TY - JOUR

T1 - Natural selection on EPAS1 (HIF2alpha) associated with low hemoglobin concentration in Tibetan highlanders

AU - Beall, Cynthia M.

AU - Cavalleri, Gianpiero L.

AU - Deng, Libin

AU - Elston, Robert C.

AU - Gao, Yang

AU - Knight, Jo

AU - Li, Chaohua

AU - Li, Jiang Chuan

AU - Liang, Yu

AU - McCormack, Mark

AU - Montgomery, Hugh E.

AU - Pan, Hao

AU - Robbins, Peter A.

AU - Shianna, Kevin V.

AU - Tam, Siu Cheung

AU - Tsering, Ngodrop

AU - Veeramah, Krishna R.

AU - Wang, Wei

AU - Wangdui, Puchung

AU - Weale, Michael E.

AU - Xu, Yaomin

AU - Xu, Zhe

AU - Yang, Ling

AU - Zaman, M. Justin

AU - Zeng, Changqing

AU - Zhang, Li

AU - Zhang, Xianglong

AU - Zhaxi, Pingcuo

AU - Zheng, Yong Tang

PY - 2010/6/22

Y1 - 2010/6/22

N2 - 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 HIF2alpha, 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.

AB - 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 HIF2alpha, 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.

KW - Alleles

KW - Altitude

KW - Altitude Sickness

KW - Anoxia

KW - Basic Helix-Loop-Helix Transcription Factors

KW - Genetic Variation

KW - Genome, Human

KW - Hemoglobins

KW - Homozygote

KW - Humans

KW - Linkage Disequilibrium

KW - Polymorphism, Single Nucleotide

KW - Selection, Genetic

KW - Tibet

U2 - 10.1073/pnas.1002443107

DO - 10.1073/pnas.1002443107

M3 - Journal article

C2 - 20534544

VL - 107

SP - 11459

EP - 11464

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 25

ER -