Biology Commission on Life Sciences National Research Council NATIONAL ACADEMY PRESS Washington, D.C. 1988

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NATIONAL ACADEMY PRESS 2101 CONSTITUTION AVENUE, NW WASHrNGTON, DC 20418 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This report has been reviewed by a group other than the authors according to procedures approved by a Report Review Committee consisting of members of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The National Academy of Sciences is a private nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the further- ance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Frank Press is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964' under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the resonsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Robert M. White is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Samuel O. Thier is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy~s purposes of furthering knowledge and of advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. It is administered jointly by both Academies and the Institute of Medicine. Dr. Frank Press and Dr. Robert M. White are chairman and vice chairman, respectively, of the National Research Council. This study by the Board on Basic Biology was funded by the James S. McDonnell Foundation of Saint Louis, Missouri. Library of Congress Catalog Card Number 88-60584 International Standard Rook Number 0-309-03840-5 Copyright @) 1988 by the National Academy of Sciences No part of this book may be reporoduced by any mechanical, photographic, or electronic process, or in the form of a phonographic recording, nor may it be stored in a retrieval system, transmitted, or otherwise copied for public or private use' without written permission from the publisher, except for the purposes of official use by the United States Government Printed in the United States of America. Few Printing, April 1988 Second Printing, January 1989 Third Prinung, Junc 1990 Fourth Printing, February 1991

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Committee on Mapping and Sequencing the Human Genome BRUCE M. ALBERTS (Chairman), University of California, San Francisco, California DAVID BOTSTEIN, Massachusetts Institute of Technology, Cambridge, Massachusetts SYDNEY BRENNER, MRC Unit of Molecular Genetics, Cambridge, United Kingdom CHARLES R. CANTOR, Columbia University College of Physicians and Surgeons, New York, New York RUSSELL F. DOOLITTLE, University of California, San Diego, California LEROY HOOD, California Institute of Technology, Pasadena California VICTOR A. McKUSICK, Johns Hopkins Hospital, Baltimore, Maryland DANIEL NATHANS, The Johns Hopkins University School of Medicine, Baltimore, Maryland MAYNARD V. OLSON, Washington University School of Medicine, St. :Louis, Missouri STUART ORKIN, Harvard Medical School, Boston, Massachusetts LEON E. ROSENBERG, Yale University School of Medicine, New Haven, Connecticut FRANCIS H. PUDDLE, Yale University, New Haven, Connecticut SHIRLEY TILGHMAN, Princeton University, Princeton, New Jersey JOHN TOOZE, European Molecular Biology Organization, Heidelberg, Federal Republic of Germany JAMES D. WATSON, Cold Spring Harbor Laboratory, Long Island, New York Advisers to the Committee ALBERT R. JONSEN, University of California, San Francisco, California ERIC JUENGST, University of California, San Francisco, California National Research Council Staff JOHN E. BURRIS, Study Director ROBERT A. MATHEWS, Staff Officer (through August 7, 1987) CAITILIN GORDON, Editor FRANCES WALTON, Administrative Secretary . . .

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Board on Basic Biology FRANCISCO J. AYALA (Chairman), University of California, Irvine NINA V. FEDOROFF, Carnegie Institution of Washington, Baltimore, Maryland TIMOTHY H. GOLDSMITH, Yale University, New Haven, Connecticut RALPH W. F. HARDY, Cornell University, Ithaca, New York ERNEST G. JAWORSKI, Monsanto Company, St. Louis, Missouri SIMON A. LEVIN, Cornell University, Ithaca, New York HAROLD A. MOONEY, Stanford University, Stanford, California HAROLD J. MOROWITZ, Yale University, New Haven, Connecticut WILLIAM E. PAUL, National Institutes of Health, Bethesda, Maryland DAVID D. SABATINI, New York University, New York, New York MALCOLM S. STEINBERG, Princeton University, Princeton, New Jersey JOSEPH E. VARNER, Washington University, St. Louis, Missouri DAVID B. WAKE, University of California, Berkeley JOHN E. DOWLING (ax-officio), Harvard University, Cambridge, Massachusetts JOHN E. BURRIS, Director IV

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Commission on Life Sciences JOHN E. DOWLING (Chairman), Harvard University, Cambridge, Massachusetts PERRY L. ADKISSON, The Texas A&M University System, College Station FRANCISCO J. AYALA, University of California, Irvine J. MICHAEL BISHOP, The G. W. Hooper Research Foundation, San Francisco, California NINA V. FEDOROFF, Carnegie Institution of Washington, Baltimore, Maryland TIMOTHY H. GOLDSMITH, Yale University, New Haven, Connecticut RICHARD W. HANSON, Case Western Reserve University School of Medicine, Cleveland, Ohio RALPH W. F. HARDY, Cornell University, Ithaca, New York RICHARD J. HAVEL, University of California, San Francisco School of Medicine DONALD F. HORNIG, Harvard School of Public Health, Boston, Massachusetts ERNEST G. JAWORSKI, Monsanto Company, St. Louis, Missouri SIMON A. LEVIN, Cornell University, Ithaca, New York FRANKLIN M. LOEW, School of Veterinary Medicine, Tufts University, North Grafton, Massachusetts ROBERT W. MANN, Massachusetts Institute of Technology, Cambridge, Massachusetts HAROLD A. MOONEY, Stanford University, Stanford, California JOSEPH E. RALL, National Institutes of Health, Bethesda, Maryland RICHARD D. REMINGTON, University of Iowa, Iowa City RICHARD B. SETLOW, Brookhaven National Laboratory, Upton, New York JOSEPH E. VARNER, Washington University, St. Louis, Missouri ALVIN G. LAZEN, Executive Director v

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Preface In the past 2 years a great deal of attention has been focused on a proposed project to map and sequence the human genome. Numerous meetings, including one sponsored by the Board on Basic Biology, have been held and a debate has developed in the biological community over the merits of such an effort. In response to questions raised by biologists about such a project, the board appointed a committee to examine the desirability and feasibility of mapping and sequencing the human genome and to suggest options for implementing the project, if it were deemed feasible. The members of the committee are biological scientists from a variety of disciplines that deal directly or indirectly with DNA and genetic mechanisms. The committee members differ greatly in the extent of their past involvement with research on the human genome and in their potential interest in future projects to map and sequence this genome. Many of us came to this assignment with little prior knowledge of the present state of mapping and sequencing efforts. For this reason, major portions of our meetings were devoted to workshop discussions with outside experts who are deeply involved in relevant research (see Appendix C for list of speakers). The committee asked many questions in its deliberations. Should the analysis of the human genome be left entirely to the traditionally uncoordinated, but highly successful, support systems that fund the vast majority of biomedical research? Or should a more focused and coordinated additional support system be developed that is limited to encouraging and facilitating the mapping and eventual sequencing of the human genome? If so, how can this be done without distorting . . V11

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. . . V111 PREFACE the broader goals of biological research that are crucial for any understanding of the data generated in such a human genome project? As the committee became better informed on the many relevant issues, the opinions of its members coalesced, producing a shared consensus of what should be done. This report reflects that consensus. The committee thanks those who contributed to its work. We are grateful to all who shared their expertise with us at our meetings. In particular, we would like to thank Michael Witunski of the James S. McDonnell Foundation, which funded this study, for his insight and contributions to the process. Walter Gilbert contributed to the dis- cussion of the issues during an initial period when he was a member of the committee. Eric Juengst and Albert lonsen provided valuable guidance in developing and discussing the ethical and social implica- tions of the project. The committee is indebted to the Commission on Life Sciences staff, Frances Walton, Caitilin Gordon, and Robert Mathews, whose excellent work greatly expeditecl the production of this report. Special thanks are due to John Burris, director of the Board on Basic Biology, for the long hours, including nights and weekends, during which he skillfully guided the report through its many drafts to a successful conclusion. BRUCE ALBERTS, Chairman Committee on Mapping and Sequencing the Human Genome

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Contents 1. EXECUTIVE SUMMARY Genome Mapping, 3 Genome Sequencing, 6 Information and Materials Handling, 8 Implementation Strategies, 8 Management Strategy, 10 2. INTRODUCTION ..................................... Genomes, Genes, and Genomic Maps, 13 Medical Implications of Detailed Human Genome Maps, 22 Implications for Basic Biology, 22 Expected Technological Developments Generated by a Human Genome Project and Their Impact on Biological Research, 23 Impact on the Research bv Small Grouns. 23 References, 25 3. IMPLICATIONS FOR MEDICINE AND SCIENCE .............................. Medical Uses, 26 Implications for Basic Biology, 29 References, 32 MAPPING ............................................ Fundamentals of Genome Mapping, 37 Genetic Linkage Mapping, 40 IX 1 12 ..... 26 34

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x Making Physical Maps, 45 Immediate Applications of Chromosome Maps, 50 Conclusions and Recommendations, 50 References, 54 5. SE Q U E N CIN G .............................. Why Sequence the Entire Human Genome?, 57 Current Technology in DNA Sequencing: Chemical and Enzymatic Methods, 60 The Difficulty of Determining the Sequence of the Human Genome with Current Technology, 62 The Accuracy of DNA Sequencing, 65 Emerging and Future Technology, 67 Options and Recommendations, 69 References, 74 6. THE COLLECTION, ANALYSIS, AND DISTRIBUTION OF INFORMATION AND MATERIALS .................................. Present Information-Handling Organizations, 77 Mapping Data Bases Required for a Human Genome Project, 80 A DNA Sequence Data Bank Dedicated to a Human Genome Project, 82 Conclusions, 85 References, 85 . 7. IMPLEMENTATION AND MANAGEMENT STRATEGIES ........................................ Funding a Human Genome Project, 87 Managing a Human Genome Project, 93 Reference, 98 8. IMPLICATIONS FOR SOCIETY ........ Commercial and Legal Implications, 99 Ethical and Social Implications, 100 References, 103 APPENDIXES ......................... A. Glossary, 105 B. Curricula Vitae of Committee Members, 108 C. Invited Speakers at Committee Meetings, 111 INDEX . . CONTENTS 56 . 75 86 ...... 99 ..105 .. 113

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e a ~ ~ ~ e ~ ~ ~ ~ ~ ~ e ~ e ~ e ~ e MIND AND SE~OENCING HI ~ ~ ~ L ~ A N F N O ~ E

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