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| 1 | GCH1 plays a role in the high-altitude adaptation of Tibetans显示文摘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. | Yong-Bo Guo Yao-Xi He Chao-Ying Cui Ouzhuluobu Baimakangzhuo Duojizhuoma Dejiquzong Bianba Yi Peng Cai-juan Bai Gonggalanzi Yong-Yue Pan Qula Kangmin Cirenyangji Baimayangji Wei Guo Yangla Hui Zhang Xiao-Ming Zhang Wang-Shan Zheng Shu-Hua Xu Hua Chen Sheng-Guo Zhao Yuan Cai Shi-Ming Liu Tian-Yi Wu Xue-Bin Qi Bing Su | 2017 | Zoological Research2017，38，3： | 8 |
| 2 | Blunted nitric oxide regulation in Tibetans under high-altitude hypoxia显示文摘Nitric oxide(NO) is an important molecule for vasomotor tone, and elevated NO signaling was previously hypothesized as a unique and adaptive physiological change in highland Tibetans. However, there has been lack of NO data from Tibetans living at low altitude and lowlander immigrants living at high altitude, which is crucial to test this hypothesis. Here, through cross-altitude(1990–5018 m) and cross-population(Tibetans and Han Chinese) analyses of serum NO metabolites(NOx) of 2086 individuals, we demonstrate that although Tibetans have a higher serum NOx level compared to lowlanders, Han Chinese immigrants living at high altitude show an even higher level than Tibetans. Consequently, our data contradict the previous proposal of increased NO signaling as the unique adaptive strategy in Tibetans.Instead, Tibetans have a relatively lower circulating NOx level at high altitude. This observation is further supported by data from the hypoxic experiments using human umbilical vein endothelial cells and gene knockout mice. No difference is detected between Tibetans and Han Chinese for endothelial nitric oxide synthase(e NOS), the key enzyme for circulating NO synthesis, suggesting that e NOS itself is unlikely to be the cause. We show that other NO synthesis-related genes(e.g. GCH1) carry Tibetan-enriched mutations significantly associated with the level of circulating NOx in Tibetans. Furthermore, gene network analysis revealed that the downregulation and upregulation of NOx is possibly achieved through distinct pathways.Collectively, our findings provide novel insights into the physiological and genetic mechanisms of the evolutionary adaptation of Tibetans to high-altitude hypoxia. | Yaoxi He Xuebin Qi Ouzhuluobu Shiming Liu Jun Li Hui Zhang Baimakangzhuo Caijuan Bai Wangshan Zheng Yongbo Guo Duojizhuoma Baimayangji Dejiquzong Bianba Gonggalanzi Yongyue Pan Qula Kangmin Cirenyangji Wei Guo Yangla Yi Peng Xiaoming Zhang Kun Xiang Zhaohui Yang Liangbang Wang Gengdeng Yanfeng Zhang Tianyi Wu Bing Su Chaoying Cui | 2018 | National Science Review2018，5，4： | 7 |
| 3 | EP300 contributes to high-altitude adaptation in Tibetans by regulating nitric oxide production显示文摘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. Col ectively, we propose that EP300 harbors adaptive variants in Tibetans, which might contribute to high-altitude adaptation through regulating NO production. | Wang-Shan Zheng Yao-Xi He Chao-Ying Cui Ouzhuluobu Dejiquzong Yi Peng Cai-Juan Bai Duojizhuoma Gonggalanzi Bianba Baimakangzhuo Yong-Yue Pan Qula Kangmin Cirenyangji Baimayangji Wei GUO Yangla Hui Zhang Xiao-Ming Zhang Yong-Bo Guo Shu-Hua Xu Hua Chen Sheng-Guo Zhao Yuan Cai Shi-Ming Liu Tian-Yi Wu Xue-Bin Qi Bing Su | 2017 | Zoological Research2017，38，3： | 4 |
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