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Microbial Status and Genetic Evaluation of Mice and Rats

PROCEEDINGS OF THE 1999 US/JAPAN CONFERENCE

International Committee of the Institute for Laboratory Animal Research

National Research Council

NATIONAL ACADEMY PRESS
Washington, D.C



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Microbial Status and Genetic Evaluation of Mice and Rats: PROCEEDINGS OF THE 1999 US/JAPAN CONFERENCE Microbial Status and Genetic Evaluation of Mice and Rats PROCEEDINGS OF THE 1999 US/JAPAN CONFERENCE International Committee of the Institute for Laboratory Animal Research National Research Council NATIONAL ACADEMY PRESS Washington, D.C

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Microbial Status and Genetic Evaluation of Mice and Rats: PROCEEDINGS OF THE 1999 US/JAPAN CONFERENCE NATIONAL ACADEMY PRESS 2101 Constitution Avenue, NW Washington, DC 20218 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 study was supported by Grant No. N0-0D-4-2139 between the National Academies and the National Institutes of Health of the U.S. Department of Health and Human Services. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the views of the organizations or agencies that provided support for the project. International Standard Book Number 0-309-07195-X Additional copies of this book are available from the National Academy Press , 2101 Constitution Avenue, N.W., Box 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); http://www.nap.edu. Copyright 2000 by the National Academy of Sciences. All rights reserved. Printed in the United States of America

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Microbial Status and Genetic Evaluation of Mice and Rats: PROCEEDINGS OF THE 1999 US/JAPAN CONFERENCE THE NATIONAL ACADEMIES National Academy of Sciences National Academy of Engineering Institute of Medicine National Research Council 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. Bruce Alberts 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. William Wulf 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. Kenneth I. Shine 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 National 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. Bruce Alberts and Dr. William Wulf are chairman and vice chairman, respectively, of the National Research Council.

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Microbial Status and Genetic Evaluation of Mice and Rats: PROCEEDINGS OF THE 1999 US/JAPAN CONFERENCE This page in the original is blank.

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Microbial Status and Genetic Evaluation of Mice and Rats: PROCEEDINGS OF THE 1999 US/JAPAN CONFERENCE INTERNATIONAL COMMITTEE OF THE INSTITUTE FOR LABORATORY ANIMAL RESEARCH COUNCIL JOHN VANDENBERGH (Chair), Department of Zoology, North Carolina State University, Raleigh, NC HILTON J. KLEIN, Department of Laboratory Animal Resources, Merck Research Laboratories, West Point, PA WILLIAM MORTON, Regional Primate Research Center, University of Washington, Seattle, WA ROBERT J. RUSSELL, Harlan Sprague Dawley, Inc., Indianapolis, IN WILLIAM S. STOKES, Environmental Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC PETER A. WARD, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI Staff RALPH B. DELL, Director KATHLEEN A. BEIL, Administrative Assistant SUSAN S. VAUPEL, Managing Editor, ILAR Journal MARSHA K. WILLIAMS, Project Assistant

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Microbial Status and Genetic Evaluation of Mice and Rats: PROCEEDINGS OF THE 1999 US/JAPAN CONFERENCE INSTITUTE FOR LABORATORY ANIMAL RESEARCH COUNCIL PETER A. WARD (Chair), Department of Pathology, University of Michigan Medical School, Ann Arbor, MI BENNETT DYKE, Southwest Foundation for Biomedical Research, San Antonio, TX ROSEMARY W. ELLIOTT, Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY GERALD F. GEBHART, Department of Pharmacology, College of Medicine, University of Iowa, Iowa City, IA GAIL E. HERMAN, Wexner Research Facility, Children's Hospital, Columbus, OH HILTON J. KLEIN, Department of Laboratory Animal Resources, Merck Research Laboratories, West Point, PA MARGARET LANDI, Department of Laboratory Animal Science, SmithKline Beecham Pharmaceuticals, King of Prussia, PA WILLIAM MORTON, Regional Primate Research Center, University of Washington, Seattle, WA RANDALL J. NELSON, Department of Anatomy and Neurobiology, University of Tennessee, Memphis, TN ROBERT J. RUSSELL, Harlan Sprague Dawley, Inc., Indianapolis, IN WILLIAM S. STOKES, Environmental Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC MICHAEL K. STOSKOPF, Department of Companion Animal and Special Species Medicine, North Carolina State University, Raleigh, NC JOHN G. VANDENBERGH, Department of Zoology, North Carolina State University, Raleigh, NC THOMAS WOLFLE, Annapolis, MD JOANNE ZURLO, Center for Alternatives to Animal Testing, Johns Hopkins School of Hygiene and Public Health, Baltimore, MD Staff RALPH B. DELL, Director KATHLEEN A. BEIL, Administrative Assistant SUSAN S. VAUPEL, Managing Editor, ILAR Journal MARSHA K. WILLIAMS, Project Assistant

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Microbial Status and Genetic Evaluation of Mice and Rats: PROCEEDINGS OF THE 1999 US/JAPAN CONFERENCE COMMISSION ON LIFE SCIENCES MICHAEL T. CLEGG (Chair), College of Natural and Agricultural Sciences, University of California, Riverside, CA PAUL BERG (Vice Chair), Stanford University School of Medicine, Stanford, CA FREDERICK R. ANDERSON, Cadwalader, Wickersham & Taft, Washington, DC JOANNA BURGER, Division of Life Sciences, Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ JAMES E. CLEAVER, University of California Cancer Center, San Francisco, CA DAVID EISENBERG, University of California, Los Angeles, CA JOHN L. EMMERSON, Eli Lilly and Co. (ret.), Indianapolis, IN NEAL L. FIRST, Department of Animal Science, University of Wisconsin, Madison, WI DAVID J. GALAS, Chiroscience R&D, Inc., Bothell, WA DAVID V. GOEDDEL, Tularik, Inc., South San Francisco, CA ARTURO GOMEZ-POMPA, Department of Botany and Plant Sciences, University of California, Riverside, CA COREY S. GOODMAN, Department of Molecular and Cell Biology, University of California, Berkeley, CA JON W. GORDON, Department of Obstetrics and Gynecology, Mount Sinai School of Medicine, New York, NY DAVID G. HOEL, Department of Biometry and Epidemiology, Medical University of South Carolina, Charleston, SC BARBARA S. HULKA, Department of Epidemiology, University of North Carolina, Chapel Hill, NC CYNTHIA J. KENYON, Department of Biochemistry, University of California, San Francisco, CA BRUCE R. LEVIN, Department of Biology, Emory University, Atlanta, GA DAVID M. LIVINGSTON, Dana-Farber Cancer Institute, Boston, MA DONALD R. MATTISON, March of Dimes, White Plains, NY ELLIOT M. MEYEROWITZ, Division of Biology, California Institute of Technology, Pasadena, CA ROBERT T. PAINE, Department of Zoology, University of Washington, Seattle, WA RONALD R. SEDEROFF, Department of Forestry, North Carolina State University, Raleigh, NC ROBERT R. SOKAL, Department of Ecology and Evolution, State University of New York at Stony Brook, NY CHARLES F. STEVENS, MD, The Salk Institute for Biological Studies, La Jolla, CA

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Microbial Status and Genetic Evaluation of Mice and Rats: PROCEEDINGS OF THE 1999 US/JAPAN CONFERENCE SHIRLEY M. TILGHMAN, Department of Molecular Biology, Princeton University, Princeton, NJ RAYMOND L. WHITE, Department of Oncological Sciences, University of Utah, Salt Lake City, UT Staff WARREN MUIR, Executive Director

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Microbial Status and Genetic Evaluation of Mice and Rats: PROCEEDINGS OF THE 1999 US/JAPAN CONFERENCE Preface US/Japan meetings on laboratory animal science have been held virtually every year since 1980 under the US/Japan Cooperative Program on Science and Technology. Over the years these meetings have resulted in a number of important documents including the Manual of Microbiologic Monitoring of Laboratory Animals published in 1994 and the article Establishment and Preservation of Reference Inbred Strains of Rats for General Purposes. In addition to these publications, the meetings have been instrumental in increasing awareness of the need for microbiologic monitoring of laboratory rodents and the need for genetic definition and monitoring of mice and rats. In cooperation with the Comparative Medicine section of NCRR/NIH, the ILAR Council and staff are pleased to become the host for this important annual meeting and look forward to participating in future meetings. The support and sponsorship of NCRR (P40 RR 11611) in the United States and the Central Institute for Experimental Animals in Japan are gratefully acknowledged. Bringing together the leading scientists in the field of laboratory animal care has resulted in increased understanding of American and Japanese approaches to laboratory animal science and should continue to strengthen efforts to harmonize approaches aimed at resolving common challenges in the use of animal models for biomedical research and testing. This effort to improve understanding and cooperation between Japan and the United States should also be useful in developing similar interaction with other regions of the world including Europe, Australia, and Southeast Asia. John Vandenbergh, Chair International Committee of the Institute for Laboratory Animal Research

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Microbial Status and Genetic Evaluation of Mice and Rats: PROCEEDINGS OF THE 1999 US/JAPAN CONFERENCE Contents     Opening Remarks Judith L. Vaitukaitis   1     Opening Remarks Shin-Ichi Ota   4     Introductory Comments on Microbiologic Testing of Laboratory Mice and Rats: Uniformity of Results Anton M. Allen   6     Development of a Performance Assessment Program for Research Animal Diagnostic Laboratories and Defining Microbiologic Testing Standards Lela K. Riley   7     Standardization of Rodent Health Surveillance: Regulation Versus Competition William Shek   11      Introduction,   11      Animal Health,   12      Health Surveillance,   14      Summary,   15

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Microbial Status and Genetic Evaluation of Mice and Rats: PROCEEDINGS OF THE 1999 US/JAPAN CONFERENCE     Factors Causing Difficulties in Uniformity of Results Among Testing Facilities in Microbiologic Monitoring of Laboratory Animals Toshio Itoh   16      Discrepancies in Results,   16      Conclusion,   20     Necessity of Reexamining the Pathogenicity and Elimination of Parasites in Rats and Mice Toshiyuki Shibahara   21      Microbiologic Contamination in Laboratory Rats and Mice,   21      Pinworms as Possible Indicators of Biologically Contaminated Animal Facilities,   23      Need for Elimination of Parasites,   23      Conclusion and Recommendations,   26     Emerging (and Reemerging) Viruses of Laboratory Mice and Rats Abigail L. Smith   27      Introduction,   27      Agents of Concern,   27      Conclusions,   32     Emerging Infections as a Cause of Concern Stephen Morse   35      Imperfectly Controlled Environment,   35      Recognized Threats,   36      Opportunities to Learn,   36      Past Surprises,   37      Future Discoveries,   38      DARPA,   38     Emerging Diseases in Mice and Rats Toshio Itoh   40      H. hepaticus Contamination of Human Tumor Tissues Passaged in Immunodificient Mice,   40      Establishment of Test Agents,   42     Survey of Helicobacter Species in Laboratory Mice and Gerbils in Japan Kazuo Goto   44      Materials and Methods,   63      Results,   64      Conclusion,   65

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Microbial Status and Genetic Evaluation of Mice and Rats: PROCEEDINGS OF THE 1999 US/JAPAN CONFERENCE     Genetic Evaluation of Outbred Rats Joseph J. DeGeorge   47      Regulatory Perspective and Information,   47      New Technology,   48      Genetically Engineered Mice,   49      Summary,   49      Question and Answer,   50     Genetic Evaluation of Outbred Rats from the Breeder's Perspective William J. White   51      Population Management,   51      Supply and Demand,   52      Variables Affecting Comparisons of Subpopulations by Genetic Monitoring,   54      Causes and Amelioration of Genetic Divergence,   54      Development of a Foundation Colony-Based Outbred Production System,   56      Conclusion,   62      Questions and Answers,   63     Concept for Establishment of Rat Outbred Global Standard Strains Tatsuji Nomura   65      Introduction,   65      History of Genetic Quality Control,   66      Quality Standards,   66      Concept of Global Standards for Outbred Rats,   66      Selection of a Global Standard Outbred Rat Strain,   71      Summary,   71     Necessity of Genetic and Microbiologic Quality Network from the Pharmaceutical Industry's Perspective Naoko Kagiyama   77      Background,   77      Issues Related to the Quality of Outbred Mice and Rats,   77      Conclusion,   83     International Harmonization of Laboratory Animals Hideki Katoh   85      Strains and Colonies Used in Animal Experimentation,   85      Safety Studies and Laboratory Animals,   86      International Harmonization of Laboratory Animals,   87      Conclusion,   95

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Microbial Status and Genetic Evaluation of Mice and Rats: PROCEEDINGS OF THE 1999 US/JAPAN CONFERENCE     Rat Genetics and Toxicology Michael F.W. Festing   97      Summary,   97      Introduction,   98      From the Literature,   98      Conclusions,   103     A Phenotype-driven Approach to the Molecular and Functional Analysis of the Mouse Genome Dabney K. Johnson, Donald A. Carpenter, Cymbeline T. Culiat, Karen A. Goss, Mitchell L. Klebig, Edward J. Michaud, Darla R. Miller, Liane B. Russell, Yun You, and Eugene M. Rinchik   105      Background,   105      Experience Applied to New Experiments,   106      Robust and Broad-Spectrum Phenotype Screening,   108      Summary,   113      Questions and Answers,   114     Evaluation of Targeted Mutations Eugenia Floyd   116     Defining Behavioral Phenotypes in Transgenic and Knockout Mice Jacqueline N. Crawley   119      Introduction,   119      Critical Issues Preceding Behavioral Phenotyping,   120      Behavioral Tests,   121     Defining Phenotype in Genetically Engineered Mice Norikazu Tamaoki   130      Introduction,   130      Historical Development,   130      Conclusions,   131     Development of the Mouse Model Dramatype for Human Clinical Benefit Kazunori Nakajima   132     Concluding Remarks Tatsuji Nomura   137

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Microbial Status and Genetic Evaluation of Mice and Rats: PROCEEDINGS OF THE 1999 US/JAPAN CONFERENCE     Implication of Wild-derived Genes, Mitochondria, and Chromosomes in the Genetic Background of Mouse Models for Diseases and Biologic Functions Kazuo Moriwaki   138      Introduction,   138      Genetic Position of Asian Wild Mice,   138      Use of the Asian Wild-Derived Recombination Host-Spot Gene for Surveying Novel Genes That Determine Susceptibility to Diabetes,   139      Use of Asian Wild-Derived Mitochondria for Studying Mouse Behavior,   139      Use of Asian Wild-Derived Chromosomes for Developing New Consomic Mouse Strains,   139     Concluding Comments John Strandberg   142     Concluding Comments John Vandenbergh   144  Appendix A     147  Appendix B     149

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