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

Nature. 2003 Oct 23;425(6960):832-6. doi: 10.1038/nature02064.


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). The identification of mutations underlying QTLs is a challenge because each locus explains only a fraction of the phenotypic variation. 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. 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 variation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Body Composition / genetics
  • CpG Islands / genetics
  • DNA Methylation
  • Gene Expression Regulation / genetics*
  • Genetic Variation / genetics
  • Insulin-Like Growth Factor II / genetics*
  • Introns / genetics
  • Molecular Sequence Data
  • Muscle Development / genetics*
  • Muscles / anatomy & histology
  • Muscles / metabolism
  • Point Mutation / genetics*
  • Polymorphism, Genetic / genetics
  • Quantitative Trait Loci / genetics
  • Quantitative Trait, Heritable*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Swine / anatomy & histology
  • Swine / genetics*
  • Swine / growth & development*


  • RNA, Messenger
  • Insulin-Like Growth Factor II

Associated data

  • GENBANK/AY242098
  • GENBANK/AY242099
  • GENBANK/AY242100
  • GENBANK/AY242101
  • GENBANK/AY242102
  • GENBANK/AY242103
  • GENBANK/AY242104
  • GENBANK/AY242105
  • GENBANK/AY242106
  • GENBANK/AY242107
  • GENBANK/AY242108
  • GENBANK/AY242109
  • GENBANK/AY242110
  • GENBANK/AY242111
  • GENBANK/AY242112