Abstract
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.
Highlights
Understanding the mechanisms that underlie phenotypic variation within species is crucial to addressing fundamental issues in medicine, agriculture, and evolutionary biology [1]
Identifying genes that contribute to variation in traits affected by multiple genetic and environmental factors has proven extremely difficult [2], the molecular basis of a few quantitative trait loci (QTLs) has been elucidated [3,4,5]
In previous work that examined lines of mice divergently selected for body size, we showed that much of the selection response is due to a large-effect quantitative trait locus (QTL) on chromosome (Chr) X that causes an approximately 20% difference in growth rate between homozygotes [13,14] and explains 14% of the phenotypic variance at 6 wk in an F2 cross between the selection lines [15]
Summary
Understanding the mechanisms that underlie phenotypic variation within species is crucial to addressing fundamental issues in medicine, agriculture, and evolutionary biology [1]. Mice with the high-line allele showed 15% lower expression of Gpc in liver and kidney ( p = 0.017 and p = 0.012, respectively, from a general linear model fitting effects of genotype, sex, and litter; Figure 2), whereas the differences in transcript levels for Gpc were non-significant ( p = 0.08 and p = 0.74, respectively), and the trends varied in direction between tissues (Figure 2; Table S2). Given the phenotypic effects of the QTL (Table 1), we would expect the difference in Gpc expression between hemizygous low-allele males and hemizygous high-allele males to be greater than the difference between homozygous lowallele females and heterozygous females.
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