chronic mountain sickness, high altitude, human genome variation, hypoxia, hypoxia-inducible factor
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 employed 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 (3200-3500m) 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 4200m, 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 gm/dl lower in the major allele homozygotes compared with the heterozygotes. These findings were replicated in a third cohort of Tibetans residing at 4300m. 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.
Biochemistry, Biophysics, and Structural Biology | Genetics and Genomics | Pharmacology
Beall CM, Cavalleri GL , Deng L, Elstond RC, Gao Y, Knight J, Lic C, Li JC, Liangh Y, McCormack M, Montgomery HE, Panc H, Robbins PA, Shiannak KV, Tam SC, Tsering N, Veeramah K, Wangh W, Wangdui P, Weale ME, Xuo Y, Xu Z, Yang L, Zaman MJ, Zeng C, Zhang L, Zhang X, Zhaxi P, Zheng YT. Natural selection on EPAS1 (HIF2α) associated with low hemoglobin concentration in Tibetan highlanders. Proceedings of the National Academy of Sciences of the United States of America Early Edition June 7 2010