Arising selective sweeps in Andean high altitude populations

The high-altitude atmosphere is significantly depleted in oxygen. Andean populations have lived in this environment for hundreds of generations, evolving physiological adaptations to contend with the effects of hypobaric hypoxia. So far, only a few genes have been proposed as candidates for these adaptations and clear functional variants are yet to be identified. Here we report the results of a search of single nucleotide substitutions that may have been targets of positive selection. Whole genome sequences from 19 Colla highlanders from the Argentinean Andes (>3500 m) were compared with 16 genome sequences of Native American lowlanders. By combining a statistic searching for high-frequency extended haplotypes, the test for number of segregating sites by length (nSL) and the population branch statistic (PBS), we developed an approach to detect incomplete/early stage selective sweeps. Focussing on likely damaging missense variants, we identified two SNPs at rising intermediate frequencies likely to have been important in Andean adaptation to high altitude. The first variant, located within the GPR126 gene, has previously been suggested to be associated with forced expiratory volume/forced vital capacity ratio. Phenotypic data from the 19 Collas who were sequenced in this study confirmed this association with lung function. The location of the second novel missense variant was within EPAS1, which is known to be the major selection candidate gene in Tibetans. This work provides evidence for convergent evolution, in Andean and Tibetan highland populations, towards genotypes promoting high altitude human survival.