Adaptation to High Altitude: Phenotypes and Genotypes

Populations residing for millennia on the high-altitude plateaus of the world started natural experiments that we can evaluate to address questions about the processes of evolution and adaptation. A 2001 assessment in this journal summarized abundant evidence that Tibetan and Andean high-altitude natives had different phenotypes, and the article made a case for the hypothesis that different genetic bases underlie traits in the two populations. Since then, knowledge of the prehistory of high-altitude populations has grown, information about East African highlanders has become available, genomic science has grown exponentially, and the genetic and molecular bases of oxygen homeostasis have been clarified. Those scientific advances have transformed the study of high-altitude populations. The present review aims to summarize recent advances in understanding with an emphasis on the genetic bases of adaptive phenotypes, particularly hemoglobin concentration among Tibetan highlanders. EGLN1 and EPAS1 encode two crucial proteins contributing to oxygen homeostasis, the oxygen sensor PHD2 and the transcription factor subunit HIF-2α, respectively; they show signals of natural selection such as marked allele frequency differentiation between Tibetans and lowland populations. EPAS1 genotypes associated in several studies with the dampened hemoglobin phenotype that is characteristic of Tibetans at high altitude but did not associate with the dampened response among Amhara from Ethiopia or the vigorous elevation of hemoglobin concentration among Andean highlanders. Future work will likely develop understanding of the integrative biology leading from genotype to phenotype to population in all highland areas.