Humans and other mammals inhabit hypoxic high-altitude locales. In many of these species, genes under positive selection include ones in the Hypoxia Inducible Factor (HIF) pathway. One is PHD2 (EGLN1), which encodes for a key oxygen sensor. Another is HIF2A (EPAS1), which encodes for a PHD2-regulated transcription factor. Recent studies have provided insights into mechanisms for these high-altitude alleles. These studies have (i) shown that selection can occur on nonconserved, unstructured regions of proteins, (ii) revealed that high altitude-associated amino acid substitutions can have differential effects on protein–protein interactions, (iii) provided evidence for convergent evolution by different molecular mechanisms, and (iv) suggested that mutations in different genes can complement one another to produce a set of adaptive phenotypes.

人类和其他哺乳动物居住在缺氧的高海拔地区。在许多此类物种中，正向选择的基因包括缺氧诱导因子 (HIF) 途径中的基因。其中之一是PHD2 ( EGLN1 )，它为关键的氧传感器进行编码。另一个是HIF2A ( EPAS1 )，它编码 PHD2 调节的转录因子。最近的研究为这些高海拔等位基因的机制提供了见解。这些研究（i）表明选择可以发生在蛋白质的非保守、非结构化区域，（ii）揭示与高海拔相关的氨基酸取代可能对蛋白质-蛋白质相互作用产生不同的影响，（iii）为趋同进化提供了证据不同的分子机制，以及（iv）表明不同基因的突变可以相互补充以产生一组适应性表型。