Texel sheep are renowned for their exceptional meatiness. To identify the genes underlying this economically important feature, we performed a whole-genome scan in a Romanov × Texel F2 population. We mapped a quantitative trait locus with a major effect on muscle mass to chromosome 2 and subsequently fine-mapped it to a chromosome interval encompassing the myostatin (GDF8) gene. We herein demonstrate that the GDF8 allele of Texel sheep is characterized by a G to A transition in the 3′ UTR that creates a target site for mir1 and mir206, microRNAs (miRNAs) that are highly expressed in skeletal muscle. This causes translational inhibition of the myostatin gene and hence contributes to the muscular hypertrophy of Texel sheep. Analysis of SNP databases for humans and mice demonstrates that mutations creating or destroying putative miRNA target sites are abundant and might be important effectors of phenotypic variation.
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Marcq, F. et al. Preliminary results of a whole-genome scan targeting QTL for carcass traits in a Texel-Romanov intercross. Proc. 7th World Cong. On Genetics Appl. Livest. Prod., Montpellier, France 323–326 (2002).
Laville, E. et al. Effects of a QTL for muscle hypertrophy from Belgian texel sheep on carcass conformation and muscularity. J. Anim. Sci. 82, 3128–3137 (2004).
Haley, C.S., Knott, S.A. & Elsen, J.-M. Mapping quantitative trait loci in crosses between outbred lines using least squares. Genetics 136, 1195–1207 (1994).
Johnson, P.L., McEwan, J.C., Dodds, K.G., Purchas, R.W. & Blair, H.T. A directed search in the region of GDF8 for quantitative trait loci affecting carcass traits in Texel sheep. J. Anim. Sci. 83, 1988–2000 (2005).
Terwilliger, J.D. A powerful likelihood method for the analysis of linkage disequilibrium between trait loci and one or more polymorphic loci. Am. J. Hum. Genet. 56, 777–787 (1995).
Lee, S.J. & McPherron, A.C. Myostatin and the control of skeletal muscle mass. Curr. Opin. Genet. Dev. 9, 604–607 (1999).
Tobin, J.F. & Celeste, A.J. Myostatin, a negative regulator of muscle mass: implications for muscle degenerative diseases. Curr. Opin. Pharmacol. 5, 328–332 (2005).
Xie, X. et al. Systematic discovery of regulatory motifs in human promoters and 3′ UTRs by comparison of several mammals. Nature 434, 338–345 (2005).
Zhao, Y., Samal, E. & Srivastava, D. Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis. Nature 436, 214–220 (2005).
Zimmers, T.A. et al. Induction of cachexia in mice by systematically administered myostatin. Science 296, 1486–1488 (2002).
Schuelke, M. et al. Myostatin mutation associated with gross muscle hypertrophy in a child. N. Engl. J. Med. 350, 2682–2688 (2004).
Zamore, P.D. & Haley, B. Ribo-gnome: the big world of small RNAs. Science 309, 1519–1524 (2005).
Bartel, D.P. & Chen, C.-Z. Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs. Nat. Rev. Genet. 5, 396–400 (2004).
Abelson, J.F. et al. Sequence variants in SLITRK1 are associated with Tourette's syndrome. Science 310, 317–320 (2005).
Lander, E. & Green, P. Construction of multilocus genetic linkage maps in humans. Proc. Natl. Acad. Sci. USA 84, 2363–2367 (1987).
Seaton, G., Haley, C.S., Knott, S.A., Kearsey, M. & Visscher, P.M. QTL Express: mapping quantitative trait loci in simple and complex pedigrees. Bioinformatics 18, 339–340 (2002).
Davis, E. et al. RNAi-mediated allelic trans-interaction at the imprinted callipyge locus. Curr. Biol. 15, 743–749 (2005).
Hill, J.J. et al. The myostatin propeptide and the follistatin-related gene are inhibitory binding proteins of myostatin in normal serum. J. Biol. Chem. 277, 40735–40741 (2002).
Uejima, H., Lee, M.P., Cui, H. & Feinberg, A.P. Hot-stop PCR: a simple and general assay for linear quantitation of allele ratios. Nat. Genet. 25, 375–376 (2000).
Hofacker, I.L. et al. Fast folding and comparison of RNA secondary structures. Monatsh. Chem. 125, 167–188 (1994).
This project was supported by grants from the (i) Walloon Ministry of Agriculture (D31/1036), (ii) the 'GAME' Action de Recherche Concertée from the Communauté Française de Belgique, (iii) the Interuniversity Attraction Pole P5/25 from the Belgian Federal Science Policy Office (R.SSTC.0135), (iv) the European Union 'Callimir' Specific Targeted Research Project (STREP), (v) the University of Liège, (vi) the French Research Agency Genanimal, (vii) Région Auvergne + Départements INRA de Génétique Animale + CEPIA (Caractérisation et élaboration des produits issus de l'agriculture) and (viii) the Région Limousin and Université de Limoges. A.C. benefited from a fellowship of the Département de Génétique Animale, INRA. A.C. and H.T. both benefit from an E.U. Marie-Curie postdoctoral fellowship. C.C. is a 'chercheur qualifié' from the Fonds National de la Recherche Scientifique. We are grateful to P. Leroy and H. Leveziel for their continuous interest and support for this work; to the technical personnel at the Langlade experimental station; to Labogena and France-Upra-Sélection for providing us with DNA samples; to the Centre d'Insémination de Faulx-les-Tombes in Belgium; to C. Fasquelle, V. Marot and V. Dhennin for technical assistance; to J. Vandessompele for advice with real-time PCR and to M. Van Poucke for the primer sequences of the endogenous controls.
The authors declare no competing financial interests.
'Within–sire family' QTL analysis demonstrating the TR genotype of the three F1 rams. (PDF 31 kb)
Marker-assisted segregation analysis. (PDF 110 kb)
Comparing the amounts of GDF8 (MSTN) mRNA in skeletal muscle of Texel and wild-type sheep using real-time quantitative RT-PCR. (PDF 65 kb)
SNPs discovered in the ovine GDF8 (MSTN) gene and allelic frequencies in hypermuscled Texels and wild-type controls. (PDF 32 kb)
Sequence context of the polymorphic miRNA-GDF8 interaction in sheep. (PDF 64 kb)
Effects of the OAR2 QTL on muscularity, fat deposition and body composition significant at the genome-wide 5% level. (PDF 26 kb)
Genotypes of 42 Texel, 90 controls and four TR rams (three F1, one F2) for the 20 SNPs discovered in the GDF9 (MSTN) gene. (PDF 29 kb)
Primer sequences. (PDF 19 kb)
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Clop, A., Marcq, F., Takeda, H. et al. A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep. Nat Genet 38, 813–818 (2006). https://doi.org/10.1038/ng1810
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