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High-throughput discovery of novel developmental phenotypes.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Dickinson, Mary E 
Flenniken, Ann M 
Ji, Xiao 
Teboul, Lydia 
Wong, Michael D 

Abstract

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.

Description

Keywords

Animals, Conserved Sequence, Disease, Embryo, Mammalian, Genes, Essential, Genes, Lethal, Genome-Wide Association Study, High-Throughput Screening Assays, Humans, Imaging, Three-Dimensional, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Penetrance, Phenotype, Polymorphism, Single Nucleotide, Sequence Homology

Journal Title

Nature

Conference Name

Journal ISSN

0028-0836
1476-4687

Volume Title

537

Publisher

Springer Science and Business Media LLC

Rights

All rights reserved