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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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