Three Evolutionary Routes to the Roof of the World: The Andes, Tibet, and Ethiopia

High-altitude native populations, exposed to the lifelong stress of low barometric pressure and partial pressure of inspired oxygen, represent natural experiments in evolution and adaptation.  Fieldwork on the major high-altitude plateaus discovered that Andean, Tibetan, and Ethiopian Amhara highlanders differ from their lowland counterparts in ways that appear to offset the unavoidable stress of hypoxia.  Unexpectedly, the three highland populations also differ among themselves.  For example, Andean highlanders have persistently elevated hemoglobin concentration levels, while Tibetan and Ethiopian Amhara do not.   The Tibetan trait of relatively low-hemoglobin concentration associates, in multiple studies, with single nucleotide polymorphism sites in an oxygen sensor (EGLN1) and an oxygen homeostasis transcription factor (EPAS1) gene.  In contrast, the Ethiopian Amhara trait of relatively low-hemoglobin concentration associates, in one study, with one SNP.  The genetic basis of the Andean response of elevated hemoglobin concentration is unknown, although the trait reverses when Andean highlanders migrate to low altitudes, suggesting that for some reason this population has acclimatized while the other two have undergone natural selection.   Discovering the explanation for the three different microevolutionary patterns offers insight into ongoing evolutionary processes.  Identification of relevant genes paradoxically leads to considering other environmental factors that may influence their expression in these three populations.  The different phenotypes and involved pathways have implications for vulnerability to disease and have the potential to point the way to new therapies for hypoxic patients at all altitudes.