A regulatory mutation in IGF2 causes a major QTL effect on muscle growth in the pig
A regulatory mutation in IGF2 causes a major QTL effect on muscle growth in the pig
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DOI：
10.1038/nature02064
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发表时间：
2003-10-23
期刊：
影响因子：
64.8
通讯作者：
Andersson, L
中科院分区：
文献类型：
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作者：
Van Laere, AS;Nguyen, M;Andersson, L
大多数性状和疾病具有多因子背景，这表明它们受环境因素的控制，以及数量未知的性状位点（qtl）（1,2）。鉴定qtl的突变是一个挑战，因为每个位点只能解释表型变异的一小部分（3,4）。父系表达的影响猪肌肉生长、脂肪沉积和心脏大小的QTL映射到IGF2（胰岛素样生长因子2）区域（5,6）。在这里，我们发现这个QTL是由IGF2内含子3的核苷酸替换引起的。突变发生在骨骼肌中低甲基化的进化保守的CpG岛。该突变消除了体外与核因子（可能是抑制因子）的相互作用，从父系遗传该突变的猪在出生后肌肉中IGF2信使RNA的表达增加了三倍。我们的研究建立了非编码区单碱基对替换与QTL效应之间的因果关系。这一结果支持了长期以来的观点，即调控突变对控制表型变异很重要(7)。
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 variation(7).