Adaptive genetic changes related to haemoglobin concentration in native high-altitude Tibetans

Some native Tibetan, Andean and Ethiopian populations have lived at altitudes ranging from 3000 to >4000 m above sea level for hundreds of generations and exhibit distinct combinations of traits at altitude. It was long hypothesized that genetic factors contribute to adaptive differences in these populations, and recent advances in genomics provide evidence that some of the strongest signatures of positive selection in humans are those identified in Tibetans. Many of the top adaptive genomic regions highlighted thus far harbour genes related to hypoxia sensing and response. Putatively adaptive copies of three hypoxia-inducible factor pathway genes, EPAS1, EGLN1 and PPARA, are associated with sea-level range, rather than elevated, haemoglobin concentration observed in many Tibetans at high altitude, and recent studies provide insight into some of the precise adaptive variants, timing of adaptive events and functional roles. While several studies in highland Tibetans have converged on a few hypoxia-inducible factor pathway genes, additional candidates have been reported in independent studies of Tibetans located throughout the Qinghai-Tibetan Plateau. Various aspects of adaptive significance have yet to be identified, integrated, and fully explored. Given the rapid technological advances and interdisciplinary efforts in genomics, physiology and molecular biology, careful examination of Tibetans and comparisons with other distinctively adapted highland populations will provide valuable insight into evolutionary processes and models for both basic and clinical research.