Adaptive Selection Of GCH1 And Their Contribution To Adaptation To High Altitude Hypoxia In Tibetans

Tibetans are a well-known example of successful adaptation to extreme environments at high-altitude,Compared to lowlanders moving to the high altitude,after a long-term altitude hypoxia adaptation in Tibetans,they have acquired a lot of major adaptive traits to deal with hypoxia condition,included greater lung capacity and better lung function,better lung diffusion capacity and lung ventilation,lower hemoglobin levels,better level of blood oxygen saturation of,low hypoxic pulmonary vasoconstriction,high nitric oxide level,and lower incidence of reduced birth weight.Due to long-term positive natural selection at high altitude,therefore,they have generated these heritable traits,resulting in genetic modifications of genes in genome.Specifically,EPAS1 and EGLN1 is two key genes in hypoxic pathway,they play a important role in Tibetans at hypoxia adaptation,they have been systematically studied and shown to be responsible for the blunted physiological responses.In fact,besides the two previously identified key genes,there were other candidates that may also contribute to the genetic adaptation in Tibetans.In this study,we reported a hypoxia gene(GCH1,GTP-cyclohydrolase I),involved in maintaining NOS function and normal blood pressure,harbors many potentially adaptive variants in Tibetans.We performed re-sequencing an 80.8kb fragment covering the gene region of GCH1 and its flanking sequences(10kb up-and down-stream of GCH1).In total,we sequenced 50 unrelated Tibetan individuals.Combined with previous published data,we performed analyses of molecular evolution and genetic association with multiple physiological traits,including hemoglobin concentration,blood oxygen saturation,pulmonary pressure and blood nitric oxide concentration.We identified a total of 384 GCH1 sequence variants in the sequenced Tibetans.And we found that there were 49 GCH1 variants showing deep divergence between highlander Tibetans and lowlander Han Chinese(Fst>0.2).And these high-Fst variants also showed high i HS and XPEHH values.These results suggested a clear signal of Darwinian positive selection on GCH1 in Tibetans.By testing 9 GCH1 tag variants,we observed significant associations of these variants with multiple physiological traits in Tibetans.Including hemoglobin concentration,blood nitric oxide concentration,pulmonary artery pressure and blood oxygen saturation.Taken together,we demonstrated that GCH1 has been under positive selection in Tibetans.We identified many variants with deep divergence between Tibetans and lowlanders.The known function of GCH1 suggests its potentially major involvement in pulmonary regulation of Tibetans’ adaptation to high altitude hypoxia.