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

摘要

Previous speed congenic analysis has suggested that the expression of growth and obesity quantitativentrait loci (QTL) on distal mouse chromosomes (MMU) 2 and 11, segregating between the CAST/EiJn(CAST) and C57BL/6J-hg/hg (HG) strains, is dependent on sex. To confirm, fine map, and further evaluatenQTL 3 sex interactions, we constructed congenic by recipient F2 crosses for the HG.CAST-(D2Mit329-nD2Mit457)N(6) (HG2D) and HG.CAST-(D11Mit260-D11Mit255)N(6) (HG11) congenic strains. Over 700nF2 mice were densely genotyped and phenotyped for a panel of 40 body and organ weight, skeletal length,nand obesity-related traits at 9 weeks of age. Linkage analysis revealed 20 QTL affecting a representativensubset of phenotypes in HG2DF2 and HG11F2 mice. The effect of sex was quantified by comparing twonlinear models: the first model included sex as an additive covariate and the second incorporated sex as annadditive and an interactive covariate. Of the 20 QTL, 8 were sex biased, sex specific, or sex antagonistic.nMost traits were regulated by single QTL; however, two closely linked loci were identified for five traits innHG2DF2 mice. Additionally, the confidence intervals for most QTL were significantly reduced relative tonthe original mapping results, setting the stage for quantitative trait gene (QTG) discovery. These resultsnhighlight the importance of assessing the contribution of sex in complex trait analyses.