Pleiotropic EPAS1 enhancer behind Tibetan high-altitude adaptation is active in fat cells, preprint reports

A preprint posted to bioRxiv describes functional dissection of the EPAS1 locus, which carries some of the strongest signatures of positive selection in Tibetan populations and encodes hypoxia-inducible factor 2-alpha (HIF-2α). Previous work identified ENH5, an enhancer within the Tibetan adaptive haplotype, as showing a blunted transcriptional response to hypoxic stress in Tibetans compared with Han Chinese controls.

The new preprint reports that ENH5 is active not only in tissues directly related to hypoxia response but also in adipocytes (fat cells). The researchers propose that the strong selection at EPAS1 may reflect adaptive pleiotropy — natural selection acting simultaneously on hypoxia tolerance and cold-temperature adaptation, both of which are relevant to the high-altitude Tibetan plateau environment.

The study contributes to understanding of how single regulatory elements can mediate multiple physiological adaptations and offers a mechanistic explanation for the extreme selection coefficients previously estimated at this locus. As a preprint, these findings have not yet been peer-reviewed.