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Cacheiro, P.* ; Muñoz-Fuentes, V.* ; Murray, S.A.* ; Dickinson, M.E.* ; Bucan, M.* ; Nutter, L.M.J.* ; Peterson, K.A.* ; Haselimashhadi, H.* ; Flenniken, A.M.* ; Morgan, H.* ; Westerberg, H.* ; Konopka, T.* ; Hsu, C.W.* ; Christiansen, A.V.* ; Lanza, D.G.* ; Beaudet, A.L.* ; Heaney, J.D.* ; Fuchs, H. ; Gailus-Durner, V. ; Sorg, T.* ; Prochazka, J.* ; Novosadova, V.* ; Lelliott, C.J.* ; Wardle-Jones, H.* ; Wells, S.* ; Teboul, L.* ; Cater, H.* ; Stewart, M.* ; Hough, T.* ; Wurst, W. ; Sedlacek, R.* ; Adams, D.J.* ; Seavitt, J.R.* ; Tocchini-Valentini, G.* ; Mammano, F.* ; Braun, R.E.* ; McKerlie, C.* ; Herault, Y.* ; Hrabě de Angelis, M. ; Mallon, A.M.* ; Lloyd, K.C.K.* ; Brown, S.D.M.* ; Parkinson, H.* ; Meehan, T.F.* ; Smedley, D.* ; International Mouse Phenotyping Consortium (Marschall, S. ; Lengger, C. ; Maier, H. ; Seisenberger, C. ; Bürger, A. ; Kühn, R. ; Schick, J. ; Hörlein, A. ; Oritz, O. ; Giesert, F. ; Beig, J.)

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

Nat. Commun. 11:655 (2020)
Postprint Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 11, Issue: 1, Pages: , Article Number: 655 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Experimental Genetics (IEG)
Institute of Developmental Genetics (IDG)