Genome-wide Generation and Systematic Phenotyping of Knockout Mice Reveals New Roles for Many Genes

TLDR

Mutations in whole organisms are powerful ways of interrogating gene function in a realistic context. The study aims to knock out all genes and screen each line for a broad range of traits through the Sanger Institute Mouse Genetics Project. This program systematically generates knockout mice and performs comprehensive phenotyping across many traits. We found that novel genes are as likely as known genes to reveal phenotypes, many unexpected phenotypes emerged only through broad screening, haploinsufficiency and pleiotropy were common, and 42 % of genes were essential for viability, often lacking paralogs and more likely to form protein complexes. Phenotypic data and more than 900 mutants are openly available for further analysis.

Abstract

Mutations in whole organisms are powerful ways of interrogating gene function in a realistic context. We describe a program, the Sanger Institute Mouse Genetics Project, that provides a step toward the aim of knocking out all genes and screening each line for a broad range of traits. We found that hitherto unpublished genes were as likely to reveal phenotypes as known genes, suggesting that novel genes represent a rich resource for investigating the molecular basis of disease. We found many unexpected phenotypes detected only because we screened for them, emphasizing the value of screening all mutants for a wide range of traits. Haploinsufficiency and pleiotropy were both surprisingly common. Forty-two percent of genes were essential for viability, and these were less likely to have a paralog and more likely to contribute to a protein complex than other genes. Phenotypic data and more than 900 mutants are openly available for further analysis.PaperClip/cms/asset/e2870fc0-4980-42ad-905d-f0f0edb74a34/mmc9.mp3Loading ...(mp3, 3.09 MB) Download audio