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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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.).
Integrated supplementary information
Reproducibility of 2547 MGI curated gene–phenotype associations that have also been assessed by the IMPC.
Comparison of human mendelian disease caused by known gene mutations with targeted null mice.
Summary of phenotypes for human mendelian disease mapping to mouse mutations with adult mutant phenotypes.
Manual curation of human disease and mouse phenotypes for 100 genes.
Mutant mouse gene IDs with phenotypes having no or minimal Gene Ontology annotations.
Candidate genes for genetically mapped human mendelian disease.
Contributing institute animal welfare approvals.
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