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

2020; Nature Portfolio; Volume: 11; Issue: 1 Linguagem: Inglês

10.1038/s41467-020-14284-2

2041-1723

Pilar Cacheiro, Violeta Muñoz‐Fuentes, Stephen A. Murray, Mary E. Dickinson, Maja Bućan, Lauryl M. J. Nutter, Kevin A. Peterson, Hamed Haselimashhadi, Ann M. Flenniken, Hugh W. Morgan, Henrik Westerberg, Tomasz Konopka, Chih‐Wei Hsu, Audrey E. Christiansen, Denise G. Lanza, Arthur L. Beaudet, Jason D. Heaney, Helmut Fuchs, Valérie Gailus‐Durner, Tania Sorg, Jan Procházka, Vendula Novosadová, Christopher J. Lelliott, Hannah Wardle‐Jones, Sara Wells, Lydia Teboul, Heather Cater, Michelle Stewart, Tertius Hough, Wolfgang Wurst, Radislav Sedláček, David J. Adams, John R. Seavitt, Glauco P. Tocchini‐Valentini, Fabio Mammano, Robert E. Braun, Colin McKerlie, Yann Hérault, Martin Hrabĕ de Angelis, Ann‐Marie Mallon, K. C. Kent Lloyd, Steve D. M. Brown, Helen Parkinson, Terrence F. Meehan, Damian Smedley, J. C. Ambrose, P. Arumugam, E. L. Baple, Marta Bleda, F. Boardman-Pretty, J. M. Boissiere, C. R. Boustred, H. Brittain, Mark J. Caulfield, Gcf Chan, C. E. H. Craig, Louise C. Daugherty, A. de Burca, A. Devereau, Greg Elgar, Rebecca E. Foulger, Tom Fowler, P. Furió-Tarí, J.M. Hackett, Dina Halai, Angela Hamblin, Seton Henderson, J. E. Holman, Tim Hubbard, Kristina Ibáñez, Richard V. Jackson, Lesley Jones, Dalia Kasperavičiūtė, M. Kayikci, L. Lahnstein, Kim Lawson, S. E. A. Leigh, Ivone Leong, F. J. Lopez, F. Maleady-Crowe, Joanne Mason, Ellen M. McDonagh, L. Moutsianas, Michael Mueller, Nirupa Murugaesu, A. C. Need, Christopher A. Odhams, C. Patch, D. Perez-Gil, Dimitris Polychronopoulos, J. Pullinger, T. Rahim, Álvaro Rendón, Pablo Riesgo-Ferreiro, Tim Rogers, Mina Ryten, K Savage, K. Sawant, Richard H. Scott, A. Siddiq, A. Sieghart, K. R. Smith, Alona Sosinsky, W. Spooner, Hallam Stevens, Ashley Stuckey, Rosy Sultana, Elizabeth R. Thomas, S. R. Thompson, C. Tregidgo, Arianna Tucci, E. Walsh, Scott Watters, M. J. Welland, Eric O. Williams, Kate Witkowska, S. M. Wood, Magdalena Zarowiecki, Susan Marschall, Christoph Lengger, Holger Maier, Claudia Seisenberger, Antje Bürger, Ralf Kühn, Joel Schick, Andreas Hörlein, Oskar Oritz, Florian Giesert, Joachim Beig, Janet Kenyon, Gemma Codner, Martin Fray, Sara Johnson, James Cleak, Zsombor Szoke-Kovacs, David Lafont, Valerie E. Vancollie, Robbie S. B. McLaren, Lena Hughes-Hallett, Christine Rowley, Emma Sanderson, Antonella Galli, Elizabeth Tuck, Angela Green, Catherine Tudor, Emma Siragher, Monika Dabrowska, Cecilia Mazzeo, Mark Griffiths, David Gannon, Brendan Doe, Nicola Cockle, Andrea Kirton, Joanna Bottomley, Catherine Ingle, Edward J. Ryder, Diane Gleeson, Ramiro Ramírez‐Solis, Marie‐Christine Birling, Guillaume Pavlovic, Abdel Ayadi, Meziane Hamid, Ghina Bou About, Marie‐France Champy, Hugues Jacobs, Olivia Wendling, Sophie Leblanc, Laurent Vasseur, Elissa J. Chesler, Vivek Kumar, Jacqueline K. White, Karen L. Svenson, Jean-Paul Wiegand, Laura L. Anderson, Troy Wilcox, James Clark, Jennifer Ryan, James M. Denegre, Timothy M. Stearns, Vivek M. Philip, Catherine Witmeyer, Lindsay Bates, Zachary Seavey, Pamela Stanley, Amelia Willet, Willson Roper, Julie Creed, Michayla Moore, Alex Dorr, Pamelia Fraungruber, Rose E. Presby, Matthew Mckay, Dong Nguyen-Bresinsky, Leslie O. Goodwin, Rachel Urban, Coleen Kane,

RNA and protein synthesis mechanisms

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.