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

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.

Genetics of Rapid and Extreme Size Evolution in Island Mice

“…Although a few of these QTL overlap with those we identified, most do not. For example, a major X-linked QTL for body weight discovered from another artificial selection experiment (Liu et al 2001;Oliver et al 2005) is not found in our study.…”

Fine Mapping Reveals Sex Bias in Quantitative Trait Loci Affecting Growth, Skeletal Size and Obesity-Related Traits on Mouse Chromosomes 2 and 11

“…Although a plethora of QTL have been discovered (Flint et al 2005), the transition to the next more important step of identifying quantitative trait genes (QTG) has proven difficult. In spite of this, the number of QTG identified has steadily increased in recent years (Bodnar et al 2002;Klein et al 2004;Yalcin et al 2004;Oliver et al 2005;Wang et al 2005;Clee et al 2006).…”

Signalling Mechanisms Underlying Congenital Malformation: The Gatekeepers, Glypicans

“…The role of GPC-3 in this disorder was then confirmed by the generation of Gpc-3-deficient mice, since these mice recapitulate several phenotypes of the Simpson-GolabiBehmel Syndrome patients including developmental outgrowth and dysplastic kidneys (Cano-Gauci et al, 1999;Paine-Saunders et al, 2000). Moreover, recent findings showing that GPC3 polymorphisms have a significant impact in the body size of mice have provided additional support for a role of GPC3 in the regulation of body size (Oliver et al, 2005).…”