Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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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 -