[en] Studying the muscular hypertrophy of Texel sheep by forward genetics, we have identified an A-to-G transition in the 3'UTRof the GDF8 gene that reveals an illegitimate target site for microRNAs miR-1 and miR-206 that are highly expressed in skeletal muscle. This causes the down-regulation of this muscle-specific chalone and hence contributes to the muscular hypertrophyof Texel sheep. We demonstrate that polymorphisms which alter the content of putative miRNA target sites are commonin human and mice, and provide evidence that both conserved and nonconserved target sites are selectively constrained. Wespeculate that these polymorphisms might be important mediators of phenotypic variation including disease. To facilitatestudies along those lines, we have constructed a database (www.patrocles.org) listing putative polymorphic microRNA–targetinteractions.
Research center :
Systmod
Disciplines :
Computer science Genetics & genetic processes
Author, co-author :
Georges, Michel ; Université de Liège - ULiège > Département de productions animales > GIGA-R : Génomique animale
Clop, Alex; Université de Liège - ULiège > Département de productions animales > GIGA-R : Génomique animale
Marcq, Fabienne ; Université de Liège - ULiège > Département clinique des animaux de compagnie et des équidés > Département clinique des animaux de compagnie et des équidés
Takeda, Haruko ; Université de Liège - ULiège > Département de productions animales > GIGA-R : Génomique animale
Pirottin, Dimitri ; Université de Liège - ULiège > Département de sciences fonctionnelles > Département de sciences fonctionnelles
Tordoir, Xavier ; Université de Liège - ULiège > Dép. d'électric., électron. et informat. (Inst.Montefiore) > Systèmes et modélisation
Hiard, Samuel ; Université de Liège - ULiège > Dép. d'électric., électron. et informat. (Inst.Montefiore) > Systèmes et modélisation
Bibé, B.; Institut National de la Recherche Agronomique > Station d'Amélioration Génétique des Animaux
Bouix, J.; Institut National de la Recherche Agronomique > Station d'Amélioration Génétique des Animaux
Caiment, Florian ; Université de Liège - ULiège > Département de productions animales > GIGA-R : Génomique animale
Eychenne, F.; Institut National de la Recherche Agronomique > Station d'Amélioration Génétique des Animaux
Larzul, C.; Institut National de la Recherche Agronomique > Station d'Amélioration Génétique des Animaux
Laville, E.; Institut National de la Recherche Agronomique > Station d'Amélioration Génétique des Animaux
Meish, F.; Université de Liège - ULiège > Département de productions animales > GIGA-R : Génomique animale
Milenkovic, D.; Institut Scientifique de Recherche Agronomique - INRA > Faculté des sciences
Tobin, J.; University of Cambridge > Wyeth Research > Cardiovascular and Metabolic Diseases
Charlier, Carole ; Université de Liège - ULiège > Département de productions animales > GIGA-R : Génomique animale
Abelson J.F., Kwan K.Y., O'Roak B.J., Baek D.Y., Stillman A.A., Morgan T.M., Mathews C.A., Pauls D.L., Rasin M.R., Gunel M., et al. 2005. Sequence variants in SLITRK1 are associated with Tourette's syndrome. Science 310: 317.
Andersson L. and Georges M. 2004. Domestic animal genomics: Deciphering the genetics of complex traits. Nat. Rev. Genet. 5: 202.
Bartel D.P. and Chen C.Z. 2004. Micromanagers of gene expression: The potentially widespread influence of metazoan microRNAs. Nat. Rev. Genet. 5: 396.
Charlier C., Segers K., Karim L., Shay T., Gyapay G., Cockett N., and Georges M. 2001. The callipyge mutation enhances the expression of coregulated imprinted genes in cis without affecting their imprinting status. Nat. Genet. 27: 367.
Clop A., Marcq F., Takeda H., Pirottin D., Tordoir X., Bibe B., Bouix J., Caiment F., Elsen J.M., Eychenne F., et al. 2006. A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep. Nat. Genet. 38: 813.
Davis E., Jensen C.H., Schroder H.D., Shay-Hsdfield T., Kliem A., Cockett N., Georges M., and Charlier C. 2004. Ectopic expression of DLK1 protein in skeletal muscle of padumnal heterozygotes causes the callipyge phenotype. Curr. Biol. 14: 1858.
Doerge R.W. and Churchill G.A. 1996. Permutation tests for multiple loci affecting a quantitative character. Genetics 142: 285.
Farh K.K., Grimson A., Jan C., Lewis B.P., Johnston W.K., Lim L.P., Burge C.B., and Bartel D.P. 2005. The widespread impact of mammalian MicroRNAs on mRNA repression and evolution. Science 310: 1817.
Freking B.A., Murphy S.K., Wylie A.A., Rhodes S.J., Keele J.W., Leymaster K.A., Jirtle R.L., and Smith T.P. 2002. Identification of the single base change causing the callipyge muscle hypertrophy phenotype, the only known example of polar overdominance in mammals. Genome Res. 12: 1496.
Fujii J., Otsu K., Zorzato F., de Leon S., Khanna V.K., Weiler J.E., O'Brien P.J., and MacLennan D.H. 1991. Identification of a mutation in porcine ryanodine receptor associated with malignant hyperthermia. Science 253: 448.
Grobet L., Royo Martin L.J., Poncelet D., Pirottin D., Brouwers B., Riquet J., Schoeberlein A., Dunner S., Menissier F., Massabanda J., et al. 1997. A deletion in the myostatin gene causes double-muscling in cattle. Nat. Genet. 17: 71.
Haley C.S., Knott S.A., and Elsen J.-M. 1994. Mapping quantitative trait loci in crosses between outbred lines using least squares. Genetics 136: 1195.
Lee S.J. 2004. Regulation of muscle mass by myostatin. Annu. Rev. Cell Dev. Biol. 20: 61.
Lewis B.P., Burge C.B., and Bartel D.P. 2005. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120: 15.
Lim L.P., Lau N.C., Garrett-Engele P., Grimson A., Schelter J.M., Castle J., Bartel D.P., Linsley P.S., and Johnson J.M. 2005. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433: 769.
Schuelke M., Wagner K.R., Stolz L.E., Hubner C., Riebel T., Komen W., Braun T., Tobin J.F., and Lee S.J. 2004. Myostatin mutation associated with gross muscle hypertrophy in a child. N. Engl. J. Med. 350: 2682.
Van Laere A.-S., Nguyen M., Braunschweig M., Nezer C., Collette C., Moreau L., Archibald A.L., Haley C.S., Buys N., Tally M., et al. 2003. Positional identification of a regulatory mutation in IGF2 causing a major QTL effect on muscle growth in the pig. Nature 425: 832.
Visscher P.M., Thompson R., and Haley C.S. 1996. Confidence intervals in QTL mapping by bootstrapping. Genetics 143:1013.
Xie X., Lu J., Kulbokas E.J., Golub T.R., Mootha V., Lindblad-Toh K., Lander E.S., and Kellis M. 2005. Systematic discovery of regulatory motifs in human promoters and 3?UTRs by comparison of several mammals. Nature 434: 338.
Zimmers T.A., Davies M.V., Koniaris L.G., Haynes P., Esquela A.F., Tomkinson K.N., McPherron A.C., Wolfman N.M., and Lee S.J. 2002. Induction of cachexia in mice by systemically administered myostatin. Science 296: 1486.
