1. Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala University, BMC, Box 597, SE-751 24 Uppsala, Sweden
2. Department of Medical Biochemistry and Microbiology, Uppsala University, BMC, Box 597, SE-751 24 Uppsala, Sweden
3. Department of Genetics, Faculty of Veterinary Medicine, University of Liege (B43), 20, bd. de Colonster, 4000 Liege, Belgium
4. Roslin Institute (Edinburgh), Roslin, Midlothian EH25 9PS, Scotland, UK
5. Gentec, Kapelbaan 15, 9255 Buggenhout, Belgium
6. Tally Consulting, SE-11458 Stockholm, Sweden
7. These authors contributed equally to this work

Correspondence to: Michel Georges³Leif Andersson^1,2 Email: Leif.Andersson@imbim.uu.se
Email: michel.georges@ulg.ac.be
The sequence data reported in this paper have been deposited in GenBank under accession numbers AY242098–AY242112.

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 variation^{3, 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) region^{5, 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.