ArticleProceedings of the National Academy of Sciences of the United States of America2010
Natural selection on EPAS1 (HIF2alpha) associated with low hemoglobin concentration in Tibetan highlanders.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 446 papers.
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446 citing papers in PubMed, 829 citations in OpenAlex.
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- A second-generation "hypoxia in a pill" rescues neurodegenerative phenotypes across distinct mouse models.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Identifying adaptive variation in spatially structured populations using low-coverage whole-genome sequencing data.Molecular biology and evolution · 2026Article
- Hepatic HIF2α Modulates Extra-Hepatic Disease-Associated Phenotypes During Metabolic Dysfunction-Associated Steatotic Liver Disease.Comprehensive physiology · 2026Article
- Understanding physiological adaptations of pregnancy to the chronic hypoxia of high altitude to inform obstetrical and neonatal care.Physiological reviews · 2026Review
- Genomic insights into natural selection in recent human history.Nature reviews. Genetics · 2026Review
- Variants ofLife science alliance · 2026Article
- Multi-Organ Comparative Transcriptomic Study on Short-Term and Long-Term Hypoxia Adaptation in Cattle.Biology · 2026Article
- Hypoxia-inducible factor-1a (HIF1a) as a context-dependent integrator of metabolic stress in skeletal muscle.The Journal of physiology · 2026Review
- Synergistic Effects of Diabetes, Inflammatory/Coagulopathy Biomarkers, TG and Hypoxic Stress on Premature Coronary Heart Disease in High-Altitude Populations.Journal of cardiovascular development and disease · 2026Article
- Genomic Evidence for Natural Selection Underlying High-Altitude Adaptive Hemoglobin Levels Among Peruvian Andeans.Genome biology and evolution · 2026Article
- Adaptation across an extreme elevational gradient in Andean leaf-eared mice, the world's highest-dwelling mammal.Science (New York, N.Y.) · 2026Article
- EssTFNet: integration of adaptive time-frequency and DNA language models for interpretable human essential gene prediction.Briefings in bioinformatics · 2026Article
- Molecular mechanisms of EPAS1 in regulating pulmonary vascular remodeling in COPD: a review.Molecular biology reports · 2026Review
- Hypoxic Preconditioning: An Underestimated Endogenous Protective Strategy?Biomolecules · 2026Review
- Is altitude-induced polycythaemia an unintended evolutionary mistake?Experimental physiology · 2026Article
- Large-Scale Genomics Reveals Three-Source Ancestry and Layered Adaptation to High Altitude in Tibetan Chickens.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Highland environment and genetic background are associated with myopia risk in Tibetans and Hans.Eye (London, England) · 2026Article
- A Perturb-seq screen guided by species divergence uncovers pathways for collateral artery formation.bioRxiv : the preprint server for biology · 2026Article
- Alternative splicing and polyadenylation facilitate transcriptome diversity underlying high-altitude adaptation in pigs.Communications biology · 2026Article
386 more citing papers are in PubMed but not listed here.
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29 authors at 16 institutions in 5 countries.
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No grant is acknowledged in the PubMed record.
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 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.
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