Fig. 4

Examples of genes (in red) within the HIF pathway in which positive selection has been identified in high-altitude populations. Activation of the HIF response involves prolyl hydroxylases (PHD), which, in the presence of oxygen, hydroxylates HIFα thus targeting it for destruction by the ubiquitin–proteasome pathway. Under hypoxic conditions, HIFα persists to combine with the constitutively present HIFβ, and this dimer acts as a transcription factor, influencing the expression of over 100 genes, which possess hypoxia response elements in their promoter regions, and play a role in the cellular and systemic response to hypoxia. The HIF response involves increasing oxygen delivery to hypoxic tissues (through effects on angiogenesis, vascular tone, and erythropoiesis) as well as modifying cell metabolism, proliferation, and survival pathways. High-altitude positive selection has been demonstrated in all parts of this pathway, but none of the alleles affected have been demonstrated in more than one population. Data summarized from [31]. HIF hypoxia-inducible factor, HRE hypoxia response elements, PHD prolyl hydroxylase