RT Journal Article
SR Electronic
T1 Human and mouse essentiality screens as a resource for disease gene discovery
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 678250
DO 10.1101/678250
A1 Pilar Cacheiro
A1 Violeta Muñoz-Fuentes
A1 Stephen A. Murray
A1 Mary E. Dickinson
A1 Maja Bucan
A1 Lauryl M.J. Nutter
A1 Kevin A. Peterson
A1 Hamed Haselimashhadi
A1 Ann M. Flenniken
A1 Hugh Morgan
A1 Henrik Westerberg
A1 Tomasz Konopka
A1 Chih-Wei Hsu
A1 Audrey Christiansen
A1 Denise G. Lanza
A1 Arthur L. Beaudet
A1 Jason D. Heaney
A1 Helmut Fuchs
A1 Valerie Gailus-Durner
A1 Tania Sorg
A1 Jan Prochazka
A1 Vendula Novosadova
A1 Christopher J. Lelliott
A1 Hannah Wardle-Jones
A1 Sara Wells
A1 Lydia Teboul
A1 Heather Cater
A1 Michelle Stewart
A1 Tertius Hough
A1 Wolfgang Wurst
A1 Radislav Sedlacek
A1 David J. Adams
A1 John R. Seavitt
A1 Glauco Tocchini-Valentini
A1 Fabio Mammano
A1 Robert E. Braun
A1 Colin McKerlie
A1 Yann Herault
A1 Martin Hrabě de Angelis
A1 Ann-Marie Mallon
A1 K.C. Kent Lloyd
A1 Steve D.M. Brown
A1 Helen Parkinson
A1 Terrence F. Meehan
A1 Damian Smedley
A1 on behalf of the Genomics England Research Consortium and the International Mouse Phenotyping Consortium
YR 2019
UL http://biorxiv.org/content/early/2019/06/24/678250.abstract
AB 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.