Genetic dissection of a major mouse obesity QTL (Carfhg2): integration of gene expression and causality modeling.

HG.CAST-(D9Mit249-D9Mit133) (HG9) congenic mice are homozygous for CAST/EiJ chromosome (Chr) 9 alleles from approximately 9 to 84 Mbp on a C57BL6/J-hg/hg (HG) background. This region contains the carcass fat in high growth mice (Carfhg2) quantitative trait locus (QTL), and while its obesity-promoting effects have been confirmed in HG9 mice, its underlying genetic basis remains elusive. To refine the location of Carfhg2, we preformed a linkage analysis in two congenic F2 intercrosses and progeny-tested a recombinant F2 male. These analyses narrowed Carfhg2 to between 33.0 and 40.8 Mbp on Chr 9. To identify candidate genes we measured the expression of 44 transcripts surrounding the Carfhg2 peak in adipose, brain, liver, and muscle tissues from F2 mice using Biomark 48.48 Dynamic Arrays. In total, 68% (30 of the 44) of genes were regulated by a significant expression QTL (eQTL) in at least one tissue. To prioritize genes with eQTL we used Network Edge Orienting, a causality modeling tool. These analyses advance our goal of identifying the molecular basis of Carfhg2.