The International Mouse Phenotyping Consortium (IMPC): a functional catalogue of the mammalian genome that informs conservation

Abstract

The International Mouse Phenotyping Consortium (IMPC) is building a catalogue of mammalian gene function by producing and phenotyping a knockout mouse line for every protein-coding gene. To date, the IMPC has generated and characterised 5186 mutant lines. One-third of the lines have been found to be non-viable and over 300 new mouse models of human disease have been identified thus far. While current bioinformatics efforts are focused on translating results to better understand human disease processes, IMPC data also aids understanding genetic function and processes in other species. Here we show, using gorilla genomic data, how genes essential to development in mice can be used to help assess the potentially deleterious impact of gene variants in other species. This type of analyses could be used to select optimal breeders in endangered species to maintain or increase fitness and avoid variants associated to impaired-health phenotypes or loss-of-function mutations in genes of critical importance. We also show, using selected examples from various mammal species, how IMPC data can aid in the identification of candidate genes for studying a condition of interest, deliver information about the mechanisms involved, or support predictions for the function of genes that may play a role in adaptation. With genotyping costs decreasing and the continued improvements of bioinformatics tools, the analyses we demonstrate can be routinely applied.Electronic supplementary materialThe online version of this article (10.1007/s10592-018-1072-9) contains supplementary material, which is available to authorized users.

Human and mouse essentiality screens as a resource for disease gene discovery

“…We obtained high-to moderate-confidence human orthologues and integrated selected human genetic data. In particular, we incorporated gene viability data obtained in human cell screens (initially 11 cell lines corresponding to three studies) 19 ; in this study we used the Broad Institute Project Achilles Avana dataset comprising 485 cell lines, release 18Q3 of August 2018). We also incorporate constraint scores (shet, RVIS, pLI and O/E LoF), disease information (OMIM, ORPHANET, HPO, DDD) and DMDD annotations (see below for details).…”

“…Previously, human cell-essential genes have been analysed [16][17][18] in conjunction with lethal genes identified in the mouse 23 by either characterising a core set of essential genes at the intersection 14 or studying the union of the two 32 . In these studies, cellular essential genes were shown to have a nearly complete concordance with mouse lethal genes 19,23 . Here, we have taken the human orthologue genes for which the IMPC has viability assessments and integrate the gene essentiality characterisation based on the cell proliferation scores determined by the Project Achilles Avana CRISPR-Cas9 screening performed on over 400 cell lines.…”

“…We conducted an analysis on 4,934 genes with primary adult viability data currently available in IMPC Data Release (DR) 9.1. This release included the 1,751 genes previously analysed in Dickinson, et al 23 and the 4,237 genes analysed in Munoz-Fuentes, et al 19 , corresponding to DR4.0 and DR7.0, respectively, and additional data collected since then.…”

“…Gene essentiality, or the requirement of a gene for an organism's survival, is known to correlate with intolerance to variation 12 and has been directly assessed in a number of species using high-throughput cellular and animal models [13][14][15] . In humans, essentiality has been investigated at the cellular level using cancer cell line screens based on gene-trap, RNAi or CRISPR-Cas9 approaches with the findings that ~10% of protein-coding genes are essential for cell proliferation and survival [16][17][18][19] . The Broad Institute Project Achilles is extending this approach to characterise 1,000 cancer cell lines and, critically, corrects for copy number in their essentiality scoring 20,21 .…”

A resource of targeted mutant mouse lines for 5,061 genes

“…To date, more than 17,500 individual production attempts (microinjection or aggregation) have resulted in the germline transmission of KO alleles for 5,061 unique genes ( Figure 1A; Supplemental Table ST1). These lines have been expanded for phenotyping, providing key insights into mammalian biology and disease [10][11][12][13][14][15] ; www.mousephenotype.org). The IMPC contribution extends the total number of genes with targeted KO alleles produced by the scientific community from the 8,391 reported and curated by Mouse Genome Informatics (MGI; 16 )( Figure 1B; Supplemental Table ST2), to 11,241, or more than half of the genome.…”