The International Mouse Phenotyping Consortium Web Portal, a unified point of access for knockout mice and related phenotyping data

Abstract

The International Mouse Phenotyping Consortium (IMPC) web portal (http://www.mousephenotype.org) provides the biomedical community with a unified point of access to mutant mice and rich collection of related emerging and existing mouse phenotype data. IMPC mouse clinics worldwide follow rigorous highly structured and standardized protocols for the experimentation, collection and dissemination of data. Dedicated ‘data wranglers’ work with each phenotyping center to collate data and perform quality control of data. An automated statistical analysis pipeline has been developed to identify knockout strains with a significant change in the phenotype parameters. Annotation with biomedical ontologies allows biologists and clinicians to easily find mouse strains with phenotypic traits relevant to their research. Data integration with other resources will provide insights into mammalian gene function and human disease. As phenotype data become available for every gene in the mouse, the IMPC web portal will become an invaluable tool for researchers studying the genetic contributions of genes to human diseases.

An alternative effector gene at the type 2 diabetes-associated TCF7L2 locus?

“…Reported whole-body Acsl5 knockout mice show a consistent reduction in blood glucose levels [8,9] and improvements in insulin sensitivity [8]. In line with this, the study by Xia et al shows lower ACSL5 expression in the non-risk C allele compared with the type 2 diabetes risk-increasing T allele [6].These findings are also in agreement with previous observations in human islets, which demonstrate that the T allele confers greater enhancer activity at rs7903146 [10].…”

Contrasting genetic architectures in different mouse reference populations used for studying complex traits

“…Thousands and perhaps millions of DNA sequence variants that differ among these strains contribute individually and collectively to phenotypic variation and disease risk (Keane et al 2011;Grubb et al 2014). These naturally occurring variants are thought to more appropriately model the kinds of genetic variants found in humans as opposed to engineered or induced loss-of-function mutations in single genes that are currently being systematically produced and that are essential for functional, mechanistic, and systems studies (Bradley et al 2012;Brown and Moore 2012;Koscielny et al 2014). The phenotypic consequences of these naturally occurring variants are expected to involve subtle regulatory or functional changes, rather than the often severe loss-of-function variants that result from genetic engineering.…”

Increased burden of deleterious variants in essential genes in autism spectrum disorder

“…These studies identified an overlapping core set of genes that were essential in the majority of cell lines tested (n = 956), although a subset of genes were essential in specific cell lines. In an alternative and complementary approach, we assembled a catalog of human orthologs of EGs in the mouse (n = 3,326) (14) based on the organismal-level phenotypes of loss-of-function mouse mutants from the Mouse Genome Informatics (MGI) database (23) and the International Mouse Phenotyping Consortium (IMPC) web portal (24). Based on these data, homozygous loss-of-function mutations in 3,326 genes lead to prenatal or preweaning lethality, with a significant overlap between the core set of human cell EGs and human orthologs of EGs in the mouse (14).…”