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A regulatory mutation in IGF2 causes a major QTL effect on muscle growth in the pig

Nature volume 425, pages 832–836 (2003)Cite this article

Abstract

Most traits and disorders have a multifactorial background indicating that they are controlled by environmental factors as well as an unknown number of quantitative trait loci (QTLs)1,2. The identification of mutations underlying QTLs is a challenge because each locus explains only a fraction of the phenotypic variation3,4. A paternally expressed QTL affecting muscle growth, fat deposition and size of the heart in pigs maps to the IGF2 (insulin-like growth factor 2) region5,6. Here we show that this QTL is caused by a nucleotide substitution in intron 3 of IGF2. The mutation occurs in an evolutionarily conserved CpG island that is hypomethylated in skeletal muscle. The mutation abrogates in vitro interaction with a nuclear factor, probably a repressor, and pigs inheriting the mutation from their sire have a threefold increase in IGF2 messenger RNA expression in postnatal muscle. Our study establishes a causal relationship between a single-base-pair substitution in a non-coding region and a QTL effect. The result supports the long-held view that regulatory mutations are important for controlling phenotypic variation7.

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Figure 1: Polymorphisms in a 28.6-kb segment containing TH (exon 14), INS and IGF2 among 15 pig chromosomes with deduced QTL status.
Figure 2: Methylation status, EMSA and transfection assays assessing the significance of the IGF2 mutation.
Figure 3: Analysis of IGF2 mRNA expression.

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Acknowledgements

We thank C. Charlier and H. Ronne for discussions, M. Laita, B. McTeir, J. Pettersson, A.-C. Svensson and M. Köping-Höggård for technical assistance, and the Pig Improvement Company for providing DNA samples from Berkshire and Gloucester Old Spot pigs. This work was supported by the Belgian Ministère des Classes Moyennes et de l'Agriculture, the AgriFunGen program at the Swedish University of Agricultural Sciences, the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning, Gentec, the UK Department for Environment, Food and Rural Affairs, the UK Pig Breeders Consortium, and the Biotechnology and Biological Sciences Research Council.

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Author notes

  1. Anne-Sophie Van Laere and Minh Nguyen: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala University, BMC, Box 597, Uppsala, SE-751 24, Sweden

    Anne-Sophie Van Laere, Martin Braunschweig, Göran Andersson & Leif Andersson

  2. Department of Medical Biochemistry and Microbiology, Uppsala University, BMC, Box 597, Uppsala, SE-751 24, Sweden

    Leif Andersson

  3. Department of Genetics, Faculty of Veterinary Medicine, University of Liege (B43), Liege, 20, bd. de Colonster, 4000, Belgium

    Minh Nguyen, Carine Nezer, Catherine Collette, Laurence Moreau & Michel Georges

  4. Roslin Institute (Edinburgh), Roslin, Midlothian, EH25 9PS, Scotland, UK

    Alan L. Archibald & Chris S. Haley

  5. Gentec, Kapelbaan 15, Buggenhout, 9255, Belgium

    Nadine Buys

  6. Tally Consulting, Stockholm, SE-11458, Sweden

    Michael Tally

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Corresponding authors

Correspondence to Michel Georges or Leif Andersson.

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Competing interests

Patent applications concerning the commercial application of the IGF2 QTL have been filed by Melica HB, Sweden (represented by Leif Andersson), University of Liege, Belgium (represented by Michel Georges) and Gentec, Belgium (represented by Nadine Buys).

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Van Laere, AS., Nguyen, M., Braunschweig, M. et al. A regulatory mutation in IGF2 causes a major QTL effect on muscle growth in the pig. Nature 425, 832–836 (2003). https://doi.org/10.1038/nature02064

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