Human genetic adaptation to high altitudes: Current status and future prospects

The question of whether human populations have adapted genetically to high altitude has been of interest since studies began there in the early 1900s. Initially there was debate as to whether genetic adaptation to high altitude has taken place based, in part, on disciplinary orientation and the sources of evidence being considered. Studies centered on short-term responses, termed acclimatization, and the developmental changes occurring across lifetimes. A paradigm shift occurred with the advent of single nucleotide polymorphism (SNP) technologies and statistical methods for detecting evidence of natural selection, resulting in an exponential rise in the number of publications reporting genetic adaptation. Reviewed here are the various kinds of evidence by which adaptation to high altitude has been assessed and which have led to widespread acceptance of the idea that genetic adaptation to high altitude has occurred. While methodological and other challenges remain for determining the specific gene or genes involved and the physiological mechanisms by which they are exerting their effects, considerable progress has been realized as shown by recent studies in Tibetans, Andeans and Ethiopians. Further advances are anticipated with the advent of new statistical methods, whole-genome sequencing and other molecular techniques for finer-scale genetic mapping, and greater intradisciplinary and interdisciplinary collaboration to identify the functional consequences of the genes or gene regions implicated and the time scales involved.