TY - JOUR
T1 - Human and mouse essentiality screens as a resource for disease gene discovery
AU - The Genomics England Research Consortium
AU - The International Mouse Phenotyping Consortium
AU - Cacheiro, Pilar
AU - Muñoz-Fuentes, Violeta
AU - Murray, Stephen A.
AU - Dickinson, Mary E.
AU - Bucan, Maja
AU - Nutter, Lauryl M.J.
AU - Peterson, Kevin A.
AU - Haselimashhadi, Hamed
AU - Flenniken, Ann M.
AU - Morgan, Hugh
AU - Westerberg, Henrik
AU - Konopka, Tomasz
AU - Hsu, Chih Wei
AU - Christiansen, Audrey
AU - Lanza, Denise G.
AU - Beaudet, Arthur L.
AU - Heaney, Jason D.
AU - Fuchs, Helmut
AU - Gailus-Durner, Valerie
AU - Sorg, Tania
AU - Prochazka, Jan
AU - Novosadova, Vendula
AU - Lelliott, Christopher J.
AU - Wardle-Jones, Hannah
AU - Wells, Sara
AU - Teboul, Lydia
AU - Cater, Heather
AU - Stewart, Michelle
AU - Hough, Tertius
AU - Wurst, Wolfgang
AU - Sedlacek, Radislav
AU - Adams, David J.
AU - Seavitt, John R.
AU - Tocchini-Valentini, Glauco
AU - Mammano, Fabio
AU - Braun, Robert E.
AU - McKerlie, Colin
AU - Herault, Yann
AU - de Angelis, Martin Hrabě
AU - Mallon, Ann Marie
AU - Lloyd, K. C.Kent
AU - Brown, Steve D.M.
AU - Parkinson, Helen
AU - Meehan, Terrence F.
AU - Smedley, Damian
AU - Ambrose, J. C.
AU - Arumugam, P.
AU - Baple, E. L.
AU - Bleda, M.
AU - Boardman-Pretty, F.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85078825003&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85078825003&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-14284-2
DO - 10.1038/s41467-020-14284-2
M3 - Article
C2 - 32005800
AN - SCOPUS:85078825003
VL - 11
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 655
ER -