Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics

Martin Hrabě de Angelis, George Nicholson, Mohammed Selloum, Jacqueline K White, Hugh Morgan, Ramiro Ramirez-Solis, Tania Sorg, Sara Wells, Helmut Fuchs, Martin Fray, David J Adams, Niels C Adams (+157 others)
2015 Nature Genetics  
The function of the majority of genes in the mouse and human genomes remains unknown. The mouse ES cell knockout resource provides a basis for characterisation of relationships between gene and phenotype. The EUMODIC consortium developed and validated robust methodologies for broad-based phenotyping of knockouts through a pipeline comprising 20 disease-orientated platforms. We developed novel statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes
more » ... h high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no prior functional annotation. We captured data from over 27,000 mice finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. Novel phenotypes were uncovered for many genes with unknown function providing a powerful basis for hypothesis generation and further investigation in diverse systems. A statistical power analysis was performed to quantify the mutant-genotype standardized effect size, d, that would be detectable under a variety of experimental workflows and analysis methods, where is the absolute difference between de Angelis et al.
doi:10.1038/ng.3360 pmid:26214591 pmcid:PMC4564951 fatcat:mbfwpaop3fh45p5fn2t4zwme6a