Volume 117, Issue 5, September 2025, 111079Author links open overlay panel, , , , , , , , Highlights•

26 hypoxia-adaptive genes regulating pulmonary hypertension and HBV infection were identified.

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RCAN1 is a central regulator orchestrating hypoxic stress defense.

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Tibetan hypoxia-adapted genes dually optimize cardiopulmonary function and antiviral immunity.

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Novel molecular mechanisms underlying hypoxia tolerance and immune regulation are revealed.

Abstract

The global dispersal of modern humans has driven genetic adaptations to diverse local environments, including high-altitude hypoxia and tropical rainforests, which represent some of the most extreme conditions. Different local environments exert distinct selective pressures on innate immunity. Here, we conducted a systematic analysis of innate immune gene variations and their evolutionary patterns in high-altitude populations using large-scale genomic data. The result posed that Tibetans harbored 26 Darwinian-positive selection genes, and they may confer protection against pulmonary hypertension by reducing infiltration and inflammatory responses and preventing cardiac hypertrophy. In particularly, we discovered four genes, OAS3, IRAK4, RAB11A, and PLK1 with strong signals of positive selection. These genes are hypothesized to contribute to resistance against hepatitis B infection and the development of tolerance in Tibetans. Overall, the Tibetan population, facing the high-altitude hypoxic environment, has evolved a set of immune genes that combat hypoxia-induced inflammation and the hepatitis B virus infection.

Keywords

Innate immunity

Nature selection

Tibetans

Hepatitis B virus

Hypoxia

Data availabilityThe whole-genome sequencing data used in this study have been deposited to the Genome Sequence Archive under the accession number (PRJCA007843 [11],PRJCA000246 [71] and PRJNA189439 [72]) (https:// bigd. big.ac.cn/gsa- human/ browse/ HRA00 1809).

© 2025 The Authors. Published by Elsevier Inc.