People have occupied many different habitats since leaving Africa, probably during the past 100,000 years (Trinkaus, 2005). Behavioral buffering and biological adaptability have enabled human occupation of environments spanning large ranges in features such as temperature, UV radiation, and diet. However, only biological adaptability has contributed to our success in occupying high-altitude lands (to ≈5,400 m), because traditional technology could not buffer us from the unavoidable environmental stress of high-altitude hypoxia (less than the normal amount of oxygen in the air because of reduced atmospheric pressure).

Indigenous human populations on the Tibetan and Andean Plateaus are descendents of colonizers who arrived at most ≈25,000 and 11,000 years ago, respectively (Aldenderfer, 2003). Abundant evidence documents the reduced physical function of low-altitude natives visiting high altitudes who engage many homeostatic responses yet do not restore preexposure function (Ward et al., 2000). The two high-altitude populations can be viewed as the current outcome of separate replications of a natural experiment in which an ancestral founding population moved from low to high altitude, and its descendents have been exposed for millennia to the opportunity for natural selection to improve function under high-altitude hypoxia. Both experiments have been successful, as indicated by the rise of great civilizations, long-term persistence, and population growth. However, the experiments have proceeded differently, as indicated by large quantitative differences in physiological traits related to offsetting the stress of high-altitude hypoxia. Evolutionary theory suggests that features of physiology or metabolism that are distinctive as compared with ancestral conditions or other populations represent functional adaptations. The purpose of this paper is to present evidence for Tibetan–Andean contrasts in functional adaptations that offset the stress of hypoxia and to consider the evidence for a genetic basis for these differences between Tibetan and Andean high-altitude natives.

The environmental stress of high altitude is hypoxia that, in turn, creates the conditions for physiological hypoxia (less than the normal amount of oxygen in the organism). The severity of high-altitude hypobaric hypoxia is illustrated in Fig. 13.1 by the regular decrease in the partial pressure of oxygen in the atmosphere with increasing altitude. Studies of adaptation to high-altitude hypoxia usually focus on populations living at