Identification of HMOX2 promoter variants linked to adaptation in Tibetans

Populations living at high altitude have been subjected to the selective pressure of hypoxia due to low atmospheric pressure for hundreds of generations. Adaptive genetic signals are apparent in the genomes of present-day populations, but the links to physiological changes and underlying mechanisms are not completely understood. Our recent physiological studies revealed that Tibetans residing at intermediate altitude (2200 m; 13,780 ft) have lower hemoglobin concentration ([Hb]) and elevated carbon monoxide (CO) relative to other populations resident at the same altitude. Our previous genetic studies revealed that Tibetans residing at 4200 m (13,780 ft) exhibit a haplotype (20 kilobases) encompassing the Heme Oxygenase 2 (HMOX2) gene region. Heme oxygenase 2 protein produces carbon monoxide (CO) as a byproduct of hemoglobin breakdown. We hypothesize that HMOX2 underlies the observed CO levels at high altitude. We further hypothesize that regulatory variants could be linked to elevated heme oxygenase activity and, therefore, elevated CO levels in people of Tibetan ancestry.We measured carboxyhemoglobin (COHb) in Tibetan (n = 10) and Han Chinese (n = 8) male residents of Xining (2,200 m; 7,218 ft), China, using a co-oximeter and Tibetan (13 women, 8 men) and Han Chinese (6 women, 10 men) residents of Salt Lake City, Utah (1,413 m/4,637 ft) with a finger pulse oximeter. In the Xining cohort, COHb levels were 97% higher in Tibetans (1.01 ± 0.59 %) compared to their Han Chinese counterparts (0.51 ± 0.39 %, p < 0.048). This result was replicated in Salt Lake City, where Tibetans exhibited significantly higher COHb (4.31 ± 0.48%) compared to Han Chinese (2.00 ± 0.6%, p = 0.004).We also examined localized signals of natural selection (Composite of Multiple Signals test, CMS) from 27 previously published Tibetan genomes and identified single nucleotide variants (SNVs) within the selected haplotype with potential functional impacts on heme-oxygenase expression. Eleven variants were located within the promoter region of the HMOX2 gene. These variants exhibit significant delta allele frequencies (DAF) between Tibetans and Han Chinese (DAF > 0.2, p < 0.005) and are in high linkage disequilibrium (R2 > 0.9) in both populations. Literature and in-silico prediction tools (CIS-BP, JASPAR) indicate some of these variants have a potential gain-of-function roles as transcription factor binding sites.These results suggest adaptive, regulatory variants in HMOX2 may contribute to the observed increased endogenous CO in highland Tibetans, conferring protection from the selective stresses of high-altitude hypoxia. This project is funded by NIH R01HL145470. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.