Residents of the Tibetan Plateau show heritable adaptations to extreme altitude. We sequenced 50 exomes of ethnic Tibetans, encompassing coding sequences of 92% of human genes, with an average coverage of 18X per individual. Genes showing population-specific allele frequency changes, which represent strong candidates for altitude adaptation, were identified. The strongest signal of natural selection came from EPAS1, a transcription factor involved in response to hypoxia. One SNP at EPAS1 shows a 78% frequency difference between Tibetan and Han samples, representing the fastest allele frequency change observed at any human gene to date. This SNP’s association with erythrocyte abundance supports the role of EPAS1 in adaptation to hypoxia. Thus, a population genomic survey has revealed a functionally important locus in genetic adaptation to high altitude.

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P. Gong et al. land-cover classification system as well as the International Geosphere-Biosphere Programme (IGBP) system. Using the four classification algorithms, we obtained the initial set of global land-cover maps. The SVM produced the highest overall classification accuracy (OCA) of 64.9% assessed with our test samples, with RF (59.8%), J4.8 (57.9%), and MLC (53.9%) ranked from the second to the fourth. We also estimated the OCAs using a subset of our test samples (8629) each of which represented a homogeneous area greater than 500 m × 500 m. Using this subset, we found the OCA for the SVM to be 71.5%. As a consistent source for estimating the coverage of global land-cover types in the world, estimation from the test samples shows that only 6.90% of the world is planted for agricultural production. The total area of cropland is 11.51% if unplanted croplands are included. The forests, grasslands, and shrublands cover 28.35%, 13.37%, and 11.49% of the world, respectively. The impervious surface covers only 0.66% of the world. Inland waterbodies, barren lands, and snow and ice cover 3.56%, 16.51%, and 12.81% of the world, respectively.

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 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 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.chronic mountain sickness | high altitude | human genome variation | hypoxia | hypoxia-inducible factor