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Standardized methods for an international initiative to decipher the gene functions

Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics.

Hrabe de Angelis M, Nicholson G, Selloum M, White JK, 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, AndrE P, Atkins S, Auburtin A, Ayadi A, Becker J, Becker L, Bedu E, Bekeredjian R, Birling MC, Blake A, Bottomley J, Bowl MR, 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, Fertak LE, 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, Gotz A, Graw J, Guimond A, Hans W, Hicks G, Holter SM, Hofler 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-Demouliere 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, Schable KH, Schiller E, Schrewe A, Schulz H, Steinkamp R, Simon M, Stewart M, Stoger C, Stoger 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, Wattenhofer-Donze M, Weber B, Wendling O, Westerberg H, Willershauser M, Wolf E, Wolter A, Wood J, Wurst W, Yildirim AO, Zeh R, Zimmer A, Zimprich A; EUMODIC Consortium, Holmes C, Steel KP, Herault Y, Gailus-Durner V, Mallon AM, Brown SD.

Nat Genet Sep 2015

July 27, 2015

One of the major current challenges of biology is to assign one or several function(s) to each of the genes in the genome. To achieve these functional annotations, 4 European centers have embarked on large-scale analyzes (phenotyping) on mouse genes. After setting up standardized, reproducible and reliable tests, they now produce the results of the analysis of 449 genes with functional annotation for 83% of them. These results are published in the journal Nature Genetics.

Today we know the function to about one third of the mouse genes. Yet this annotation very often depends on the expertise and interests of the investigators who conducted the analysis. Indeed, most researchers only target the sole function that fits to their interests when they study a gene, and this usually in a single physiological area. While these functions are sometimes complex and interconnected, the researchers aim to produce one day a complete functional identity card of each gene with all associated functions. By pooling their efforts, several research centers have taken up the challenge of a large-scale analysis of mouse genes, addressing all physiological areas in a controlled environment.

Standardized analysis process

In order to launch a global study, the researchers first standardized 20 minimally invasive functional tests, to measure more than 400 direct and 146 indirect variables, from morphological and behavioral observations to blood measurements. This program, EUMORPHIA, allowed to refine the methods and to provide an efficient process. Through extensive statistical studies, researchers have even reduced the number of individuals per group required to an average of only 7 specimens.

The EUMODIC program launched in 2007 then implemented the sequence of these 20 standard protocols. It thus constitutes a pilot to validate this succession of phenotypic evaluation and to characterize genetically modified mouse lines. The tests were carried out in four main worldwide research centers dedicated to the mouse model: the Medical Research Council in Harwell, the Helmholtz Zentrum in München, the Welcome Trust Sanger Institute in Cambridge and the Mouse Clinical Institute (ICS) in Strasbourg, member of the National PHENOMIN infrastructure. After producing 9.5 million data, the researchers were able to assign one or several functions to 374 genes among the 449 analyzed. This annotation was also standardized to facilitate the understanding of the results. The results of these analyzes conducted in parallel in 4 institutes shows that this standardized method is effective as the heterogeneity of the results between different centers is only about 9%, which confirms the robustness and reproducibility of the tests.

Surprising results

Ultimately, these results available to the scientific community lift the veil on some genes of the "ignorome" (sets of genes for which there is no information). Moreover, comparing the 43 lines for which both homozygous (two identical alleles) and heterozygous (two different alleles) genes were analyzed, the researchers were surprised to observe a high rate of defects in heterozygous mice. These data provide an important source of analysis to better understand diseases where the lack of one allele prevents it to play its role normally (haploinsufficiency). Finally, these results show that most of the genes have multiple functions (pleiotropy), confirming the need to systematize an integrated functional approach for the study of genes, covering several physiological areas.

Overall, this study confirms that these pilot tests can be used on a larger scale. 20,000 genes whose functions remain to be characterized are also currently being analyzed as part of the program led by the International Mouse Phenotyping Consortium (IMPC) involving not less than 18 research centers around the world, including the ICS and PHENOMIN.

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