Fine-mapping of obesity-related quantitative trait loci in an F9/10 advanced intercross line.

Obesity develops in response to a combination of environmental effects and multiple genes of small effect. Although there has been significant progress in characterizing genes in many pathways contributing to metabolic disease, knowledge about the relationships of these genes to each other and their joint effects upon obesity lags behind. The LG,SM advanced intercross line (AIL) model of obesity has been used to characterize over 70 loci involved in fatpad weight, body weight, and organ weights. Each of these quantitative trait loci (QTLs) encompasses large regions of the genome and require fine-mapping to isolate causative sequence changes and possible mechanisms of action as indicated by the genetic architecture. In this study we fine-map QTLs first identified in the F(2) and F(2/3) populations in the combined F(9/10) advanced intercross generations. We observed significantly narrowed QTL confidence regions, identified many single QTL that resolve into multiple QTL peaks, and identified new QTLs that may have been previously masked due to opposite gene effects at closely linked loci. We also present further characterization of the pleiotropic and epistatic interactions underlying these obesity-related traits.