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

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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Figure 1: IMPC mutant models of human disease and gene function.
Figure 2: Mouse models for mendelian disease.
Figure 3: Mouse model of phosphoserine phosphatase deficiency.
Figure 4: Novel mouse models of disease.

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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.).

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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.

Corresponding author

Correspondence to Damian Smedley.

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The authors declare no competing financial interests.

Additional information

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

Integrated supplementary information

Supplementary Figure 1 Precision and recall of the automated PhenoDigm algorithm.

IMPC mouse strains were ranked by the PhenoDigm algorithm for diseases involved in 650 known gene associations from OMIM and Orphanet then the precision and recall of the lines involving the orthologue of the known disease gene were plotted. Performance was measured where models were excluded below a threshold of either 1.0, 1.25, 1.35, 1.5 or 1.75 for the geometric mean of the information content and Jaccard index of the best phenotype match.

Supplementary information

Supplementary Text and Figures

Supplementary Figure 1 and Supplementary Note. (PDF 259 kb)

Supplementary Table 1

Reproducibility of 2547 MGI curated gene–phenotype associations that have also been assessed by the IMPC. (XLSX 114 kb)

Supplementary Table 2

Comparison of human mendelian disease caused by known gene mutations with targeted null mice. (XLSX 82 kb)

Supplementary Table 3

Summary of phenotypes for human mendelian disease mapping to mouse mutations with adult mutant phenotypes. (XLSX 53 kb)

Supplementary Table 4

Manual curation of human disease and mouse phenotypes for 100 genes. (XLSX 66 kb)

Supplementary Table 5

Mutant mouse gene IDs with phenotypes having no or minimal Gene Ontology annotations. (XLSX 164 kb)

Supplementary Table 6

Candidate genes for genetically mapped human mendelian disease. (XLSX 51 kb)

Supplementary Table 7

Contributing institute animal welfare approvals. (XLSX 10 kb)

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Meehan, T., Conte, N., West, D. et al. Disease model discovery from 3,328 gene knockouts by The International Mouse Phenotyping Consortium. Nat Genet 49, 1231–1238 (2017). https://doi.org/10.1038/ng.3901

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