Exciting Times in the Study of Permanent Residents of High Altitude

These are heady times for scientists interested in the evolution of people who have successfully adapted to permanent residence at high altitude (“Highlanders”). The principal populations are those of Tibet, the South American Andes, and smaller groups in East Africa. In the Guest Editorial in last month's issue of this Journal (Volume 11, Number 4), Jim Rupert discussed the three landmark papers that were published in the summer of 2010 on genetic differences between Tibetans and Han Chinese (Beall et al., 2010; Simonson et al., 2010; Yi et al., 2010). These three studies, done essentially independently, took different but complementary approaches to identifying the genetic differences between Tibetans and ethnically different lowlanders in neighboring China. One of the most striking findings was differences in the frequency of the gene EPAS1, which codes for HIF-2α, a transcriptional regulator that plays a role in a host of responses to hypoxia including erythropoiesis, angiogenesis, carotid body function, anaerobic metabolism, and energy utilization. In one study, the frequency of one variant of the EPAS1 gene differed between Tibetans and Han Chinese by 78% (87% vs. 9%).

One of the reasons why this is so interesting is the difference in the reduced erythropoietic response in Tibetans compared with Han Chinese. This difference is consistent with the much lower incidence of chronic mountain sickness in the former compared with the latter. Whether this obvious phenotypical response is the tip of the iceberg and many other more important responses to hypoxia are as yet unrecognized remains to be clarified. Many investigators are placing their bets on this possibility.

One of the most provocative, though controversial, assertions is that the two populations diverged in less than 3,000 years. If true, this is probably the most rapid example of Darwinian evolution that has ever been observed in humans. The only other contender for this honor is the selection for lactose tolerance seen, for example, in northern Europeans that benefited populations who kept cattle. This intriguing finding thrusts high altitude studies into the center of human evolutionary biology. This is indeed a turnaround for high altitude research which is sometimes seen by some people as a niche area of marginal interest. Incidentally such people tend to overlook the fact that many millions of people live permanently at high altitude, and in addition an increasing number of lowlanders are now called upon to work at high altitude.

Another fascinating issue having to do with permanent residents at high altitude is the striking phenotypical differences between two different populations. Beall (2000) has pointed out that Tibetans compared with Aymara in the South American Andes have a higher resting ventilation, greater hypoxic ventilatory response, higher resting arterial oxygen saturations, lower hemoglobin concentrations, and a smaller degree of hypoxic pulmonary vasoconstriction. How is it that two populations that have both very successfully adapted to the severe hypoxia of high altitude over many generations have reached such different solutions? It should be noted here that there is a problem in studying high altitude residents of the Andes because there is considerable admixture with European genes. Nevertheless there is strong evidence for these differences and the reasons why evolution took these different courses represents a fascinating area of study.

All of this reminds us that high altitude medicine and biology is alive and well, and that we can expect further eye-popping developments in the future. The next issue of the Journal (Volume 12, Number 2) will have a Special Topic section devoted to some of the related issues prompted by the new findings. We are fortunate indeed to be in this stimulating discipline.