Cis-regulatory evolution shapes dehydration response in a desert-adapted house mouse

Deserts are among the most extreme environments on Earth. High temperatures and a lack of water impose powerful selective pressures on desert species, offering an opportunity to investigate the genetic basis of local adaptation. Despite the unique challenges of desert living, house mice (Mus musculus domesticus), a species native to Western Europe, have recently colonized the Sonoran Desert in North America within the last 400-600 generations. House mice from the Sonoran Desert show phenotypic differences consistent with adaptation to water scarcity, including maintaining weight better under water stress than non-desert mice. To investigate the genetic basis of the physiological responses to water deprivation, we compared gene expression responses of desert house mice and an interfertile non-desert dwelling subspecies (M. m. musculus) and their F1 hybrids after 72 hours without water access. First, we show that desert and non-desert mice exhibit highly divergent transcriptional responses to water deprivation across three tissues (hypothalamus, liver, and kidney). Then, by surveying allele-specific expression in intersubspecific hybrids between desert and non-desert mice, we uncover cis-regulatory differences driving changes in the transcriptional response to dehydration (e.g., cis-by-environment interactions). These cis-regulatory changes were highly tissue-specific, consistent with modular regulatory changes shaping expression divergence. Intriguingly, we find that genes with cis-regulatory differences induced by water access were involved in the arachidonic acid pathway, a primary adaptation pathway across many desert species, and lipid metabolism. Finally, our results highlight several candidate genes of interest for understanding rapid adaptation to desert living. Together, our results identify context-dependent cis-regulatory evolution as a key contributor to variation in dehydration response and a potential mechanism facilitating rapid adaptation to extreme environments.