Variants of Epas1 contribute to hypoxia adaptation in the subterranean rodents Eospalax and Spalax.

Oxygen-sensing and the hypoxia stress response play vital roles in physiological homeostasis. Subterranean species that are naturally adapted to hypoxia provide powerful tools for understanding the mechanisms of hypoxia tolerance. The plateau zokor Eospalax baileyi and the Gansu zokor Eospalax cansus, which inhabit the Qinghai-Tibet Plateau of China, and the blind mole rat Spalax galili, which lives in Israel, are all subterranean rodents adapted to hypoxic environments. Here, we showed that the T480S variant of the hypoxia-inducible factor-2ɑ (encoded by the endothelial PAS domain protein 1 gene, Epas1) in Chinese zokors stabilized EPAS1 by reducing phosphorylation, thereby regulating fibrosis and contributing to hypoxia adaptation on the Qinghai-Tibet Plateau. In Israeli blind mole rats, variants at positions -2023/-1810 in the Epas1 regulatory region distinguish two abutting populations undergoing incipient sympatric speciation by altering the binding of cMYB and hepatocyte nuclear factor 4 gamma, linking transcriptional activity to the interferon mRNA transcription. This finding reveals an adaptive regulation of metabolism and O2 homeostasis by the Epas1 gene in adaptation to diverse habitats, providing evidence for both divergent and convergent functional molecular evolution.