Coordinated shifts in gene expression and regulation during mole-rat evolution

Abstract Changes in gene expression and regulation are central to mammalian phenotypic evolution. Yet, distinguishing adaptive gene expression shifts from neutral divergence remains challenging. Here, we integrate comparative transcriptomics and regulatory genomics to investigate how natural selection has shaped gene expression in African mole-rats, a group of subterranean rodents with phenotypic adaptations to underground environments. Using RNA-seq from liver and heart in two mole-rat species (naked mole-rat and Damaraland mole-rat) and two rodent outgroups (mouse and guinea pig), we leveraged phylogenetic models of expression evolution and identified hundreds of genes whose transcriptional levels have experienced accelerated evolution in each tissue and mole-rat species. These lineage-specific shifts account for only a small fraction of gene expression differences identified by classical differential expression analysis between species, underscoring the importance of phylogeny-aware inference to disentangle accelerated evolution from drift. To connect expression divergence with regulatory evolution, we integrated transcriptomic profiles with cis-regulatory landscapes. Genes with lineage-specific expression shifts displayed concordant changes in cis-regulatory activity, particularly at promoters, and the magnitude of expression divergence increased with the number of shifted cis-regulatory elements. Our results demonstrate that adaptive shifts in mole-rat gene expression are mirrored by regulatory evolution, providing genome-wide coordinated evidence of accelerated evolution on expression and regulation during mammalian evolution. Our approach thereby prioritises candidate loci that may have shaped adaptations specific to mole-rat physiology, including metabolic rewiring and stress responses.