New models for human disease from the International Mouse Phenotyping Consortium

Abstract

The International Mouse Phenotyping Consortium (IMPC) continues to expand the catalogue of mammalian gene function by conducting genome and phenome-wide phenotyping on knockout mouse lines. The extensive and standardized phenotype screens allow the identification of new potential models for human disease through cross-species comparison by computing the similarity between the phenotypes observed in the mutant mice and the human phenotypes associated to their orthologous loci in Mendelian disease. Here, we present an update on the novel disease models available from the most recent data release (DR10.0), with 5861 mouse genes fully or partially phenotyped and a total number of 69,982 phenotype calls reported. With approximately one-third of human Mendelian genes with orthologous null mouse phenotypes described, the range of available models relevant for human diseases keeps increasing. Among the breadth of new data, we identify previously uncharacterized disease genes in the mouse and additional phenotypes for genes with existing mutant lines mimicking the associated disorder. The automated and unbiased discovery of relevant models for all types of rare diseases implemented by the IMPC constitutes a powerful tool for human genetics and precision medicine.

Fig. 1

Evolution of the number of genes with null mutant mice produced and phenotyped by the IMPC over the last years. a Number of knockout genes with significant phenotype associations and the corresponding number of genes with human orthologs associated with disease according to OMIM or ORPHANET resources. b Time between data releases and number of IMPC genes with a phenotype and orthology to a known human disease gene

Fig. 2

Disease-associated genes with phenotypic abnormalities described in DR10.0 and potential models for human disease. Disease genes: IMPC knockout mice with significant phenotype annotations and a human ortholog associated to disease according to OMIM or Orphanet; No HPO annotations: No HPO-encoded phenotypes available for the disorders associated to the gene; HPO annotations: HPO-encoded phenotypes available for the associated disease; No PhenoDigm match: no phenotypic similarity was found between the IMPC knockout mouse and the human clinical phenotypes; PhenoDigm match: the IMPC null mutant recapitulates at least partially the disease phenotypes