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Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics

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Abstract

The function of the majority of genes in the mouse and human genomes remains unknown. The mouse embryonic stem cell knockout resource provides a basis for the characterization of relationships between genes and phenotypes. The EUMODIC consortium developed and validated robust methodologies for the broad-based phenotyping of knockouts through a pipeline comprising 20 disease-oriented platforms. We developed new statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no previous functional annotation. We captured data from over 27,000 mice, finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. New phenotypes were uncovered for many genes with previously unknown function, providing a powerful basis for hypothesis generation and further investigation in diverse systems.

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Figure 1: Detectable effect size and the distribution of annotations.
Figure 2: Phenotyping variance.
Figure 3: Heat map comparing the annotations of reference lines across centers.
Figure 4: Heat map of annotations for the complete data set.
Figure 5: Phenotyping similarity.
Figure 6: Analysis of genes with no previous annotations.

Change history

  • 14 August 2015

    In the version of this article initially published online, the authors neglected to acknowledge one of the funding sources for their study. The acknowledgements should have recognized support from the Medical Research Council under project number MC_U142684172. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

The EUMODIC project was funded by European Commission contract number LSHG-CT-2006-037188. The work at MRC-Harwell was funded by the Medical Research Council under project MC_U142684172. The work at the Toronto Centre for Phenogenomics (TCP) was funded under the NorCOMM project by the government of Canada through Genome Canada and Genome Prairie. The Institut Clinique de la Souris (ICS) has been supported by French state funds through the Agence Nationale de la Recherche under the framework program Investissements d'Avenir by ANR-10-IDEX-0002-02, ANR-10-LABX-0030-INRT and ANR-10-INBS-07 PHENOMIN. A full list of members of the EUMODIC consortium who contributed to the goals of the project is available in the Supplementary Note, and a list of partners is available at http://www.eumodic.org/partners.html.

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M.H.d.A., K.P.S., Y.H. and S.D.M.B. conceived the study and directed the research. G.N., H. Morgan, A.-M.M. and S.D.M.B. wrote the manuscript. M. Selloum, J.K.W., R.R.-S., T. Sorg, S.W., H.F., M.F., D.J.A., N.C.A., T.A., A.A.-P., D.A.-H., G.A., P.A., S.A., A. Auburtin, A. Ayadi, J. Becker, L.B., E.B., R.B., M.-C.B., J. Bottomley, M.R.B., V.B., D.H.B., J.N.B., J.C.-W., H.C., M.-F.C., P.C., C.C., F.C., G.F.C., R. Combe, R. Cox, E.D., A. Dierich, B.D., A. Duchon, O.E., C.T.E., L.E.F., I.E., J.E., J.F., A.F., A. Gambadoro, L. Garrett, H.G., A.-K.G., L. Glasl, P.G., I.G.D.C., A. Götz, J.G., A. Guimond, W.H., G.H., S.M.H., H.H., T.H., R. Houghton, A.H., B.I., H.J., S.J., H.A.K., S.K., T.K.-R., M.K., T.K., V.L., E.l.M., T.L., A.L., C. McKerlie, J.-L.M., S. Marschall, M.M., H. Meziane, K.M., C. Mittelhauser, L.M., D.M., S. Muller, B.N., F.N., P.M.N., L.M.J.N., M.O., G.P., N.S.P., E.P., B.P.-D., A.P., C.P., P.P., L.P., O.P., D.R., S.R., L.Q.-F., M.M.Q., I.R., B.R., F.R., J. Rossant, M.R., J. Rozman, E.R., J.S., K.-H.S., E.S., A.S., H.S., R.S., M. Stewart, C.S., T. Stöger, M. Sun, D.S., L.T., I. Tilly, G.P.T.-V., M.T., I. Treise, E.V., D.V.-W., C.W., B.W., O.W., M.W., E.W., A. Wolter, W.W., A.Ö.Y., R.Z., A. Zimmer, A. Zimprich and V.G.-D. undertook mouse generation, phenotyping, and data acquisition and assessment from the phenotyping pipelines. G.N., H. Morgan, A.B., A.D.F., T.F., G.G., S.G., J.M.H., R. Hoehndorf, N.J., N.A.K., S.L., C.L., H. Maier, D.G.M., L.S., M. Simon, L.V., A. Walling, M.W.-D., H.W., J.W., C.H. and A.-M.M. developed data tools and databases, and carried out data and statistical analyses.

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Correspondence to Steve D M Brown.

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A list of members and affiliations is provided in the Supplementary Note.

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Supplementary Text and Figures

Supplementary Figures 1–7, Supplementary Tables 1 and 2, and Supplementary Note. (PDF 2819 kb)

Supplementary Data Set

Between-center workflow comparison. (PDF 899 kb)

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Hrabě de Angelis, M., Nicholson, G., Selloum, M. et al. Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics. Nat Genet 47, 969–978 (2015). https://doi.org/10.1038/ng.3360

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