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.
Oliver
Fiona
F
University of Edinburgh, Institute of Evolutionary Biology, School of Biological Sciences, Edinburgh, United Kingdom.
Christians
Julian K
JK
Liu
Xiaojun
X
Rhind
Susan
S
Verma
Vinesh
V
Davison
Claire
C
Brown
Steve D M
SD
Denny
Paul
P
Keightley
Peter D
PD
D000375:Aging / Q000235:genetics; D000818:Animals; D003433:Crosses, Genetic; D005260:Female; D018507:Gene Expression Regulation, Developmental; D014644:Genetic Variation; D005838:Genotype; D053673:Glypicans; D019812:Heparan Sulfate Proteoglycans / Q000235:genetics*; D016013:Likelihood Functions; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains / Q000235:genetics* / Q000254:growth & development; D009154:Mutation; D040641:Quantitative Trait Loci; D012333:RNA, Messenger / Q000235:genetics; D011995:Recombination, Genetic; D014960:X Chromosome
D053673:Glypicans; D019812:Heparan Sulfate Proteoglycans; D012333:RNA, Messenger