Tissue-specific and cis-regulatory changes underlie parallel, adaptive gene expression evolution in house mice

Abstract

Changes in gene regulation have long been appreciated as a driving force of adaptive evolution, however the relative contributions of cis- and trans-acting changes to gene regulation over short evolutionary timescales remain unclear. Instances of recent, parallel phenotypic evolution provide an opportunity to assess whether parallel patterns are seen at the level of gene expression, and to assess the relative contribution of cis- and trans-changes to gene regulation in the early stages of divergence. Here, we studied gene expression in liver and brown adipose tissue in two wild-derived strains of house mice that independently adapted to cold, northern environments, and we compared them to a strain of house mice from a warm, southern environment. To investigate gene regulatory evolution, we studied expression in parents and allele-specific expression in F1 hybrids of crosses between warm-adapted and cold-adapted strains. First, we found that the different cold-adapted mice showed both unique and shared changes in expression, but that the proportion of shared changes (i.e. parallelism) was greater than expected by chance. Second, we discovered that expression evolution occurred largely at tissue-specific and cis-regulated genes, and that these genes were over-represented in parallel cases of evolution. Finally, we integrated the expression data with scans for selection in natural populations and found substantial parallelism in the two northern populations for genes under selection. Furthermore, selection outliers were associated with cis-regulated genes more than expected by chance; cis-regulated genes under selection influenced phenotypes such as body size, fat content, immune functioning, and skeletal morphology. These results demonstrate that parallel patterns of gene expression in mice that have independently adapted to cold environments are driven largely by tissue-specific and cis-regulatory changes, providing insight into the mechanisms of adaptive gene regulatory evolution at the earliest stages of divergence. Author summaryThe parallel movement of organisms into novel environments provides an opportunity to understand the molecular basis of adaptation and the repeatability of this process. Mutations affecting the expression of genes are known to underlie much of adaptive evolution. Such mutations can arise in cis-(near the gene of interest) or in trans-(at a distant locus), but the relative contribution of these different kinds of changes to adaptation is poorly understood, especially during very recent divergence. Here, we compared evolved gene expression differences between a warm-adapted house mouse strain and two different cold-adapted strains that have independently evolved similar phenotypic traits, such as increased body size and decreased extremity length during the last few hundred years. Using crosses between warm-adapted and cold-adapted mice, we found that mutations acting in a context specific manner (cis-regulatory and tissue-specific changes) predominate expression divergence and are more likely to be involved in parallel evolution. We used population level selection scans in wild animals to identify regions of the genome under selection and combined these findings with the gene expression data to identify candidate genes underlying adaptation to novel environments. Together, our work describes the gene regulatory dynamics of rapid environmental adaptation, and the repeatability of these patterns over multiple instances of adaptation.