Lessons in hypoxic adaptation from high-altitude populations.

An increase in hemoglobin level is seen in virtually all lowlanders who move to or train at altitude; however, studies of high-altitude native populations illustrate that this response is not necessary for successful long-term residence. Indigenous populations living at the same altitude have differences not only in hemoglobin level but also in other traits like oxygen saturation. Support for a genetic causation for differences in features of oxygen transport, namely hemoglobin levels and oxygen saturation, is derived from kindred studies among the highlander populations. Indeed, evidence from Tibet suggests that inferred genes for high oxygen saturation are associated with higher offspring survival. It may be that signaling molecules like nitric oxide and transcription factors such as hypoxia-inducible factor could act as an upstream regulator for highlander traits. However, the preponderance of data suggests that it is unlikely that one process or even a common set of processes is responsible for successful biologic adaptation shown in all three resident high-altitude populations. Future studies will require the ability to identify combinations of genetic variants with outcomes including expression levels, appropriate phenotypes, and functional responses.