A genetic mechanism for Tibetan high-altitude adaptation

Abstract

Tibetans do not exhibit increased hemoglobin concentration at high altitude. We describe a high-frequency missense mutation in the EGLN1 gene, which encodes prolyl hydroxylase 2 (PHD2), that contributes to this adaptive response. We show that a variant in EGLN1, c.[12C>G; 380G>C], contributes functionally to the Tibetan high-altitude phenotype. PHD2 triggers the degradation of hypoxia-inducible factors (HIFs), which mediate many physiological responses to hypoxia, including erythropoiesis. The PHD2 p.[Asp4Glu; Cys127Ser] variant exhibits a lower Km value for oxygen, suggesting that it promotes increased HIF degradation under hypoxic conditions. Whereas hypoxia stimulates the proliferation of wild-type erythroid progenitors, the proliferation of progenitors with the c.[12C>G; 380G>C] mutation in EGLN1 is significantly impaired under hypoxic culture conditions. We show that the c.[12C>G; 380G>C] mutation originated ~8,000 years ago on the same haplotype previously associated with adaptation to high altitude. The c.[12C>G; 380G>C] mutation abrogates hypoxia-induced and HIF-mediated augmentation of erythropoiesis, which provides a molecular mechanism for the observed protection of Tibetans from polycythemia at high altitude.

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

“…This derived allele, c.12G > C (p.Asp4Glu), is reported in high frequency in Tibetans (0.64-0.85) (22,37) (37,39). In contrast, reads supporting derived alleles at the EPAS1 SNPs were found in two of the three later Samdzong individuals (S35 and S41), but not in the earlier Chokhopani (C1) or Mebrak (M63) individuals.…”

“…Currently, there is broad agreement for selection on the derived EGLN1 alleles beginning ca. 8,000 ya (22,37), but dating the onset of selection for the derived EPAS1 haplotype has proved more controversial. The derived EPAS1 haplotype was recently shown to have originated in the Denisova genome and its presence in the human genome represents a recent archaic introgression (36).…”

“…Encouraged by the genetic profiles of the ACA individuals, we investigated whether the five more deeply sequenced ACA individuals share high-altitude adaptive genetic variants (15)(16)(17) with Tibetan populations (SI Appendix, Table S2). More specifically, we determined whether they have derived alleles at 20 noncoding SNPs that tag the selected haplotype at the EPAS1 gene (36) or at two nonsynonymous SNPs (rs12097901 and rs186996510) with signatures of adaptive allele frequency divergence at the EGLN1 gene (22,37). Currently, there is broad agreement for selection on the derived EGLN1 alleles beginning ca.…”

“…Evolution of such beneficial mutations across time provides crucial information for understanding the strength and cause of natural selection. Contemporary high-altitude East Asians on the Tibetan plateau have at least two such genes, EPAS1 and EGLN1, that exhibit strong signatures of positive natural selection as well as functional properties consistent with an adaptive role in high-altitude environments (15,16,37,39,48). Importantly, we found that the oldest Chokhopani sample (C1) and three later Samdzong individuals (S10, S35, and S41) are most likely homozygous for a derived nonsynonymous allele of the EGLN1 SNP (rs186996510), suggesting that this allele was already common in the founding population.…”

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.…”