Regulatory Variation at Glypican-3 Underlies a Major Growth QTL in Mice

The genetic basis of variation in complex traits remains poorly understood, and few genes underlying variation have been identified. Previous work identified a quantitative trait locus (QTL) responsible for much of the response to selection on growth in mice, effecting a change in body mass of approximately 20%. By fine-mapping, we have resolved the location of this QTL to a 660-kb region containing only two genes of known function, Gpc3 and Gpc4, and two other putative genes of unknown function. There are no non-synonymous polymorphisms in any of these genes, indicating that the QTL affects gene regulation. Mice carrying the high-growth QTL allele have approximately 15% lower Gpc3 mRNA expression in kidney and liver, whereas expression differences at Gpc4 are non-significant. Expression profiles of the two other genes within the region are inconsistent with a factor responsible for a general effect on growth. Polymorphisms in the 3′ untranslated region of Gpc3 are strong candidates for the causal sequence variation. Gpc3 loss-of-function mutations in humans and mice cause overgrowth and developmental abnormalities. However, no deleterious side-effects were detected in our mice, indicating that genes involved in Mendelian diseases also contribute to complex trait variation. Furthermore, these findings show that small changes in gene expression can have substantial phenotypic effects.复杂性状变异的遗传基础仍未被充分阐明，目前已被探明参与该变异的基因寥寥无几。既往研究已在小鼠中鉴定出一个可解释针对生长选择的大部分响应的数量性状位点（quantitative trait locus, QTL），该位点可使小鼠体质量产生约20%的变化。通过精细定位，我们将该QTL的位置锁定在一段660kb的基因组区域内，该区域仅包含两个功能已知的基因Gpc3和Gpc4，以及另外两个功能未知的推定基因。上述基因均未出现非同义多态性，提示该QTL通过调控基因表达发挥作用。携带高生长QTL等位基因的小鼠，其肾脏与肝脏组织中Gpc3的mRNA表达水平约降低15%，而Gpc4的表达差异未达到统计学显著性。该区域内另外两个基因的表达谱并不符合能对生长产生普遍调控作用的因子的特征。Gpc3的3'非翻译区多态性是该因果序列变异的强候选位点。人类与小鼠中Gpc3的功能丧失型突变会导致个体过度生长及发育异常。但本研究中的小鼠未出现任何不良副作用，这表明参与孟德尔式疾病的基因同样可参与复杂性状的变异调控。此外，本研究结果证实，基因表达的微小变化即可产生显著的表型效应。