Natural selection on EPAS1 ( HIF2α ) associated with low hemoglobin concentration in Tibetan highlanders

Abstract

By impairing both function and survival, the severe reduction in oxygen availability associated with high-altitude environments is likely to act as an agent of natural selection. We used genomic and candidate gene approaches to search for evidence of such genetic selection. First, a genome-wide allelic differentiation scan (GWADS) comparing indigenous highlanders of the Tibetan Plateau (3,200-3,500 m) with closely related lowland Han revealed a genome-wide significant divergence across eight SNPs located near EPAS1. This gene encodes the transcription factor HIF2α, which stimulates production of red blood cells and thus increases the concentration of hemoglobin in blood. Second, in a separate cohort of Tibetans residing at 4,200 m, we identified 31 EPAS1 SNPs in high linkage disequilibrium that correlated significantly with hemoglobin concentration. The sex-adjusted hemoglobin concentration was, on average, 0.8 g/dL lower in the major allele homozygotes compared with the heterozygotes. These findings were replicated in a third cohort of Tibetans residing at 4,300 m. The alleles associating with lower hemoglobin concentrations were correlated with the signal from the GWADS study and were observed at greatly elevated frequencies in the Tibetan cohorts compared with the Han. High hemoglobin concentrations are a cardinal feature of chronic mountain sickness offering one plausible mechanism for selection. Alternatively, as EPAS1 is pleiotropic in its effects, selection may have operated on some other aspect of the phenotype. Whichever of these explanations is correct, the evidence for genetic selection at the EPAS1 locus from the GWADS study is supported by the replicated studies associating function with the allelic variants.chronic mountain sickness | high altitude | human genome variation | hypoxia | hypoxia-inducible factor

Pulmonary Vascular and Ventricular Dysfunction in the Susceptible Patient (2015 Grover Conference Series)

“…Separate genomic studies detailed variants in Tibetan highlanders in the genes EPAS1 (encoding HIF-2α) and EGLN1 (one of the prolyl hydroxylases that regulate HIF1α/2α). [100][101][102][103][104] Furthermore, a genetic mutation resulting in HIF-2α overexpression was associated with development of PH. 105 Andeans have lived at high altitude for approximately 11,000 years.…”

Serum testosterone levels and excessive erythrocytosis during the process of adaptation to high altitudes

“…However, there can be various responses to the same hypoxic stimulus. [17][18][19] In the Peruvian Andes, a great range of values of pulse oxygen saturation has been described in people living at the same altitude. [20][21][22][23] Differences in hormone levels may explain some of these varying responses to hypoxic stimuli, 11,15,21 according to several studies.…”

Long-term genetic stability and a high-altitude East Asian origin for the peoples of the high valleys of the Himalayan arc

“…Tibetans and Sherpa are the only two present-day high-altitude East Asian ethnic groups that have been studied to date, using genome-wide markers. Although the Tibetan plateau has been the subject of intense study regarding its population history and high-altitude adaptation (15,(20)(21)(22), far less is known about the much later colonization of the surrounding high transverse valleys along the Himalayan arc. Elucidating this history is important because these valleys have long served as natural corridors and trade routes connecting the Tibetan plateau to the Indian subcontinent.…”

“…Successful permanent habitation of high-altitude environments requires numerous physiological adaptations, and recent genetic studies have identified robust signals of positive natural selection underlying adaptations to hypoxia in Tibetans (15)(16)(17) and in the Sherpa (18), an ethnic group that migrated from the eastern Tibetan plateau to Nepal 400-600 y ago (ya) (19). Tibetans and Sherpa are the only two present-day high-altitude East Asian ethnic groups that have been studied to date, using genome-wide markers.…”