FIGURE 4.

GeneMania (32) network constructed from candidate genes for adaptation to hypoxia

The network contains two types of edges: physical interaction (red) and known pathways (blue), and includes genes from Tables 1 and 2 (green, blue, and yellow circles), and additional genes with direct connections (gray circles). Genes with no connecting edges are not shown. Genes are shaded according to the geographical region in which they were identified. Note that many genes from the hypoxia response pathway are directly implicated in multiple populations. The hypoxia response directly affects metabolism. Specifically, the transcription factor HIF1A also upregulates Angiopoietin-like protein 4 (26), which in turn regulates the PPAR-dependent expression of LIPE. Other genes impacted by hypoxia involve the vascular system, such as the vasoconstrictor EDNRB, and MAP kinase 2, which influences pulmonary vascular permeability (12). The Fanconi anemia complex genes [which also complex with Spectrin (SPTA)] are key members of a DNA repair pathway that are regulated by hypoxic stress. In addition, the FANCG gene interacts with cytochrome P450 protein CYP2E1 (14). Together, the studies demonstrate the complex, multi-locus adaptation to hypoxia achieved by different populations.