Article | Published:

Disease model discovery from 3,328 gene knockouts by The International Mouse Phenotyping Consortium

Nature Genetics volume 49, pages 12311238 (2017) | Download Citation

Abstract

Although next-generation sequencing has revolutionized the ability to associate variants with human diseases, diagnostic rates and development of new therapies are still limited by a lack of knowledge of the functions and pathobiological mechanisms of most genes. To address this challenge, the International Mouse Phenotyping Consortium is creating a genome- and phenome-wide catalog of gene function by characterizing new knockout-mouse strains across diverse biological systems through a broad set of standardized phenotyping tests. All mice will be readily available to the biomedical community. Analyzing the first 3,328 genes identified models for 360 diseases, including the first models, to our knowledge, for type C Bernard–Soulier, Bardet–Biedl-5 and Gordon Holmes syndromes. 90% of our phenotype annotations were novel, providing functional evidence for 1,092 genes and candidates in genetically uncharacterized diseases including arrhythmogenic right ventricular dysplasia 3. Finally, we describe our role in variant functional validation with The 100,000 Genomes Project and others.

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Acknowledgements

This work was supported by NIH grants U54 HG006370 (T.F.M., P.F., A.-M.M., H.P., D.S. and S.D.M.B.), U42 OD011185 (S.A.M.), U54 HG006332 (R.E.B. and K.L.S.), U54 HG006348-S1 and OD011174 (A.L.B.), 1R24OD011883 (C.J.M., M.H., N.W. and D.S.), HG006364-03S1, U54H G006364 (K.C.K.L. and C.M.) and U42 OD011175 (C.M. and K.C.K.L.). Additional support was provided by the Wellcome Trust, Medical Research Council Strategic Award 53658 (S.W. and S.D.M.B.); the government of Canada through Genome Canada and Ontario Genomics (OGI-051) (C.M. and S.D.M.B.); the National Centre for Scientific Research (CNRS); the French National Institute of Health and Medical Research (INSERM); the University of Strasbourg (UDS); the Centre Européen de Recherche en Biologie et en Médecine; the Agence Nationale de la Recherche under the framework program Investissements d'Avenir labeled ANR-10-IDEX-0002-02, ANR-10-INBS-07 PHENOMIN (Y.H.); the German Federal Ministry of Education and Research through Infrafrontier grant 01KX1012 (S.A.M., V.G.-D. and M.H.d.A.); and the 'EUCOMM: Tools for Functional Annotation of the Mouse Genome' (EUCOMMTOOLS) project, grant agreement FP7-HEALTH-F4-2010-261492 (W.W.).

Author information

Author notes

    • Terrence F Meehan
    • , Nathalie Conte
    •  & David B West

    These authors contributed equally to this work.

Affiliations

  1. European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK.

    • Terrence F Meehan
    • , Nathalie Conte
    • , Jeremy Mason
    • , Jonathan Warren
    • , Chao-Kung Chen
    • , Ilinca Tudose
    • , Mike Relac
    • , Peter Matthews
    • , Paul Flicek
    •  & Helen Parkinson
  2. Children's Hospital Oakland Research Institute, Oakland, California, USA.

    • David B West
  3. William Harvey Research Institute, Queen Mary University of London, London, UK.

    • Julius O Jacobsen
    •  & Damian Smedley
  4. The Wellcome Trust Sanger Institute, Hinxton, UK.

    • Natasha Karp
    • , Jacqueline K White
    • , Allan Bradley
    • , William C Skarnes
    •  & David J Adams
  5. Medical Research Council Harwell, Mammalian Genetics Unit and Mary Lyon Centre, Harwell, UK.

    • Luis Santos
    • , Tanja Fiegel
    • , Natalie Ring
    • , Henrik Westerberg
    • , Simon Greenaway
    • , Duncan Sneddon
    • , Hugh Morgan
    • , Gemma F Codner
    • , Michelle E Stewart
    • , James Brown
    • , Neil Horner
    • , Sara Wells
    • , Ann-Marie Mallon
    •  & Steve D M Brown
  6. Department of Medical Informatics and Clinical Epidemiology and OHSU Library, Oregon Health & Science University, Portland, Oregon, USA.

    • Melissa Haendel
  7. Division of Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory, Berkeley, California, USA.

    • Nicole Washington
    •  & Christopher J Mungall
  8. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.

    • Corey L Reynolds
    • , Juan Gallegos
    • , John Seavitt
    • , Arthur L Beaudet
    •  & Mary E Dickinson
  9. Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Experimental Genetics, Neuherberg, Germany.

    • Valerie Gailus-Durner
    • , Wolfgang Wurst
    •  & Martin Hrabe de Angelis
  10. CELPHEDIA, PHENOMIN, Institut Clinique de la Souris (ICS), Illkirch-Graffenstaden, France.

    • Tania Sorg
    • , Guillaume Pavlovic
    •  & Yann Herault
  11. Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, Illkirch, France.

    • Tania Sorg
    • , Guillaume Pavlovic
    •  & Yann Herault
  12. Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.

    • Tania Sorg
    • , Guillaume Pavlovic
    •  & Yann Herault
  13. Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.

    • Tania Sorg
    • , Guillaume Pavlovic
    •  & Yann Herault
  14. Mouse Biology Program, University of California, Davis, Davis, California, USA.

    • Lynette R Bower
    •  & K C Kent Lloyd
  15. IMPC, San Anselmo, California, USA.

    • Mark Moore
  16. Charles River Laboratories, Wilmington, Massachusetts, USA.

    • Iva Morse
  17. SKL of Pharmaceutical Biotechnology and Model Animal Research Center, Collaborative Innovation Center for Genetics and Development, Nanjing Biomedical Research Institute, Nanjing University, Nanjing, China.

    • Xiang Gao
  18. Monterotondo Mouse Clinic, Italian National Research Council (CNR), Institute of Cell Biology and Neurobiology, Monterotondo Scalo, Italy.

    • Glauco P Tocchini-Valentini
  19. RIKEN BioResource Center, Tsukuba, Japan.

    • Yuichi Obata
  20. Korea Mouse Phenotyping Center, Seoul, Republic of Korea.

    • Soo Young Cho
    •  & Je Kyung Seong
  21. National Cancer Center, Goyang, Republic of Korea.

    • Soo Young Cho
  22. Research Institute for Veterinary Science, Seoul National University, Seoul, Republic of Korea.

    • Je Kyung Seong
  23. Centre for Phenogenomics, Toronto, Ontario, Canada.

    • Ann M Flenniken
    • , Lauryl M J Nutter
    • , Susan Newbigging
    •  & Colin McKerlie
  24. Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario, Canada.

    • Monica J Justice
  25. Jackson Laboratory, Bar Harbor, Maine, USA.

    • Stephen A Murray
    • , Karen L Svenson
    •  & Robert E Braun

Consortia

  1. The International Mouse Phenotyping Consortium

    A full list of members and affiliations appears in the Supplementary Note.

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Contributions

T.F.M., D.B.W., N.C. and D. Smedley contributed to data analysis, writing the paper and the design and execution of the work. N.H., M.H., N.W., C.J.M., P.M., J.O.J., C.-K.C., I.T., H.M., M.R., N.K., J.W., H.W., J.M. and D. Sneddon contributed to development of the software, statistical analysis, database and APIs. L.S., T.F., N.R. and S.G. performed quality control of the phenotype data. J.B., J.K.W., S.Y.C., G.F.C., M.E.S., C.L.R., J.G., V.G.-D., T.S., G.P. and L.R.B. led the experimental work and data production. I.M., J.S., A.B., M.E.D., M.H.d.A., M.M., Y.H., G.P.T.-V., K.C.K.L., X.G., C.M., M.J.J., S.A.M., K.L.S., R.E.B., S.W., A.-M.M., P.F., H.P., J.W., A.L.B., W.C.S., D.J.A., S.D.M.B., W.W., S.N., A.M.F., L.M.J.N., Y.O. and J.K.S. were senior principal investigators of the key programs that contributed to the paper and were critical in the design, management and execution of the study, and the writing and reviewing of the manuscript. The additional IMPC consortium members all contributed to data acquisition and data handling.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Damian Smedley.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figure 1 and Supplementary Note.

Excel files

  1. 1.

    Supplementary Table 1

    Reproducibility of 2547 MGI curated gene–phenotype associations that have also been assessed by the IMPC.

  2. 2.

    Supplementary Table 2

    Comparison of human mendelian disease caused by known gene mutations with targeted null mice.

  3. 3.

    Supplementary Table 3

    Summary of phenotypes for human mendelian disease mapping to mouse mutations with adult mutant phenotypes.

  4. 4.

    Supplementary Table 4

    Manual curation of human disease and mouse phenotypes for 100 genes.

  5. 5.

    Supplementary Table 5

    Mutant mouse gene IDs with phenotypes having no or minimal Gene Ontology annotations.

  6. 6.

    Supplementary Table 6

    Candidate genes for genetically mapped human mendelian disease.

  7. 7.

    Supplementary Table 7

    Contributing institute animal welfare approvals.

About this article

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DOI

https://doi.org/10.1038/ng.3901

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