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, in turn, fitness. Nevertheless, understanding the impact of GxE interactions in wild systems remains challenging. In the last 500 years, 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 studies in this system have identified candidate genes for metabolic adaptation using selection scans, however, environmental variation in diet as well as GxE interactions affecting metabolism are likely important factors in shaping body mass variation in wild populations. Here, we investigate the role of the environment and GxE interactions in shaping adaptive phenotypic variation with an experimental manipulation of diet. 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 contribute significantly to variation in aspects of body size. We also found that 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 (New York x Brazil and New York x Florida) to characterize gene expression regulatory divergence on a standard breeder diet and on a high-fat diet. We found that gene regulatory divergence is often condition-specific, particularly for trans -acting changes. Finally, we find 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 to adaptive variation in complex traits.