Gene-by-environment Interactions and Adaptive Body Size Variation in Mice From the Americas

The relationship between genotype and phenotype is often mediated by the environment. Moreover, gene-by-environment (GxE) interactions can contribute to variation in phenotypes and fitness. In the last 500 yr, house mice have invaded the Americas. Despite their short residence time, there is evidence of rapid climate adaptation, including shifts in body size and aspects of metabolism with latitude. Previous selection scans have identified candidate genes for metabolic adaptation. However, environmental variation in diet as well as GxE interactions likely impact body mass variation in wild populations. Here, we investigated the role of the environment and GxE interactions in shaping adaptive phenotypic variation. Using new locally adapted inbred strains from North and South America, we evaluated response to a high-fat diet, finding that sex, strain, diet, and the interaction between strain and diet contributed significantly to variation in body size. We also found that the transcriptional response to diet is largely strain-specific, indicating that GxE interactions affecting gene expression are pervasive. Next, we used crosses between strains from contrasting climates to characterize gene expression regulatory divergence on a standard diet and on a high-fat diet. We found that gene regulatory divergence is often condition-specific, particularly for trans-acting changes. Finally, we found evidence for lineage-specific selection on cis-regulatory variation involved in diverse processes, including lipid metabolism. Overlap with scans for selection identified candidate genes for environmental adaptation with diet-specific effects. Together, our results underscore the importance of environmental variation and GxE interactions in shaping adaptive variation in complex traits.