A regulatory mutation in IGF2 causes a major QTL effect on muscle growth in the pig.
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.
Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala University, BMC, Box 597, SE-751 24 Uppsala, Sweden.
Anne-Sophie
AS
Van Laere
Minh
M
Nguyen
Martin
M
Braunschweig
Carine
C
Nezer
Catherine
C
Collette
Laurence
L
Moreau
Alan L
AL
Archibald
Chris S
CS
Haley
Nadine
N
Buys
Michael
M
Tally
Göran
G
Andersson
Michel
M
Georges
Leif
L
Andersson
D000818:Animals; D001483:Base Sequence; D001823:Body Composition / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D005786:Gene Expression Regulation / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D007438:Introns / Q000235:genetics; D008969:Molecular Sequence Data; D024510:Muscle Development / Q000235:genetics*; D009132:Muscles / Q000033:anatomy & histology / Q000378:metabolism; D017354:Point Mutation / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D019655:Quantitative Trait, Heritable; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013552:Swine / Q000033:anatomy & histology / Q000235:genetics* / Q000254:growth & development*
D012333:RNA, Messenger; D007335:Insulin-Like Growth Factor II