Disease model discovery — from 3,328 knockouts by The International Mouse Phenotyping Consortium

Any of you who are working on human disease models in transgenic mice will be interested to read this article [attached]. With its extensive tool kit for genome modification and capacity for recapitulating human disease –– the laboratory mouse is arguably the best model organism for studying and validating effects of genetic variants in Mendelian disorders, as well as identifying previously unsuspected disease-associated genes. Null mouse mutations have been generated and described in the literature for approximately one-half of the genes in the human genome. However, hypothesis-driven phenotyp­ing of these mutants has led to discoveries in areas that largely reflect the expertise and specific research questions of individual investiga­tors. As a result, the extent of functional annotation, the potential to fully discover pleiotropy, and the opportunity to exploit mutant mouse models for disease-agnostic interrogation is limited. [“Pleiotropy” is defined as two or more seemingly unrelated phenotypes (traits) –– apparently caused by the same single gene.]

Furthermore, the lack of reproducibility in knockout mouse experiments is a well-documented challenge in drug-target development and behavioral and other trans­lational studies. This lack of reproducibility is commonly due to using poorly defined statistical methods, performing studies in only one sex, and practicing bias in animal selection. Development of a comprehensive reference phenotype database –– by using fully vali­dated, standardized and automated phenotyping procedures across all body systems in mutants of both sexes –– provides a robust dataset to corroborate disease-causing factors in humans.

The International Mouse Phenotyping Consortium (IMPC) is creat­ing just such a catalog of mammalian gene function that systematically associates mouse genotype-to-phenotype data and enables researchers to formulate hypotheses for biomedical and translational research, as well as purpose-driven preclinical studies. The IMPC adult phenotyping pipeline analyzes cohorts of male and female knockouts on an isogenic C57BL/6N background from embryonic-stem-cell resources produced by the International Knockout Mouse Consortium (IKMC) –– comprising targeted null mutations with reporter-gene elements. Homozygotes are char­acterized, except in those strains (approximately 30%) in which gene inactivation necessitates the use of heterozygotes to study mice that are lethal in the embryo, neonate or perinate, os less than fully viable and fertile.

All mice will soon be readily available to the biomedical community. Analyzing the first 3,328 genes identified models for 360 diseases [see attached], including the first models for type C Bernard–Soulier, Bardet–Biedl-5, and Gordon Holmes syndromes. About 90% of their phenotype annotations were novel, providing functional evidence for 1,092 genes and candidates in genetically uncharacterized diseases. Lastly, authors describe their role in variant functional validation –– in collaboration with The 100,000 Genomes Project and other projects.

Nature Genetics Aug 2o17; 49: 1231–1238

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