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Eileen R. Choffnes, LeighAnne Olsen, and Theresa Wizemann, Rapporteurs Forum on Microbial Threats Board on Global Health

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THE NATIONAL ACADEMIES PRESS  500 Fifth Street, NW  Washington, DC 20001 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. Financial support for this project was provided by the U.S. Department of Health and Hu- man Services: National Institutes of Health, National Institute of Allergy and Infectious Diseases, Centers for Disease Control and Prevention, and the Food and Drug Administra- tion; U.S. Department of Defense, Department of the Army: Global Emerging Infections Surveillance and Response System, Medical Research and Materiel Command, and the Defense Threat Reduction Agency; U.S. Department of Veterans Affairs; U.S. Department of Homeland Security; U.S. Agency for International Development; Uniformed Services University of the Health Sciences; the Alfred P. Sloan Foundation, American Society for Microbiology; sanofi pasteur; Burroughs Wellcome Fund; GlaxoSmithKline; Infectious Diseases Society of America; and the Merck Company Foundation. The views presented in this publication do not necessarily reflect the views of the organizations or agencies that provided support for this project. International Standard Book Number-13: 978-0-309-26819-6 International Standard Book Number-10: 0-309-26819-2 Additional copies of this report 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. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2013 by the National Academy of Sciences. All rights reserved. Printed in the United States of America The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin. Cover image: Derivation of genome trees from the comparative analyses of complete genomes. (2005) PLoS Computational Biology Issue Image | Vol. 1(7) December 2005. PLoS Comput Biol 1(7): ev01.i07. doi:10.1371/image.pcbi.v01.i07. Genome graphic rep- resentation completed with GenomeViz software, provided by Rohit Ghai. Fractal tree obtained with the FractalTrees X software, provided by Simon Woodside. Compiled by Edouard Yeramian. Suggested citation: IOM (Institute of Medicine). 2013. The Science and Applications of Microbial Genomics: Workshop Summary. Washington, DC: The National Academies Press.

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“Knowing is not enough; we must apply. Willing is not enough; we must do.” —Goethe Advising the Nation. Improving Health.

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The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance 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. Ralph J. Cicerone 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 responsibility 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. Charles M. Vest 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 examina- tion 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. Harvey V. Fineberg 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 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 Na- tional Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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PLANNING COMMITTEE FOR A WORKSHOP ON THE SCIENCE AND APPLICATIONS OF MICROBIAL GENOMICS1 BRUCE BUDOWLE, University of North Texas Health Science Center, Fort Worth, Texas ARTURO CASADEVALL, Albert Einstein College of Medicine, Bronx, New York JONATHAN EISEN, University of California, Davis, California CLAIRE FRASER, University of Maryland School of Medicine, Baltimore, Maryland PAUL KEIM, Northern Arizona University, Flagstaff, Arizona DAVID RELMAN, Stanford University, Stanford, California 1  Institute of Medicine planning committees are solely responsible for organizing the workshop, identifying topics, and choosing speakers. The responsibility for the published workshop summary rests solely with the workshop rapporteurs and the institution. v

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FORUM ON MICROBIAL THREATS1 DAVID A. RELMAN (Chair), Stanford University, and Veterans Affairs Palo Alto Health Care System, Palo Alto, California JAMES M. HUGHES (Vice-Chair), Global Infectious Diseases Program, Emory University, Atlanta, Georgia LONNIE J. KING (Vice-Chair), The Ohio State University, Columbus, Ohio KEVIN ANDERSON, Biological and Chemical Defense Division, Science and Technology Directorate, Department of Homeland Security, Washington, DC ENRIQUETA C. BOND, Burroughs Wellcome Fund (Emeritus), QE Philanthropic Advisors, Marshall, Virginia ROGER G. BREEZE, Lawrence Livermore National Laboratory, Livermore, California PAULA R. BRYANT,2 Defense Threat Reduction Agency, Medical S&T Division, Fort Belvoir, Virginia JOHN E. BURRIS, Burroughs Wellcome Fund, Research Triangle Park, North Carolina ARTURO CASADEVALL, Albert Einstein College of Medicine, Bronx, New York ANDREW CLEMENTS,3 U.S. Agency for International Development, Washington, DC PETER DASZAK, EcoHealth Alliance, New York, New York JEFFREY S. DUCHIN, Public Health–Seattle and King County, Seattle, Washington JONATHAN EISEN, Genome Center, University of California, Davis, California RALPH L. ERICKSON, Walter Reed Army Institute of Research, Silver Spring, Maryland MARK B. FEINBERG, Merck Vaccine Division, Merck & Co., Inc., West Point, Pennsylvania JACQUELINE FLETCHER, Oklahoma State University, Stillwater, Oklahoma CLAIRE FRASER, Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland JESSE L. GOODMAN, Food and Drug Administration, Rockville, Maryland EDUARDO GOTUZZO, Instituto de Medicina Tropical–Alexander von Humbolt, Universidad Peruaña Cayetano Heredia, Lima, Peru 1  Institute of Medicine Forums and Roundtables do not issue, review, or approve individual docu- ments. The responsibility for the published workshop summary rests with the workshop rapporteurs and the institution. 2  Forum member until February 8, 2013. 3  Forum member since January 1, 2013. vi

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CAROLE A. HEILMAN, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland DAVID L. HEYMANN, Health Protection Agency, London, United Kingdom ZHI HONG, GlaxoSmithKline, Research Triangle Park, North Carolina PHILIP HOSBACH, sanofi pasteur, Swiftwater, Pennsylvania STEPHEN ALBERT JOHNSTON, Arizona BioDesign Institute, Arizona State University, Tempe, Arizona KENT KESTER, Uniformed Services University of the Health Sciences, Bethesda, Maryland GERALD T. KEUSCH, Boston University School of Medicine and Boston University School of Public Health, Boston, Massachusetts RIMA F. KHABBAZ, Centers for Disease Control and Prevention, Atlanta, Georgia STANLEY M. LEMON, School of Medicine, University of North Carolina, Chapel Hill, North Carolina MARGARET McFALL-NGAI, University of Wisconsin, Madison, Wisconsin EDWARD McSWEEGAN, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland MARK A. MILLER,4 Fogarty International Center, Bethesda, Maryland PAULA J. OLSIEWSKI,5 the Alfred P. Sloan Foundation, New York, New York JULIE PAVLIN, Armed Forces Health Surveillance Center, Silver Spring, Maryland GEORGE POSTE, Complex Adaptive Systems Initiative, Arizona State University, Tempe, Arizona DAVID RIZZO, Department of Plant Pathology, University of California, Davis, California GARY A. ROSELLE, Veterans Health Administration, Department of Veterans Affairs, Cincinnati, Ohio ALAN S. RUDOLPH,6 Defense Threat Reduction Agency, Fort Belvoir, Virginia KEVIN RUSSELL, Armed Forces Health Surveillance Center, Silver Spring, Maryland JANET SHOEMAKER, American Society for Microbiology, Washington, DC P. FREDERICK SPARLING, University of North Carolina, Chapel Hill, North Carolina MURRAY TROSTLE,7 U.S. Agency for International Development, Washington, DC MARY E. WILSON, Harvard School of Public Health, Harvard University, Boston, Massachusetts 4  Forum member until August 31, 2012. 5  Forum member since January 30, 2013. 6  Forum member until February 8, 2013. 7  Forum member until December 31, 2012. vii

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IOM Staff EILEEN CHOFFNES, Scholar and Director LEIGHANNE OLSEN, Program Officer KATHERINE McCLURE, Senior Program Associate REBEKAH HUTTON, Research Associate PAMELA BERTELSON,8 Senior Program Assistant 8  Staff member until February 15, 2013. viii

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BOARD ON GLOBAL HEALTH1 RICHARD GUERRANT (Chair), Thomas H. Hunter Professor of International Medicine and Director, Center for Global Health, University of Virginia School of Medicine, Charlottesville, Virginia JO IVEY BOUFFORD (IOM Foreign Secretary), President, New York Academy of Medicine, New York, New York CLAIRE V. BROOME, Adjunct Professor, Division of Global Health, Rollins School of Public Health, Emory University, Atlanta, Georgia JACQUELYN C. CAMPBELL, Anna D. Wolf Chair, and Professor, Johns Hopkins University School of Nursing, Baltimore, Maryland THOMAS J. COATES, Michael and Sue Steinberg Professor of Global AIDS, Research Co-Director, UC Global Health Institute, David Geffen School of Medicine, University of California, Los Angeles, California GARY DARMSTADT, Director, Family Health Division, Global Health Program, Bill & Melinda Gates Foundation, Seattle, Washington VALENTIN FUSTER, Director, Wiener Cardiovascular Institute Kravis Cardiovascular Health Center Professor, Cardiology, Mount Sinai School of Medicine, Mount Sinai Medical Center, New York, New York JACOB A. GAYLE, Vice President, Community Affairs, Executive Director, Medtronic Foundation, Minneapolis, Minnesota GLENDA E. GRAY, Executive Director, Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital, University of the Witwatersrand, Diepkloof, South Africa STEPHEN W. HARGARTEN, Professor and Chair, Emergency Medicine, Director, Medical College of Wisconsin, Milwaukee, Wisconsin JAMES HOSPEDALES, Coordinator, Chronic Disease Project, Health Surveillance and Disease Management Area, Pan American Health Organization and World Health Organization, Washington, DC PETER J. HOTEZ, Professor and Chair, Department of Microbiology, Immunology, and Tropical Medicine, The George Washington University, Washington, DC CLARION JOHNSON, Global Medical Director, Medicine and Occupational Medicine Department, Exxon Mobil, Fairfax, Virginia FITZHUGH MULLAN, Professor, Department of Health Policy, The George Washington University, Washington, DC OLUFUNMILAYO F. OLOPADE, Walter L. Palmer Distinguished Service Professor of Medicine, The University of Chicago, Chicago, Illinois 1  Institute of Medicine boards do not review or approve individual workshop summaries. The responsibility for the content of the workshop summary rests with the workshop rapporteurs and the institution. ix

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GUY PALMER, Regents Professor of Pathology and Infectious Diseases, Director of the School for Global Animal Health, Washington State University, Pullman, Washington THOMAS C. QUINN, Associate Director for International Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Professor of Medicine, International Health, Epidemiology, and Molecular Biology and Immunology, Johns Hopkins University School of Medicine, Baltimore, Maryland JENNIFER PRAH RUGER, Associate Professor, Division of Health Policy and Administration, Yale University School of Public Health, New Haven, Connecticut IOM Staff PATRICK KELLEY, Director ANGELA CHRISTIAN, Program Associate x

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Reviewers This workshop summary has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council’s Report Review Com- mittee. The purpose of this independent review is to provide candid and criti- cal comments that will assist the institution in making its published workshop summary as sound as possible and to ensure that the workshop summary meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the process. We wish to thank the following individuals for their review of this workshop summary: Roger G. Breeze, Lawrence Livermore National Laboratory, Livermore, California James M. Hughes, Rollins School of Public Health, Emory University, Atlanta, Georgia Tim Stearns, Department of Biology, Stanford University, Department of Genetics, Stanford School of Medicine, Stanford, California Mary E. Wilson, Harvard School of Public Health, Harvard University, Boston, Massachusetts Although the reviewers listed above have provided many constructive com- ments and suggestions, they did not see the final draft of the workshop summary before its release. The review of this workshop summary was overseen by Dr. xi

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xiv ACKNOWLEDGMENTS The Forum gratefully acknowledges the contributions of the members of the planning committee1: Bruce Budowle (University of North Texas Health Science Center), Arturo Casadevall (Albert Einstein College of Medicine), Jonathan Eisen (University of California, Davis), Claire Fraser (University of Maryland School of Medicine, Baltimore), Paul Keim (Northern Arizona University), and David Relman (Stanford University). The Forum is also indebted to the IOM staff who tirelessly contributed throughout the planning and execution of the workshop and the production of this workshop summary report. On behalf of the Forum, we gratefully acknowledge these efforts led by Dr. Eileen Choffnes, Scholar and Director of the Forum; Dr. LeighAnne Olsen, Program Officer; Katherine McClure, Senior Program Associate; Rebekah Hutton, Research Associate; and Pamela Bertelson,2 Se- nior Program Assistant, for dedicating much effort and time to developing this workshop’s agenda and for their thoughtful and insightful approach and skill in planning for the workshop and in translating the workshop’s proceedings and discussion into this workshop summary report. We would also like to thank the following IOM staff and consultants for their valuable contributions to this activ- ity: Daniel Bethea, Laura Harbold DeStefano, Julie Wiltshire, Theresa Wizemann, and Sarah Ziegenhorn. Finally, the Forum wishes to recognize the sponsors that supported this ac- tivity. Financial support for this project was provided by the U.S. Department of Health and Human Services: National Institutes of Health, National Institute of Allergy and Infectious Diseases, Centers for Disease Control and Prevention, and the Food and Drug Administration; U.S. Department of Defense, Department of the Army: Global Emerging Infections Surveillance and Response System, Medi- cal Research and Materiel Command, and the Defense Threat Reduction Agency; U.S. Department of Veterans Affairs; U.S. Department of Homeland Security; U.S. Agency for International Development; Uniformed Services University of the Health Sciences; the Alfred P. Sloan Foundation; American Society for Micro- biology; sanofi pasteur; Burroughs Wellcome Fund; GlaxoSmithKline; Infectious Diseases Society of America; and the Merck Company Foundation. The views presented in this workshop summary are those of the workshop participants and have been summarized by the rapporteurs. They do not necessarily reflect the views of the Forum on Microbial Threats, its sponsors, or the IOM. 1  Institute of Medicine planning committees are solely responsible for organizing the workshop, identifying topics, and choosing speakers. The responsibility for the published workshop summary rests solely with the workshop rapporteurs and the institution. 2  Staff member until February 15, 2013.

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Contents Workshop Overview 1 Workshop Overview References, 107 Appendixes A Contributed Manuscripts A1  The Microbial Forensics Pathway for Use of Massively Parallel Sequencing Technologies, 117  Budowle, Sarah E. Schmedes, and Randall S. Murch Bruce A2  Microbial Virulence as an Emergent Property: Consequences and Opportunities, 134  Arturo Casadevall, Ferric C. Fang, and Liise-anne Pirofski A3  Microbial Genome Sequencing to Understand Pathogen Transmission, 141  Jennifer L. Gardy A4  Presence of Oseltamivir-Resistant Pandemic A/H1N1 Minor Variants Before Drug Therapy with Subsequent Selection and Transmission, 151 Elodie Ghedin, Edward C. Holmes, Jay V. DePasse, Lady Tatiana Pinilla, Adam Fitch, Marie-Eve Hamelin, Jesse Papenburg, and Guy Boivin A5  Design Considerations for Home and Hospital Microbiome Studies, 166  Daniel P. Smith, John C. Alverdy, Jeffrey A. Siegel, and Jack A. Gilbert xv

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xvi CONTENTS A6 Sequencing Errors, Diversity Estimates, and the Rare Biosphere, 188 Susan M. Huse, David B. Mark Welch, and Mitchell L. Sogin A7 Phylogeography and Molecular Epidemiology of Yersinia pestis in Madagascar, 207  J. Vogler, Fabien Chan, David M. Wagner, Philippe Amy Roumagnac, Judy Lee, Roxanne Nera, Mark Eppinger, Jacques Ravel, Lila Rahalison, Bruno W. Rasoamanana, Stephen M. Beckstrom-Sternberg, Mark Achtman, Suzanne Chanteau, and Paul Keim A8  Data in Biology: Pitfalls When Using Shotgun Metagenomics to Big Define Hypotheses About Microbial Communities, 230  Folker Meyer and Elizabeth M. Glass A9 High-Throughput Bacterial Genome Sequencing: An Embarrassment of Choice, A World of Opportunity, 238  Nicholas J. Loman, Chrystala Constantinidou, Jacqueline Z. M. Chan, Mihail Halachev, Martin Sergeant, Charles W. Penn, Esther R. Robinson, and Mark J. Pallen A10  Evidence for Several Waves of Global Transmission in the Seventh Cholera Pandemic, 257  Ankur Mutreja, Dong Wook Kim, Nicholas R. Thomson, Thomas R. Connor, Je Hee Lee, Samuel Kariuki, Nicholas J. Croucher, Seon Young Choi, Simon R. Harris, Michael Lebens, Swapan Kumar Niyogi, Eun Jin Kim, T. Ramamurthy, Jongsik Chun, James L. N. Wood, John D. Clemens, Cecil Czerkinsky, G. Balakrish Nair, Jan Holmgren, Julian Parkhill, and Gordon Dougan A11  Multi-Partner Interactions in Corals in the Face of Climate Change, 269  H. Sharp and Kim B. Ritchie Koty A12  Genomic Transition to Pathogenicity in Chytrid Fungi, 291  Suzanne Joneson, Jason E. Stahich, Shin-Han Shiu, and Erica Bree Rosenblum A13  Natural and Experimental Infection of Caenorhabditis Nematodes by Novel Viruses Related to Nodaviruses, 311  Marie-Anne Félix, Alyson Ashe, Joséphine Piffaretti, Guang Wu, Isabelle Nuez, Tony Békucard, Yanfang Jiang, Guoyan Zhao, Carl J. Franz, Leonard D. Goldstein, Mabel Sanroman, Eric A. Miska, and David Wang A14  Genomic Approaches to Studying the Human Microbiota, 339 George M. Weinstock A15  Sequence Analysis of the Human Virome in Febrile and Afebrile Children, 357  Kristine M. Wylie, Kathie A. Mihindukulasuriya, Erica Sodergren, George M. Weinstock, and Gregory A. Storch

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CONTENTS xvii B Agenda  379 C Acronyms 383 D Glossary 387 E Speaker Biographies 395

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Tables, Figures, and Boxes TABLES WO-1 Some Major Methods for Studying Individual Microbes Found in the Environment, 4 WO-2 Interests in Reference Collections and Management, 25 A1-1 Validation Criteria List, 128 A4-1 Virological Testing of Nasopharyngeal Aspirates, 154 A5-1 Home High-Touch Surfaces and Bacterial Reservoirs, 170 A5-2 Hospital High-Touch Surfaces and Bacterial Reservoirs, 171 A5-3 Environmental Parameters, 172 A6-1 OTU Inflation Due to Clustering Algorithm and Sequencing Error, 193 A9-1 Comparison of Next-Generation Sequencing Platforms, 245 A9-2 The Applicability of the Major High-Throughput Sequencing Platforms, 247 A12-1 The Enrichment of Cellular Component, Biological Process and Molecular Function GO Terms of 417 Bd-Specific Genes Associated with a Pfam Domain, 301 A13-1 Strain List, 317 xix

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xx TABLES, FIGURES, AND BOXES A14-1 DNA Sequencing Platforms Used for Microbiome Analysis, 342 A14-2 Characteristics of Bacteria, Microbial Eukaryotes, and Viruses in the Human Microbiome, 343 A15-1 Detection of Viruses with Next Generation Sequencing, 360 A15-2 Samples, 361 A15-3 Virus Genera Screened by PCR, 362 A15-4 Illumina Sequences with Remote Homologies to Astroviruses, 368 A15-5 Genome Coverage, 368 FIGURES WO-1 Universal tree of life based on a comparison of nucleic acid (RNA) sequences found in all cellular life (small subunit ribosomal RNA), 6 WO-2 First glimpses of the microbial world, 7 WO-3 The great plate count anomaly, 9 WO-4 The improvements in DNA sequencing efficiency over time, 13 WO-5 Genome projects and complete genomes since 1995, 14 WO-6 Growth of the viral sequence database mapped to seminal discoveries and improvements in sequencing technology, 15 WO-7 Postulated routes of spread, 18 WO-8 Plague ecology, 19 WO-9 Fully parsimonious minimal spanning tree of 933 SNPs for 282 iso- lates of Y. pestis colored by location, 21 WO-10 Microbiological identification of morphological variants of B. anthracis Ames, 27 WO-11 Bacterial genome dynamics, 30 WO-12 Molecular evolutionary mechanisms that shape bacterial species diversity, 31 WO-13 Damage-response framework and the case of S. cerevisiae, 34 WO-14 Six distinct pathogenic variants of diarrheagenic E. coli, 38 WO-15 Inconsistency of typing with whole genomes or MLST, 40 WO-16 Algorithm for the identification of attaching and effacing E. coli (AEEC) pathogens, 42 WO-17 Time dependence of dN/dS in the core and non-core genome, 44 WO-18 V. cholerae—repeated global transmission, 47 WO-19 Next generation sequencing and new methodologies will help to capture intrahost diversity, 49 WO-20 Novelty of Bd at the phylogenetic level, 53 WO-21 Interactions within coral reef communities, 55 WO-22 Microbial biofilms are necessary for larval settlement, 56

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TABLES, FIGURES, AND BOXES xxi WO-23 Timeline of sequence-based metagenomic projects showing the variety of environments sampled since 2002, 59 WO-24 Novel taxa are found in three of the major phyla associated with human stool samples, 62 WO-25 P. acnes is dominant in pilosebaceous units in both acne patients and individuals with normal skin, 64 WO-26 Genomic differences at the subspecies level (P. acnes), 65 WO-27 Overdispersion of 22 sample types from Dirichlet-multinomial distribution showing similarity between subjects, 66 WO-28 Change in HIV communities with HAART, 67 WO-29 Hydrothermal vents host substantial endolithic microbial communities, 70 WO-30 Electrical continuity yields diverse representative community, 71 WO-31 HGT is ecologically structured by functional class and at multiple spatial scales, 74 WO-32 Season and size fraction distributions and habitat predictions mapped onto Vibrionaceae isolate phylogeny inferred by maximum likelihood analysis of partial hsp60 gene sequences, 75 WO-33 Ecological differentiation in recombining microbial populations, 76 WO-34 Metagenomic approach to studying the Earth’s microbiome, 77 WO-35 Extrapolating microbial community structure, 80 WO-36 We change the microbial community of a house, 81 WO-37 Microbial genomics and tool development, 82 WO-38 Putative transmission on networks constructed from genotyping data versus whole genome data for 32 patients, 85 WO-39 Phylogenetic analysis of novel astrovirus VA1 identified in an outbreak of gastroenteritis, 90 WO-40 Distribution of OTU relative abundances across 210 Human Microbiome Project stool samples, 92 WO-41 Two Acinetobacter v6 tags differing by a single nucleotide and demonstrating a seasonally balanced abundance, 94 WO-42 Principal coordinates analysis of 1,606 Human Microbiome Project shotgun metagenomes, 95 WO-43 Principal coordinates analysis of 1,606 Human Microbiome Project shotgun metagenomes painted by sequencing technology, 95 WO-44 The costs associated with data analysis are becoming the bottleneck for metagenomic analyses, 98 WO-45 Changes in instrument capacity over the past decade, and the timing of major sequencing projects, 99 WO-46 Prototype of a nanopore sequencing technology currently under development, 103 WO-47 Phylogenetic “dark matter” left to be sampled, 106

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xxii TABLES, FIGURES, AND BOXES A1-1 The microbial forensics attribution continuum, 119 A1-2 A general overview of the work and information flow from sample to analysis to information developed based on use of second-generation sequencing technology, 123 A3-1 An example demonstrating how the limitations of field and molecular epidemiology complicate outbreak reconstructions, 142 A3-2 The dense social network in the outbreak community complicated outbreak reconstruction attempts, 144 A3-3 The number of bacterial genome projects recorded in the Genomes Online Database (GOLD) increased exponentially with the introduction of next-generation sequencing methods in the mid-2000s, 146 A3-4 Using microevolutionary events to track person-to-person spread of a pathogen over a social network, 147 A4-1 Outline of studies indicating day of onset, day when oseltamivir treatment was started, and sampling timeline, 156 A4-2 Longitudinal study of variant codon prevalence across multiple time- points in an infected immunocompromised child, 159 A4-3 Transmission study of variant codon prevalence compared between son and father specimens, 161 A6-1 An example rank abundance curve with a long-tail distribution, 190 A6-2 Rarefaction curve for OTUs generated from Human Microbiome Project stool samples using the V3-V5 region, 197 A6-3 We calculated alpha diversity (richness) using both ACE and Chao estimators with clusters based on complete linkage and average linkage algorithms, 198 A6-4 Selecting multiple random subsamples of 5,000 reads from a larger data set of 50,000 reads, we created a set of pseudo-replicate samples, 200 A6-5 The rank abundance curve shows only minor reductions in the long tail even assuming that as many as 1 in 500 reads generates a spurious OUT, 203 A7-1 SNP phylogeny of 262 Malagasy isolates, 214 A7-2 Neighbor-joining dendrograms based upon MLVA data, 215 A7-3 Geographic distribution of MLVA subclades in Madagascar, 217 A7-4 Geographic distribution of SNP-defined nodes in the strain MG05- 1020 lineage, 221

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TABLES, FIGURES, AND BOXES xxiii A8-1 The MG-RAST system has more than 58,000 metagenomic data sets totaling over 16.5 terabase pairs of information, 231 A8-2 The DRISEE error profiles for two anonymous projects with three shotgun libraries, 232 A8-3 A simple representation of average base abundance per base demon- strates that data is not distributed randomly, 233 A9-1 High-throughput sequencing platforms, 240 A10-1 A maximum-likelihood phylogenetic tree of the seventh pandemic lineage of V. cholerae based on SNP differences across the whole core genome, excluding probable recombination events, 259 A10-2 Transmission events inferred for the seventh-pandemic phylogenetic tree, drawn on a global map, 263 A11-1 Schematic of coral surfaces and associated microbes, 281 A12-1 Phylogenetic relationships among the 19 taxa used in comparative genomics analyses, 298 A12-2 Chytrid growth on cane-toad skin, 299 A12-3 Gene family copy numbers for metalloproteases (M36), serine-type proteases (S41), aspartyl proteases (ASP), and CRN-like proteins (CRN) in the Chytridiomycota (Bd, Hp and S. punctatus), and a Blas- tocladiomycota outgroup (A. macrogynus), 303 A12-4 Maximum likelihood phylogenies of gene families containing (A) M36, (B) S41, and (C) Asp Pfam domains, 304 A12-5 Left panel (paralog rates) shows box plots of synonymous substitution rates (Ks) for Bd lineage-specific duplicates in three protease families, 305 A13-1 Intestinal cell infection phenotypes in wild Caenorhabditis isolates, 316 A13-2 Transmission electron micrographs of intestinal cells of C. elegans JU1580 adult hermaphrodites, 318 A13-3 Genomic organization and phylogenetic analysis of novel viruses, 320 A13-4 Molecular evidence of viral infection, 321 A13-5 Specificity of infection by the Orsay and Santeuil viruses, 323 A13-6 Small RNAs produced upon viral infection, 324 A13-7 RNAi-deficient mutants of C. elegans can be infected by the Orsay virus, 325 A13-8 Natural variation in somatic RNAi efficacy in C. elegans, 327 A14-1 Data and analysis workflow for microbiome analysis, 345

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xxiv TABLES, FIGURES, AND BOXES A15-1 Comparison of sequencing and PCR results, 362 A15-2 Sequence analysis identifies a variety of viruses in samples from fe- brile and afebrile children, 364 A15-3 Comparison of sequencing results with Ct values from real-time PCR assays, 365 A15-4 Viruses detected by sequencing that were not screened by PCR, 367 A15-5 Febrile children have more viral sequences from a greater range of viruses than do afebrile children, 369 A15-6 Prevalence of viruses in samples from febrile compared with afebrile children, 371 BOXES WO-1 Koch’s Postulates, 8 A2-1 The Concept of Emergent Properties, 135 A9-1 The Add-On Cost of Sequencing, 241 A9-2 Oxford Nanopore: The Game Changer?, 253 A14-1 Terminology, 340