Abstract
Approximately one third of all mammalian genes are essential for life. Phenotypes resulting from mouse knockouts of these genes have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5000 knockout mouse lines, we have identified 410 lethal genes during the production of the first 1751 unique gene knockouts. Using a standardised phenotyping platform that incorporates high-resolution 3D imaging, we identified novel 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 identified in our screen, thus providing a novel dataset that facilitates prioritization and validation of mutations identified in clinical sequencing efforts.
Highlights
Our understanding of the genetic mechanisms required for normal embryonic growth and development has been advanced by the analysis of single mutations generated in individual labs or the identification of mutants through focused mutagenesis screens[1,2,3,4]
Centre-to-centre variability in the proportion of essential genes is observed ranging from 4.8%–52.7%, which likely reflects the different biases in gene selection criteria between centres and specific consortium arrangements for lethal gene characterization (TCP and UCD) (Extended Data Fig. 2A,B)
We describe the systematic characterization of embryonic lethal phenotypes as part the collaborative effort to generate a genome-wide catalogue of gene function
Summary
Our understanding of the genetic mechanisms required for normal embryonic growth and development has been advanced by the analysis of single mutations generated in individual labs or the identification of mutants through focused mutagenesis screens[1,2,3,4]. Recent challenges in reproducibility of animal model experimentation[5,6] emphasize the need for careful standardization of allele design, genetic background, and phenotyping protocols Building on these principles, the goal of the International Mouse Phenotyping Consortium (IMPC) is to generate a catalogue of gene function through systematic generation and phenotyping of a genome-wide collection of gene knockouts (KO) in the mouse. We report the results of the first international, systematic effort to identify and characterize the phenotypes of embryonic lethal mutations using a standardised[13], high-throughput pipeline These findings provide novel insights into gene function, provide new models for inherited disorders, and shed new light on the role of essential genes in a variety of monogenic and complex human disorders
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