High-throughput discovery of novel developmental phenotypes

• Published in: Nature (London) Vol. 537; no. 7621; pp. 508 - 514
• Main Authors: Dickinson, Mary E., Flenniken, Ann M., Ji, Xiao, Teboul, Lydia, Wong, Michael D., White, Jacqueline K., Meehan, Terrence F., Weninger, Wolfgang J., Westerberg, Henrik, Adissu, Hibret, Baker, Candice N., Bower, Lynette, Brown, James M., Caddle, L. Brianna, Chiani, Francesco, Clary, Dave, Cleak, James, Daly, Mark J., Denegre, James M., Doe, Brendan, Dolan, Mary E., Edie, Sarah M., Fuchs, Helmut, Gailus-Durner, Valerie, Galli, Antonella, Gambadoro, Alessia, Gallegos, Juan, Guo, Shiying, Horner, Neil R., Hsu, Chih-Wei, Johnson, Sara J., Kalaga, Sowmya, Keith, Lance C., Lanoue, Louise, Lawson, Thomas N., Lek, Monkol, Mark, Manuel, Marschall, Susan, Mason, Jeremy, McElwee, Melissa L., Newbigging, Susan, Nutter, Lauryl M. J., Peterson, Kevin A., Ramirez-Solis, Ramiro, Rowland, Douglas J., Ryder, Edward, Samocha, Kaitlin E., Seavitt, John R., Selloum, Mohammed, Szoke-Kovacs, Zsombor, Tamura, Masaru, Trainor, Amanda G., Tudose, Ilinca, Wakana, Shigeharu, Warren, Jonathan, Wendling, Olivia, West, David B., Wong, Leeyean, Yoshiki, Atsushi, Wurst, Wolfgang, MacArthur, Daniel G., Tocchini-Valentini, Glauco P., Gao, Xiang, Flicek, Paul, Bradley, Allan, Skarnes, William C., Justice, Monica J., Parkinson, Helen E., Moore, Mark, Wells, Sara, Braun, Robert E., Svenson, Karen L., de Angelis, Martin Hrabe, Herault, Yann, Mohun, Tim, Mallon, Ann-Marie, Henkelman, R. Mark, Brown, Steve D. M., Adams, David J., Lloyd, K. C. Kent, McKerlie, Colin, Beaudet, Arthur L., Bućan, Maja, Murray, Stephen A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22-09-2016; Nature Publishing Group
• Subjects: 45/70; 59; 59/57; 631/136/334/1874/345; 631/208/135; 631/208/191/1908; 64/110; 64/60; Animals; Conserved Sequence - genetics; Development Biology; Developmental biology; Disease; Embryo, Mammalian - embryology; Embryo, Mammalian - metabolism; Embryos; Genes; Genes, Essential - genetics; Genes, Lethal - genetics; Genetic research; Genome-Wide Association Study; Genomes; Genotype & phenotype; High-throughput screening (Biochemical assaying); High-Throughput Screening Assays; Humanities and Social Sciences; Humans; Imaging, Three-Dimensional; Life Sciences; Methods; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Mutation; Mutation - genetics; Penetrance; Phenotype; Phenotypes; Polymorphism, Single Nucleotide - genetics; Science; Sequence Homology
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature19356

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.
Identification and characterization, using a comprehensive embryonic phenotyping pipeline, of 410 lethal alleles during the generation of the first 1,751 of 5,000 unique gene knockouts produced by the International Mouse Phenotyping Consortium.
Embryonic phenotypes and lethal genes
Stephen Murray and colleagues, including those from the International Mouse Phenotyping Consortium, report on the first phase of the project to generate and phenotypically characterize 5,000 knockout mouse lines, the first systematic efforts to characterize the phenotypes of embryonic lethal mutations. They identify 410 lethal genes during the production of the first 1,751 unique gene knockouts, and characterize these in a comprehensive phenotyping pipeline that includes high-resolution 3D imaging methods. Unexpectedly, given the defined genetic background, they find a number of phenotypes with incomplete penetrance, including some gene knockouts with subviability. The authors also show that orthologues of these mouse essential genes are enriched in genes associated with human disease and show evidence of purifying selection in the human population.