Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics.
Fiche publication
Date publication
septembre 2015
Journal
Nature genetics
Auteurs
Membres identifiés du Cancéropôle Est :
Dr HERAULT Yann, Pr MANDEL Jean-Louis, Pr MULLER Sylviane, Dr SORG Tania, Dr MARK Manuel
Tous les auteurs :
de Angelis MH, Nicholson G, Selloum M, White J, Morgan H, Ramirez-Solis R, Sorg T, Wells S, Fuchs H, Fray M, Adams DJ, Adams NC, Adler T, Aguilar-Pimentel A, Ali-Hadji D, Amann G, André P, Atkins S, Auburtin A, Ayadi A, Becker J, Becker L, Bedu E, Bekeredjian R, Birling MC, Blake A, Bottomley J, Bowl M, Brault V, Busch DH, Bussell JN, Calzada-Wack J, Cater H, Champy MF, Charles P, Chevalier C, Chiani F, Codner GF, Combe R, Cox R, Dalloneau E, Dierich A, Di Fenza A, Doe B, Duchon A, Eickelberg O, Esapa CT, El Fertak L, Feigel T, Emelyanova I, Estabel J, Favor J, Flenniken A, Gambadoro A, Garrett L, Gates H, Gerdin AK, Gkoutos G, Greenaway S, Glasl L, Goetz P, Da Cruz IG, Götz A, Graw J, Guimond A, Hans W, Hicks G, Hölter SM, Höfler H, Hancock JM, Hoehndorf R, Hough T, Houghton R, Hurt A, Ivandic B, Jacobs H, Jacquot S, Jones N, Karp NA, Katus HA, Kitchen S, Klein-Rodewald T, Klingenspor M, Klopstock T, Lalanne V, Leblanc S, Lengger C, le Marchand E, Ludwig T, Lux A, McKerlie C, Maier H, Mandel JL, Marschall S, Mark M, Melvin DG, Meziane H, Micklich K, Mittelhauser C, Monassier L, Moulaert D, Muller S, Naton B, Neff F, Nolan PM, Nutter LM, Ollert M, Pavlovic G, Pellegata NS, Peter E, Petit-Demoulière B, Pickard A, Podrini C, Potter P, Pouilly L, Puk O, Richardson D, Rousseau S, Quintanilla-Fend L, Quwailid MM, Racz I, Rathkolb B, Riet F, Rossant J, Roux M, Rozman J, Ryder E, Salisbury J, Santos L, Schäble KH, Schiller E, Schrewe A, Schulz H, Steinkamp R, Simon M, Stewart M, Stöger C, Stöger T, Sun M, Sunter D, Teboul L, Tilly I, Tocchini-Valentini GP, Tost M, Treise I, Vasseur L, Velot E, Vogt-Weisenhorn D, Wagner C, Walling A, Weber B, Wendling O, Westerberg H, Willershäuser M, Wolf E, Wolter A, Wood J, Wurst W, Yildirim AÖ, Zeh R, Zimmer A, Zimprich A, , Holmes C, Steel KP, Herault Y, Gailus-Durner V, Mallon AM, Brown SD
Lien Pubmed
Résumé
The function of the majority of genes in the mouse and human genomes remains unknown. The mouse embryonic stem cell knockout resource provides a basis for the characterization of relationships between genes and phenotypes. The EUMODIC consortium developed and validated robust methodologies for the broad-based phenotyping of knockouts through a pipeline comprising 20 disease-oriented platforms. We developed new statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no previous functional annotation. We captured data from over 27,000 mice, finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. New phenotypes were uncovered for many genes with previously unknown function, providing a powerful basis for hypothesis generation and further investigation in diverse systems.
Mots clés
Animals, Female, Genetic Association Studies, Heterozygote, Homozygote, Humans, Male, Mice, Inbred C57BL, Mice, Knockout, Molecular Sequence Annotation, Mutation, Phenotype
Référence
Nat. Genet.. 2015 Sep;47(9):969-978