Letter | Published:

A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep

Nature Genetics volume 38, pages 813818 (2006) | Download Citation

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Abstract

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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Acknowledgements

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.

Author information

Author notes

    • Alex Clop
    • , Fabienne Marcq
    • , Haruko Takeda
    •  & Dimitri Pirottin

    These authors contributed equally to this work.

Affiliations

  1. Unit of Animal Genomics, Department of Animal Production, Faculty of Veterinary Medicine & Centre for Biomedical Integrative Genoproteomics, University of Liège (B43), 20 Boulevard de Colonster, 4000 Liège, Belgium.

    • Alex Clop
    • , Fabienne Marcq
    • , Haruko Takeda
    • , Dimitri Pirottin
    • , Xavier Tordoir
    • , Florian Caiment
    • , Françoise Meish
    • , Carole Charlier
    •  & Michel Georges
  2. Institut National de la Recherche Agronomique–Station d'Amélioration Génétique des Animaux (INRA-SAGA), BP 52627, 31326 Castanet-Tolosan CEDEX, France.

    • Bernard Bibé
    • , Jacques Bouix
    • , Jean-Michel Elsen
    • , Francis Eychenne
    •  & Catherine Larzul
  3. Station de Recherches sur la Viande, INRA, Theix, 63122 Saint-genès-Champanelle, France.

    • Elisabeth Laville
  4. INRA/Université de Limoges, Faculté des Sciences, 87060 Limoges Cedex, France.

    • Dragan Milenkovic
  5. Cardiovascular and Metabolic Diseases, Wyeth Research, 87 Cambridge Park Drive, Cambridge, Massachusetts 02140, USA.

    • James Tobin

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Michel Georges.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    'Within–sire family' QTL analysis demonstrating the TR genotype of the three F1 rams.

  2. 2.

    Supplementary Fig. 2

    Marker-assisted segregation analysis.

  3. 3.

    Supplementary Fig. 3

    Comparing the amounts of GDF8 (MSTN) mRNA in skeletal muscle of Texel and wild-type sheep using real-time quantitative RT-PCR.

  4. 4.

    Supplementary Fig. 4

    SNPs discovered in the ovine GDF8 (MSTN) gene and allelic frequencies in hypermuscled Texels and wild-type controls.

  5. 5.

    Supplementary Fig. 5

    Sequence context of the polymorphic miRNA-GDF8 interaction in sheep.

  6. 6.

    Supplementary Table 1

    Effects of the OAR2 QTL on muscularity, fat deposition and body composition significant at the genome-wide 5% level.

  7. 7.

    Supplementary Table 2

    Genotypes of 42 Texel, 90 controls and four TR rams (three F1, one F2) for the 20 SNPs discovered in the GDF9 (MSTN) gene.

  8. 8.

    Supplementary Table 3

    Primer sequences.

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DOI

https://doi.org/10.1038/ng1810

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