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

Terrence Meehan , Nathalie Conte , David West , Julius Jacobsen , Jeremy Mason , Jonathan Warren , Chao Chen , Ilinca Tudose , Mike Relac , Peter Matthews , Natasha Karp , Luis Santos , Tanja Fiegel , Natalie Ring , Henrik Westerberg , Simon Greenaway , Duncan Sneddon , Hugh Morgan , Gemma Codner , Michelle Stewart , James Brown , Neil Horner , Consortium International Mouse Phenotyping , Melissa Haendel , Nicole Washington , Christopher Mungall , Corey Reynolds , Juan Gallegos , Valerie Gailus-Durner , Tania Sorg-Guss (1, 2) , Guillaume Pavlovic (1, 2) , Lynette Bower , Mark Moore , Iva Morse , Xiang Gao , Glauco Tocchini-Valentini , Yuichi Obata , Soo Cho , Je Seong , John Seavitt , Arthur Beaudet , Mary Dickinson , Yann Herault (1, 2) , Wolfgang Wurst , Martin de Angelis , K Lloyd , Ann Flenniken , Lauryl Nutter , Susan Newbigging , Colin Mckerlie , Monica Justice , Stephen Murray , Karen Svenson , Robert Braun , Jacqueline White , Allan Bradley , Paul Flicek , Sara Wells , William Skarnes , David Adams , Helen Parkinson , Ann Mallon , Steve Brown , Damian Smedley

1 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
2 IGBMC - Institut de génétique et biologie moléculaire et cellulaire

Although next-generation sequencing has revolutionized the ability to associate variants with human diseases, diagnostic rates and development of new therapies are still limited by a lack of knowledge of the functions and pathobiological mechanisms of most genes. To address this challenge, the International Mouse Phenotyping Consortium is creating a genome- and phenome-wide catalog of gene function by characterizing new knockout-mouse strains across diverse biological systems through a broad set of standardized phenotyping tests. All mice will be readily available to the biomedical community. Analyzing the first 3,328 genes identified models for 360 diseases, including the first models, to our knowledge, for type C Bernard-Soulier, Bardet-Biedl-5 and Gordon Holmes syndromes. 90% of our phenotype annotations were novel, providing functional evidence for 1,092 genes and candidates in genetically uncharacterized diseases including arrhythmogenic right ventricular dysplasia 3. Finally, we describe our role in variant functional validation with The 100,000 Genomes Project and others.

Mots clés: Animals; *Disease Models; Animal; Female; *Gene Knockout Techniques; Genetic Diseases; Inborn; Genetic Predisposition to Disease; Humans; Male; Mice; Knockout; Phenotype

Domaines: Génétique

Terrence Meehan, Nathalie Conte, David West, Julius Jacobsen, Jeremy Mason, et al.. Disease model discovery from 3,328 gene knockouts by The International Mouse Phenotyping Consortium. Nature Genetics, 2017, 49 (8), pp.1231-1238. ⟨10.1038/ng.3901⟩. ⟨hal-03691170⟩