Hypoxia-inducible factor pathway evolution. The core components of the HIF pathway were established in the metazoan common ancestor, and the pathway has been subject to further refinements and elaborations in each of the descendant lineages. HIFα homologues are only present in metazoans, whereas PHD homologues are also found in other eukaryotes. FIH homologues are not as widespread in metazoans as PHD enzymes. Two rounds of whole-genome duplication in the stem lineage of vertebrates could be responsible for the many HIFα and PHD paralogues that are found in the human genome. In fission yeast, a PHD homologue interacts with Sre1. FIH, factor inhibiting HIF; HIF, hypoxia-inducible factor; PHD, prolyl hydroxylase; Sre1, sterol regulatory element binding protein.