RT Journal Article SR Electronic T1 Predominance of cis-regulatory changes in parallel expression divergence of sticklebacks JF bioRxiv FD Cold Spring Harbor Laboratory SP 412932 DO 10.1101/412932 A1 Jukka-Pekka Verta A1 Felicity C. Jones YR 2018 UL http://biorxiv.org/content/early/2018/09/10/412932.abstract AB Regulation of gene expression is thought to play a major role in adaptation but there are conflicting predictions for the relative importance of cis- and trans-regulatory mechanisms in the early stages adaptive divergence. Parallel evolution of marine and freshwater threespine stickleback fish provides an excellent opportunity to dissect whether the same molecular mechanisms underlie repeated adaptive divergence in gene expression. Using RNA-seq of four marine-freshwater ecotype pairs from Scotland and Canada, we first identified genes with parallel divergence in expression and show that these are found near previously reported adaptive loci and show a molecular signature of selection centered around the transcription start site. With allele-specific expression assays in F1 hybrids we next show that expression divergence is predominantly driven by cis-regulatory control in all four river systems, a pattern that is enriched in parallel divergently expressed genes. In particular, for genes whose expression is up-regulated in parallel among freshwater fish the quantitative degree of cis- and trans-regulation is also highly correlated, suggesting a shared genetic basis across populations. This stands in contrast to genes up-regulated in parallel in marine fish, whose degree of cis- and trans-regulation is less correlated and predictable. This observed asymmetry in parallelism in how genes are up-regulated in marine and freshwater fish can be explained by differences in the evolutionary contexts of the diverging ecotypes. Finally, we show that cis-regulation is predominantly additive and shows greater robustness to different in genetic backgrounds and environmental conditions. We argue that these features make cis- regulation well-poised for rapid adaptive divergence of gene expression under conditions of on-going gene flow. Combined our study highlights how natural selection on dispersed cis-regulatory elements can shape the adaptive landscape of the genome.Summary Adaptive evolution of gene expression may proceed via mutations influencing cis- regulatory elements such as promoters or enhancers or trans-acting factors such as transcription factors. There are conflicting predictions for the relative roles of cis- and trans-regulation in the early stages adaptive divergence-with-gene-flow. Populations that have evolved in parallel provide a powerful opportunity to look for general patterns and rules governing the evolution of gene expression. Here we show that parallel expression divergence in threespine stickleback fish is primarily driven by differences in cis-acting (allele-specific) gene regulation such as mutations in enhancers and promoters. We show that cis-regulation is predominantly additive and stable across genetic backgrounds and water salinities enabling cis-regulatory mutations to act as a motor for the evolution of traits in the early stages of divergence-with-gene-flow.