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Blunted nitric oxide regulation in Tibetans under high-altitude hypoxia

National Science Review 2018年第4期5卷 516-529页

作者： 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 cirenyangji Wei Guo Yangla Yi Peng Xiaoming Zhang Kun Xiang Zhaohui Yang Liangbang Wang Gengdeng Yanfeng Zhang Tianyi Wu Bing Su Chaoying Cui State Key Laboratoryof Genetic Resources and Evolution Kunming Institute of ZoologyChinese Academy of Sciences Kunming College of Life Science University of Chinese Academy of Sciences Center for Excellence in Animal Evolution and Genetics Chinese Academy of Sciences High Altitude Medical Research Center School of Medicine Tibetan University National Key Laboratory of High Altitude Medicine High Altitude Medical Research Institute Fukang International Medical Examination Center Fukang Obstetrics Gynecologyand Children Branch Hospital Tibetan Fukang Hospital 7. Yunnan Key Laboratory of Primate Biomedicine ResearchInstitute of PrimateTranslational MedicineKunming University of Science andTechnology

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.

关键词： adaptation high altitude Tibetan nitric oxide GCH1

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

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Zoological Research 2017年第3期38卷 155-162页

作者： 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 College of Animal Science and Technology Gansu Agricultural University Lanzhou Gansu 730070 China State Key Laboratory of Genetic Resources and Evolution Kunming Institute of Zoology Chinese Academy of Sciences Kunming Yunnan 650223 China High Altitude Medical Research Center School of Medicine Tibetan University Lhasa Tibet 850000 China Kunming College of Life Science University of Chinese Academy of Sciences Kunming Yunnan 650204 China Chinese Academy of Sciences Key Laboratory of Computational Biology Max Planck Independent Research Group on Population Genomics CAS-MPG Partner Institute for Computational Biology (PICB) Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai 200031 China Center for Computational Genomics Beijing Institute of Genomics Chinese Academy of Sciences Beijing 100101 China National Key Laboratory of High Altitude Medicine High Altitude Medical Research Institute Xining Qinghai 810012 China School of Life Science and Technology Shanghai Tech University Shanghai 200031 China Collaborative Innovation Center of Genetics and Development Shanghai 200438 China

Tibetans are welt 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 GCHI 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.

关键词： GCH1 Positive selection TibetanHypoxia adaptation Nitric oxide HemoglobinOxygen saturation

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

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Zoological Research 2017年第3期38卷 163-170页

作者： 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 College of Animal Science and Technology Gansu Agricultural University Lanzhou Gansu 730070 China State Key Laboratory of Genetic Resources and Evolution Kunming Institute of Zoology Chinese Academy of Sciences Kunming Yunnan 650223 China High Altitude Medical Research Center School of Medicine Tibetan University Lhasa Tibet 850000 China Kunming College of Life Science University of Chinese Academy of Sciences Kunming Yunnan 650204 China Chinese Academy of Sciences Key Laboratory of Computational Biology Max Planck Independent Research Group on Population Genomics CAS-MPG Partner Institute for Computational Biology Shanghai Institutes for Biological Sciences Chinese Academy ofSciences Shanghai 200031 China Center for Computational Genomics Beijing Institute of Genomics Chinese Academy of Sciences Beijing 100101 China National Key Laboratory of High Altitude Medicine High Altitude Medical Research Institute Xining Qinghai 810012 China School of Life Science and Technology Shanghai Tech University Shanghai 200031 China Collaborative Innovation Center of Genetics and Development Shanghai 200438 China

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.

关键词： Tibetans High altitude Hypoxia EP300 Genetic adaptation Nitric oxide

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外阴乳头状汗腺瘤1例

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中国皮肤性病学杂志 2022年第12期36卷 1435-1436页

作者：扎珍索朗曲宗王倩张韡白央慈仁央吉西藏自治区人民医院皮肤性病科西藏拉萨850000 中国医学科学院皮肤病医院病理科江苏南京210042

患者女,53岁,外阴淡红色结节半年,增大1周。皮肤科情况:右侧外阴阴蒂旁单发直径约0.5 cm的淡红色结节,质韧,触痛明显。皮损组织病理示:肿瘤位于真皮内,呈单发的结节,境界清晰,无包膜,与表皮不相连,在整体上呈迷宫样模式,向内形成乳头状... 详细信息

患者女,53岁,外阴淡红色结节半年,增大1周。皮肤科情况:右侧外阴阴蒂旁单发直径约0.5 cm的淡红色结节,质韧,触痛明显。皮损组织病理示:肿瘤位于真皮内,呈单发的结节,境界清晰,无包膜,与表皮不相连,在整体上呈迷宫样模式,向内形成乳头状突起。瘤体内有较多乳头状突起,腔面衬一层柱状细胞,可见顶浆分泌现象。诊断:外阴乳头状汗腺瘤。

关键词：乳头状汗腺瘤外阴

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牛沙门氏菌病流行特点及防控

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畜牧兽医科学（电子版） 2021年第17期 135-136页

作者：次仁央吉西藏拉萨市城关区农业农村局畜牧兽医站西藏拉萨850000

近年牛沙门氏菌病具有较高的发生率,严重威胁牛只健康生长,影响养殖户的经济利益。牛沙门氏菌病的病原为沙门氏菌,牛患病后会出现发热、呼吸困难等典型症状,牛只的生产性能严重降低。病菌还会通过病牛的粪便、尿液等进行传播,污染到牧... 详细信息

近年牛沙门氏菌病具有较高的发生率,严重威胁牛只健康生长,影响养殖户的经济利益。牛沙门氏菌病的病原为沙门氏菌,牛患病后会出现发热、呼吸困难等典型症状,牛只的生产性能严重降低。病菌还会通过病牛的粪便、尿液等进行传播,污染到牧场与水源,威胁到地区养殖业的整体发展。该文主要论述牛沙门氏菌病的流行特点、临床症状、剖检变化及防控。

关键词：牛沙门氏菌病防控

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西藏绒山羊KAP13.1基因的多态性及其与生产性状的关联分析

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黑龙江畜牧兽医 2018年第7期 79-82页

作者：吴玉江索朗达巴贵次仁德吉德吉宋天增益西多吉巴桑玉珍达瓦旦增扎巴边巴次仁边巴卓玛次仁央吉云丹罗布袁超西藏自治区农牧科学院畜牧兽医研究所拉萨850009 西藏尼木县农牧局西藏尼木851300 西藏尼玛县白绒山羊原种场西藏尼玛852000 西藏尼玛县兽医防疫站西藏尼玛852000 西藏措勤县兽医防疫站西藏措勤859000 中国农业科学院兰州畜牧与兽药研究所兰州730050

为了解角蛋白关联蛋白（KAP）13.1基因在西藏绒山羊群体中的多态性与其生产性状的关联性,试验采用PCR-SSCP和DNA测序技术对343只西藏绒山羊KAP13.1基因编码区序列进行多态性分析,采用邓肯氏法进行多重比较,并与体长、体高、胸围、产绒... 详细信息

为了解角蛋白关联蛋白（KAP）13.1基因在西藏绒山羊群体中的多态性与其生产性状的关联性,试验采用PCR-SSCP和DNA测序技术对343只西藏绒山羊KAP13.1基因编码区序列进行多态性分析,采用邓肯氏法进行多重比较,并与体长、体高、胸围、产绒量、羊绒长度、羊毛长度的关联性进行分析。结果表明：扩增产物序列中存在5个SNPs位点,分别为C73A、T115C、C124T、C213G和G447A,SNP位点都位于编码区。基因型2公羊的胸围、产绒量和毛长显著高于基因型3（P〈0.05）,而母羊的生产性能在3个基因型中差异不显著（P〉0.05））。说明KAP13.1基因可作为影响西藏绒山羊公羊胸围、产绒量和毛长的分子标记。

关键词：西藏绒山羊 KAP13.1基因多态性生产性状相关性分析

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