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A pleiotropic hypoxia-sensitive enhancer is disrupted by adaptive alleles in Tibetans. | LitMetric
In Tibetans, noncoding alleles in -whose protein product hypoxia-inducible factor 2α (HIF-2α) drives the response to hypoxia-carry strong signatures of positive selection; however, their functional mechanism has not been systematically examined. Here, we report that high-altitude alleles disrupt the activity of four enhancers in one or more cell types. We further characterize one enhancer (ENH5) whose activity is both allele specific and hypoxia dependent. Deletion of ENH5 results in down-regulation of and HIF-2α targets in acute hypoxia and in a blunting of the transcriptional response to sustained hypoxia. Deletion of ENH5 in mice results in dysregulation of gene expression across multiple tissues. We propose that pleiotropic adaptive effects of the Tibetan alleles in underlie the strong selective signal at this gene.
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