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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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.
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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