Confirmation of QTL-hg interactions
An important feature of our experimental design was the ability to test for interactions between QTL in each MMU2 donor region and genotype at the HG locus, since identical donor regions were introgressed on two genetic backgrounds, B6 (+/+) and HG (hg/hg). Significant interactions between donor region and HG genotype were viewed as strong evidence that hg modifier QTL reside within that unique genomic region.
In the original linkage analysis the mode of gene action and peak location of Wg2 were dependent on the presence of hg [24] (Table 1). In the present study, only homozygous congenic mice were characterized, thus, the overdominant effects of Wg2 were not tested. However, since its original peak location differed dependent on background we hypothesized that Wg2 represents a set of linked QTL between 74.9 and 181.8 Mbp within the 2M and 2D donor regions (Region III–V), some of which interact with hg. Following this logic we expected one or both of these strains would exhibit donor region by HG genotype interactions. Unfortunately, we were unable to characterize HG2D mice. However, as noted above, strong sex-specific effects were seen in HG2M mice. Significant 2M donor region by HG genotype by sex three-way interactions for AI (P = 0.0004; Figure 4) and TF were identified (Table 3). The basis of these interactions was a decrease in HG2M female and an increase in HG2M male adiposity, with no differences in fat accumulation across B62M sexes. Significant 2PM donor region by HG genotype two-way and 2PM donor region by HG genotype by sex three-way interactions were also seen for TF and AI (Table 3). In addition, significant 2P donor region × HG genotype interactions were observed for all traits listed, although some traits did reached significance at the critical P < 0.0071 (Table 3). The basis for each interaction was a decrease in phenotype in HG2P compared to HGC and no difference between B62P and B6C. Together these data confirm that MMU2 QTL modify the effects of the hg deletion.