High-throughput discovery of novel developmental phenotypes
journal contributionposted on 17.07.2020, 16:35 authored by Mary E Dickinson, Ann M Flenniken, Xiao Ji, Lydia Teboul, Michael D Wong, Jacqueline K White, Terrence F Meehan, Wolfgang J Weninger, Henrik Westerberg, Hibret Adissu, Candice N Baker, Lynette Bower, James M Brown, L Brianna Caddle, Francesco Chiani, Dave Clary, James Cleak, Mark J Daly, James M Denegre, Brendan Doe, Mary E Dolan, Sarah M Edie, Helmut Fuchs, Valerie Gailus-Durner, Antonella Galli, Alessia Gambadoro, Juan Gallegos, Shiying Guo, Neil R Horner, Chih-Wei Hsu, Sara J Johnson, Sowmya Kalaga, Lance C Keith, Louise Lanoue, Thomas N Lawson, Monkol Lek, Manuel Mark, Susan Marschall, Jeremy Mason, Melissa L McElwee, Susan Newbigging, Lauryl MJ Nutter, Kevin A Peterson, Ramiro Ramirez-Solis, Douglas J Rowland, Edward Ryder, Kaitlin E Samocha, John R Seavitt, Mohammed Selloum, Zsombor Szoke-Kovacs, Masaru Tamura, Amanda G Trainor, Ilinca Tudose, Shigeharu Wakana, Jonathan Warren, Olivia Wendling, David B West, Leeyean Wong, Atsushi Yoshiki, The International Mouse Phenotyping Consortium, Daniel G MacArthur, Glauco P Tocchini-Valentini, Xiang Gao, Paul Flicek, Allan Bradley, William C Skarnes, Monica J Justice, Helen E Parkinson, Mark Moore, Sara Wells, Robert E Braun, Karen L Svenson, Martin Hrabe de Angelis, Yann Herault, Tim Mohun, Ann-Marie Mallon, R Mark Henkelman, Steve DM Brown, David J Adams, KC Kent Lloyd, Colin McKerlie, Arthur L Beaudet, Maja Bućan, Stephen A Murray
Approximately one-third of all mammalian genes are essential for life. Phenotypes resulting from knockouts of these genes in mice have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5,000 knockout mouse lines, here we identify 410 lethal genes during the production of the first 1,751 unique gene knockouts. Using a standardized phenotyping platform that incorporates high-resolution 3D imaging, we identify phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts.
AnimalsConserved SequenceDiseaseEmbryo, MammalianGenes, EssentialGenes, LethalGenome-Wide Association StudyHigh-Throughput Screening AssaysHumansImaging, Three-DimensionalMiceMice, Inbred C57BLMice, KnockoutMutationPenetrancePhenotypePolymorphism, Single NucleotideSequence HomologyInternational Mouse Phenotyping ConsortiumJackson LaboratoryInfrastructure Nationale PHENOMIN, Institut Clinique de la Souris (ICS)Charles River LaboratoriesMRC HarwellToronto Centre for PhenogenomicsWellcome Trust Sanger InstituteRIKEN BioResource CenterMohun FC001117General Science & Technology