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Human and mouse essentiality screens as a resource for disease gene discovery

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Item Type:Article
Title:Human and mouse essentiality screens as a resource for disease gene discovery
Creators Name:Cacheiro, P. and Muñoz-Fuentes, V. and Murray, S.A. and Dickinson, M.E. and Bucan, M. and Nutter, L.M.J. and Peterson, K.A. and Haselimashhadi, H. and Flenniken, A.M. and Morgan, H. and Westerberg, H. and Konopka, T. and Hsu, C.W. and Christiansen, A. and Lanza, D.G. and Beaudet, A.L. and Heaney, J.D. and Fuchs, H. and Gailus-Durner, V. and Sorg, T. and Prochazka, J. and Novosadova, V. and Lelliott, C.J. and Wardle-Jones, H. and Wells, S. and Teboul, L. and Cater, H. and Stewart, M. and Hough, T. and Wurst, W. and Sedlacek, R. and Adams, D.J. and Seavitt, J.R. and Tocchini-Valentini, G. and Mammano, F. and Braun, R.E. and McKerlie, C. and Herault, Y. and de Angelis, M.H. and Mallon, A.M. and Lloyd, K.C.K. and Brown, S.D.M. and Parkinson, H. and Meehan, T.F. and Smedley, D.
Abstract:The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery.
Keywords:Disease, Essential Genes, Genetic Association Studies, Genomics, Knockout Mice, Animals, Mice
Source:Nature Communications
Publisher:Nature Publishing Group
Page Range:655
Date:31 January 2020
Additional Information:Ralf Kühn is a member of the International Mouse Phenotyping Consortium.
Official Publication:https://doi.org/10.1038/s41467-020-14284-2
PubMed:View item in PubMed

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