TY - JOUR T1 - Human and mouse essentiality screens as a resource for disease gene discovery JF - bioRxiv DO - 10.1101/678250 SP - 678250 AU - Pilar Cacheiro AU - Violeta Muñoz-Fuentes AU - Stephen A. Murray AU - Mary E. Dickinson AU - Maja Bucan AU - Lauryl M.J. Nutter AU - Kevin A. Peterson AU - Hamed Haselimashhadi AU - Ann M. Flenniken AU - Hugh Morgan AU - Henrik Westerberg AU - Tomasz Konopka AU - Chih-Wei Hsu AU - Audrey Christiansen AU - Denise G. Lanza AU - Arthur L. Beaudet AU - Jason D. Heaney AU - Helmut Fuchs AU - Valerie Gailus-Durner AU - Tania Sorg AU - Jan Prochazka AU - Vendula Novosadova AU - Christopher J. Lelliott AU - Hannah Wardle-Jones AU - Sara Wells AU - Lydia Teboul AU - Heather Cater AU - Michelle Stewart AU - Tertius Hough AU - Wolfgang Wurst AU - Radislav Sedlacek AU - David J. Adams AU - John R. Seavitt AU - Glauco Tocchini-Valentini AU - Fabio Mammano AU - Robert E. Braun AU - Colin McKerlie AU - Yann Herault AU - Martin Hrabě de Angelis AU - Ann-Marie Mallon AU - K.C. Kent Lloyd AU - Steve D.M. Brown AU - Helen Parkinson AU - Terrence F. Meehan AU - Damian Smedley AU - on behalf of the Genomics England Research Consortium and the International Mouse Phenotyping Consortium Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/06/24/678250.abstract N2 - Although genomic sequencing has been transformative in the study of rare genetic diseases, identifying causal variants remains a considerable challenge that can be addressed in part by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from the comprehensive viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and from human cell line essentiality screens. We propose a novel, 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 characteristics in the biological processes they regulate, tissue expression levels and human mutation rates. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented in the developmental lethal category, representing genes not essential for cell survival but required for organism development. Exploiting this finding, we have screened developmental disorder cases from three independent disease sequencing consortia and identified potentially pathogenic, de novo variants shared in different patients for several developmental lethal genes that have not previously been associated with rare disease. We therefore propose FUSIL as an efficient resource for disease gene discovery. ER -