Environmentally robust cis-regulatory changes underlie rapid climatic adaptation

Changes in gene expression have been proposed to play a major role in adaptive evolution. However, gene expression is highly context-dependent and very few studies have determined the influence of genetic and non-genetic effects on adaptive gene regulation in natural populations. Here, we utilize context-dependent allele-specific expression to characterize cis and trans changes underlying divergence in temperate and tropical house mice in two metabolic tissues under two thermal conditions. First, we show that gene expression divergence is pervasive between populations and across thermal conditions, with roughly 5-10% of genes exhibiting genotype-by-environment interactions. Second, we found that most intraspecific regulatory divergence was due to cis -regulatory changes that were stable across temperatures. In contrast, patterns of expression plasticity were largely attributable to trans -effects, which showed greater sensitivity to temperature. Nonetheless, we discovered a small subset of temperature-dependent cis -regulatory changes, thereby identifying loci underlying expression plasticity. Finally, we performed scans for selection in wild house mice to identify genomic signatures of rapid adaptation. Genomic outliers were enriched in genes with evidence for cis -regulatory divergence. Strikingly, these genes were associated with phenotypes that affected body weight and metabolism, identifying cis -regulatory changes as a mechanism for adaptive body size evolution between populations. Together, these results support the central role of cis -regulatory divergence in adaptive evolution over extremely short timescales. Significance Statement Little is known about the relative contributions of genetic versus environmental factors to gene expression variation in natural populations. Here, we discovered that genetic effects were far more pervasive than environmental effects on gene expression differences between house mice that have rapidly adapted to new environments. Notably, many of these genetic effects are under selection and underlie adaptive body size differences between populations. However, we also identified a few genes controlling plastic expression across different environments. Our study is one of the few to identify loci associated with plasticity in natural populations and supports the central role of genetic effects in the form of cis -regulatory divergence in adaptive evolution over extremely short timescales (a few hundred generations). ### Competing Interest Statement The authors have declared no competing interest.