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

Abstract

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 with 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.

Comparative aspects of rodent and nonrodent animal models for mechanistic and translational diabetes research

“…To date, rodents represent the predominant species in biomedical research because of their low acquisition and maintenance costs (housing and food), standardized hygienic environment, good ethical acceptance, rapid reproductive biology (Table 1), efficient and well-established techniques for genetic modification, large-scale standardized phenotyping protocols, and the availability of a large database of reference information [18]. Although wild-type and genetically engineered rodent models have had a major impact on basic research, the translation of findings in rodent models to humans, for example, the prediction of clinical efficacy and safety of novel drug candidates, may be poor [5].…”

Reproducibility and replicability of rodent phenotyping in preclinical studies

“…This section reflects experience with projects collecting phenotyping data across several laboratories, in some cases over long time periods, frequently through collaboration with researchers from other institutes and disciplines, and frequently contributing phenotyping data to public databases and services, and/or to meta-analysis and reanalysis by other researchers (Crabbe et al, 1999; Chesler et al, 2002a,b; Collaborative Cross Consortium, 2004; Wolfer et al, 2004; Kafkafi et al, 2005; Wahlsten et al, 2006; Mouse Phenotype Database Integration Consortium, 2007; Mandillo et al, 2008; Morgan et al, 2009; Beckers et al, 2009; Baker et al, 2011; Richter et al, 2011; Collaborative Cross Consortium, 2012; Bogue et al, 2014; Grubb et al, 2014; Heller et al, 2014; Karp et al, 2014; Koscielny et al, 2014; Maggi et al, 2014; de Angelis et al, 2015; Bogue et al, 2016; Karp et al, 2017; Kafkafi et al, 2017). The projects described in the rest of this section will be used to address multiple issues of replicability and reproducibility in the following sections.…”

“…The IMPC is a community effort to knock out ~20,000 genes and generate ~20,000 mutant mouse lines over the next 10 years, phenotype them using comprehensive and standardized high-throughput assays, and make them freely available to researchers over the world as animal models (De Angelis et al, 2015). At the time of the meeting the IMPC included ten “centers” – institutes over the world performing high-throughput phenotyping of mice, on the same genetic background of C57BL/6N.…”

Leveraging Naked Mole Rat (Heterocephalus glaber) Comparative Genomics to Identify Canine Genes Modulating Susceptibility to Tumorigenesis and Cancer Phenotypes

“…The mouse is the most widely studied mammalian laboratory model. Gene knockout technology has resulted in the production of mouse strains with inactivating mutations in over one third of the genes encoded in the mouse genome [15]. The International Mouse Phenotyping Consortium (IMPC), (a collaborative functional genomics effort between laboratories in America, Germany, United Kingdom, France, Canada, China and Japan) has characterized phenotype data for 2000 mouse genes and plans to have 5000 genes characterized by Ring et al [16].…”