EP300 contributes to high-altitude adaptation in Tibetans by regulating nitric oxide production

The genetic adaptation of Tibetans to high altitude hypoxia likely involves a group of genes in the hypoxic pathway,as suggested by earlier studies.To test the adaptive role of the previously reported candidate gene EP300 (histone acetyltransferase p300),we conducted resequencing of a 108.9 kb gene region of EP300 in 80 unrelated Tibetans.The allele-frequency and haplotype-based neutrality tests detected signals of positive Darwinian selection on EP300 in Tibetans,with a group of variants showing allelic divergence between Tibetans and lowland reference populations,including Han Chinese,Europeans,and Africans.Functional prediction suggested the involvement of multiple EP300 variants in gene expression regulation.More importantly,genetic association tests in 226 Tibetans indicated significant correlation of the adaptive EP300 variants with blood nitric oxide (NO) concentration.Collectively,we propose that EP300 harbors adaptive variants in Tibetans,which might contribute to high-altitude adaptation through regulating NO production.     

GCH1 plays a role in the high-altitude adaptation of Tibetans

Tibetans are well adapted to high-altitude hypoxia.Previous genome-wide scans have reported many candidate genes for this adaptation,but only a few have been studied.Here we report on a hypoxia gene (GCH1,GTP-cyclohydrolase I),involved in maintaining nitric oxide synthetase (NOS) function and normal blood pressure,that harbors many potentially adaptive variants in Tibetans.We resequenced an 80.8 kb fragment covering the entire gene region of GCH1 in 50 unrelated Tibetans.Combined with previously published data,we demonstrated many GCH1 variants showing deep divergence between highlander Tibetans and lowlander Han Chinese.Neutrality tests confirmed a signal of positive Darwinian selection on GCH1 in Tibetans.Moreover,association analysis indicated that the Tibetan version of GCH1 was significantly associated with multiple physiological traits in Tibetans,including blood nitric oxide concentration,blood oxygen saturation,and hemoglobin concentration.Taken together,we propose that GCH1 plays a role in the genetic adaptation of Tibetans to high altitude hypoxia.