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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. Next Steps for Functional Genomics: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25780.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. Next Steps for Functional Genomics: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25780.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. Next Steps for Functional Genomics: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25780.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. Next Steps for Functional Genomics: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25780.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. Next Steps for Functional Genomics: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25780.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. Next Steps for Functional Genomics: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25780.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. Next Steps for Functional Genomics: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25780.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. Next Steps for Functional Genomics: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25780.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. Next Steps for Functional Genomics: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25780.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. Next Steps for Functional Genomics: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25780.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. Next Steps for Functional Genomics: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25780.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2020. Next Steps for Functional Genomics: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25780.
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  PREPUBLICATION COPY Next Steps for Functional Genomics PROCEEDINGS OF A WORKSHOP Robert Pool, Steven M. Moss, and Frances Sharples, Rapporteurs Board on Life Sciences Division on Earth and Life Studies  

  THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001 This activity was supported by the National Science Foundation under Award Number 1927620. Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project. International Standard Book Number-13: 978-0-309-XXXXX-X International Standard Book Number-10: 0-309-XXXXX-X Digital Object Identifier: https://doi.org/10.17226/25780 Additional copies of this publication are available from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu. Copyright 2020 by the National Academy of Sciences. All rights reserved. Printed in the United States of America Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2020. Next Steps for Functional Genomics: Proceedings of a Workshop. Washington, DC: The National Academies Press. https://doi.org/10.17226/25780. Prepublication Copy

  The National Academy of Sciences was established in 1863 by an Act of Congress, signed by President Lincoln, as a private, nongovernmental institution to advise the nation on issues related to science and technology. Members are elected by their peers for outstanding contributions to research. Dr. Marcia McNutt is president. The National Academy of Engineering was established in 1964 under the charter of the National Academy of Sciences to bring the practices of engineering to advising the nation. Members are elected by their peers for extraordinary contributions to engineering. Dr. John L. Anderson is president. The National Academy of Medicine (formerly the Institute of Medicine) was established in 1970 under the charter of the National Academy of Sciences to advise the nation on medical and health issues. Members are elected by their peers for distinguished contributions to medicine and health. Dr. Victor J. Dzau is president. The three Academies work together as the National Academies of Sciences, Engineering, and Medicine to provide independent, objective analysis and advice to the nation and conduct other activities to solve complex problems and inform public policy decisions. The Academies also encourage education and research, recognize outstanding contributions to knowledge, and increase public understanding in matters of science, engineering, and medicine. Learn more about the National Academies of Sciences, Engineering, and Medicine at www.nationalacademies.org. Prepublication Copy

  Consensus Study Reports published by the National Academies of Sciences, Engineering, and Medicine document the evidence-based consensus on the study’s statement of task by an authoring committee of experts. Reports typically include findings, conclusions, and recommendations based on information gathered by the committee and the committee’s deliberations. Each report has been subjected to a rigorous and independent peer-review process and it represents the position of the National Academies on the statement of task. Proceedings published by the National Academies of Sciences, Engineering, and Medicine chronicle the presentations and discussions at a workshop, symposium, or other event convened by the National Academies. The statements and opinions contained in proceedings are those of the participants and are not endorsed by other participants, the planning committee, or the National Academies. For information about other products and activities of the National Academies, please visit www.nationalacademies.org/about/whatwedo. Prepublication Copy

  PLANNING COMMITTEE ON NEXT STEPS FOR FUNTIONAL GENOMICS: A WORKSHOP Members GENE E. ROBINSON (NAS, NAM), Chair, University of Illinois at Urbana-Champaign PHILIP N. BENFEY (NAS), Duke University CHARLES DANKO, Cornell University EMMA FARLEY, University of California, San Diego TRUDY F. C. MACKAY (NAS), Clemson University TERRY MAGNUSON (NAM), University of North Carolina at Chapel Hill LAUREN O’CONNELL, Stanford University ANDREA SWEIGART, University of Georgia Staff STEVEN M. MOSS, Associate Program Officer, Board on Life Sciences FRANCES SHARPLES, Board Director, Board on Life Sciences KOSSANA YOUNG, Senior Program Assistant, Board on Life Sciences Prepublication Copy v

  BOARD ON LIFE SCIENCES JAMES P. COLLINS, Chair, Arizona State University A. ALONSO AGUIRRE, George Mason University VALERIE H. BONHAM, Ropes & Gray LLP DOMINIQUE BROSSARD, University of Wisconsin–Madison NANCY D. CONNELL, Johns Hopkins Center for Health Security SEAN M. DECATUR, Kenyon College JOSEPH R. ECKER, Salk Institute for Biological Studies SCOTT V. EDWARDS, Harvard University GERALD EPSTEIN, National Defense University ROBERT J. FULL, University of California, Berkeley MARY E. MAXON, Lawrence Berkeley National Laboratory ROBERT NEWMAN, Independent Consultant STEPHEN J. O’BRIEN, Nova Southeastern University LUCILA OHNO-MACHADO, University of California, San Diego CLAIRE POMEROY, Albert and Mary Lasker Foundation MARY E. POWER, University of California, Berkeley SUSAN RUNDELL SINGER, Rollins College LANA SKIRBOLL, Sanofi DAVID R. WALT, Harvard Medical School PHYLLIS M. WISE, University of Colorado Boulder Staff FRANCES SHARPLES, Director KATIE BOWMAN, Senior Program Officer ANDREA HODGSON, Program Officer JO HUSBANDS, Senior Scholar KEEGAN SAWYER, Senior Program Officer AUDREY THEVENON, Program Officer STEVEN M. MOSS, Associate Program Officer JESSICA DE MOUY, Senior Program Assistant KOSSANA YOUNG, Senior Program Assistant vi Prepublication Copy

  Reviewers This Proceedings of a Workshop was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published proceedings as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the charge. The review comments and draft manuscript remain confidential to protect the integrity of the process. We thank the following individuals for their review of this proceedings: JULIA BAILEY-SERRES, University of California, Riverside EMMA FARLEY, University of California, San Diego MARC HALFON, University at Buffalo-SUNY STEVEN HENIKOFF, Fred Hutchinson Cancer Research Center Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the content of the proceedings nor did they see the final draft before its release. The review of this proceedings was overseen by JASPER RINE, University of California, Berkeley. He was responsible for making certain that an independent examination of this proceedings was carried out in accordance with standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the rapporteurs and the National Academies. Prepublication Copy vii

   

  Contents 1 INTRODUCTION ................................................................................................................................ 1 Importance of Functional Genomics, 1 Workshop Outline and Objectives, 2 2 THE GENOTYPE–PHENOTYPE CHALLENGE ........................................................................... 4 Overview of the Challenge, 4 Cells, 5 Programs, 6 Mechanisms, 10 Concluding Remarks and Summary, 12 3 CASE STUDIES ON BUILDING FUNCTIONAL GENOMICS TOOLS IN DIVERSE SYSTEMS......................................................................................................................... 13 Understanding the Genotype–Phenotype Connection in Monkeyflowers, 13 Microbial Communities and Their Interactions on Cheese Rinds, 16 Neurogenetics of Sociality and Relationships, 19 Genetic Interrogation of Diverse Plants, 22 Low-Cost, High-Resolution Chromatin Profiling, 24 Discussion, 27 4 UNDERSTANDING THE CONTRIBUTIONS OF NON-PROTEIN-CODING DNA TO PHENOTYPE .............................................................................................................................. 29 Functional Genomics of Adaptation in Sticklebacks, 29 Phylogenetics of Flightless Birds, 32 Role of Chromatin Folding in Gene Expression, 34 Discussion, 36 5 ADVANCING RESEARCH ON THE ENVIRONMENTAL REGULATION OF GENE FUNCTION ............................................................................................................................ 39 Factors Shaping Variation in Social Behavior, 39 How Environmental Factors Influence a Complex Phenotype, 43 Environmental Regulation of Gene Function in Agriculture, 46 Environmental Factors Affecting Quantitative Traits in Drosophila, 48 Discussion, 53 6 PREDICTING CURRENT AND FUTURE SOURCES OF VARIATION IN QUANTITATIVE TRAITS ............................................................................................................... 55 Discovering the Genetic Basis of a Change: An Example, 56 Exploring the Regulation of Gene Expression, 59 Conclusions and Next Steps, 62 7 INTERPRETING AND VALIDATING RESULTS FROM HIGH-THROUGHPUT SCREENING APPROACHES .......................................................................................................... 63 Lessons on Design and Validation from a CRISPR Loss-of-Function Screen on KRAS-Mutant Cancers, 63 Prepublication Copy ix

Contents Using Functional Genomics to Understand Development, 65 Validating Results from High-Throughput Enhancer Screens, 68 Harnessing Genetic Diversity to Understand Maintenance of Pluripotency in Embryonic Stem Cells, 72 Discussion, 75 8 LARGE DATABASES AND CONSORTIA .................................................................................... 77 ChRO-seq: A New Technique for Interpreting Genome Sequence, 77 Using Gene Expression to Understand the Genetics of Disease, 80 An Atlas of Atlases, 82 A Cloud-Based Platform for Genomics Data Mining, 84 Supporting Development of Methods and Tools, 86 Discussion, 88 Importance of Consortia and Large Databases, 90 9 BIG-PICTURE CHALLENGES IN RESEARCH, EDUCATION, AND TRAINING ................ 94 Education and Training, 94 Determining and Defining “Model” Systems, 97 Discussion, 104 Societal and Ethical Implications of Functional Genomics Research, 101 10 FUTURE OF FUNCTIONAL GENOMICS .................................................................................. 106 Breakout Group Discussions of the Future of Functional Genomics, 106 Comments from the Town Hall Discussion, 108 Closing Remarks and Final Overview, 110 REFERENCES ........................................................................................................................................ 112 APPENDIXES A STATEMENT OF TASK ................................................................................................................ 121 B WORKSHOP AGENDA .................................................................................................................. 123 C PLANNING COMMITTEE BIOGRAPHIES ............................................................................... 126 D SPEAKER BIOGRAPHIES ............................................................................................................ 129 E ACRONYMS AND ABBREVIATIONS ........................................................................................ 137 FIGURES 3-1 Display of the different sizes and shapes of flowers from the Mimulus guttantus species complex, 14 3-2 Different growth conditions for a microbe being tested for genes that are present or absent when grown in a microbial community, 18 3-3 General explanation of how the CUT&RUN method works, 25 4-1 Images of different types of paleognathous birds, 32 5-1 Evolutionary tree showing the different origins of eusocialtiy in the 19 different species of sweat bees studied by Kocher, 42 x Prepublication Copy

Contents 5-2 Representation of how an environmental stressor can influence various hierarchical levels of organism function, 44 5-3 Display of variation in quantitative traits due to the environment and sex, 49 6-1 Breeding of D. americana with D. novamexicana, two different species of Drosophila, to look at the outcome of the coloration phenotypes, 56 7-1 Growth in the Arabidopsis root showing that the tip of the root has the youngest cells, while those cells farther away from the tip are the most fully developed, 66 7-2 Display of asymmetric cell divisions in the Arabidopsis root, where the mature cell divides along the longitudinal axis into two cells with different fates, 67 7-3 Display of how the sequences of the enhancers ETS and GATA encode for tissue-specific expression, 69 7-4 Mediation analysis, called the “steps method,” which contains four logical statements, 73 7-5 Data of distal variation clustering in bands and representation of local QTL effects versus distal QTL effects, 74 8-1 Representation of ChRO-seq data and interpretation of those data, 78 8-2 Representation of how to identify “anchors” across datasets, 83 9-1 Ethical dimensions of consideration behind choosing a research organism, 101 Prepublication Copy xi

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One of the holy grails in biology is the ability to predict functional characteristics from an organism’s genetic sequence. Despite decades of research since the first sequencing of an organism in 1995, scientists still do not understand exactly how the information in genes is converted into an organism’s phenotype, its physical characteristics. Functional genomics attempts to make use of the vast wealth of data from “-omics” screens and projects to describe gene and protein functions and interactions. A February 2020 workshop was held to determine research needs to advance the field of functional genomics over the next 10-20 years. Speakers and participants discussed goals, strategies, and technical needs to allow functional genomics to contribute to the advancement of basic knowledge and its applications that would benefit society. This publication summarizes the presentations and discussions from the workshop.

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