Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Zheng WS

PROVIDER: S-EPMC5460085 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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

Zheng Wang-Shan WS He Yao-Xi YX Cui Chao-Ying CY Ouzhu Luobu L Deji Quzong Q Peng Yi Y Bai Cai-Juan CJ Duoji Zhuoma Z Gongga Lanzi L Bian Ba B Baima Kangzhuo K Pan Yong-Yue YY Qu la Kang Min M Ciren Yangji Y Baima Yangji Y Guo Wei W Yang la Zhang Hui H Zhang Xiao-Ming XM Guo Yong-Bo YB Xu Shu-Hua SH Chen Hua H Zhao Sheng-Guo SG Cai Yuan Y Liu Shi-Ming SM Wu Tian-Yi TY Qi Xue-Bin XB Su Bing B

Zoological research 20170501 3

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 ...[more]

PMID: 28585440

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Project description:Since their arrival in the Tibetan Plateau during the Neolithic Age, Tibetans have been well-adapted to extreme environmental conditions and possess genetic variation that reflect their living environment and migratory history. To investigate the origin of Tibetans and the genetic basis of adaptation in a rigorous environment, we genotyped 30 Tibetan individuals with more than one million SNP markers. Our findings suggested that Tibetans, together with the Yi people, were descendants of Tibeto-Burmans who diverged from ancient settlers of East Asia. The valleys of the Hengduan Mountain range may be a major migration route. We also identified a set of positively-selected genes that belong to functional classes of the embryonic, female gonad, and blood vessel developments, as well as response to hypoxia. Most of these genes were highly correlated with population-specific and beneficial phenotypes, such as high infant survival rate and the absence of chronic mountain sickness. Genetic features of Tibetans have been broadly investigated, but the properties of copy number variation (CNV) have not been well examined. To get a preliminary view of CNV in Tibetans, we scanned 29 Tibetan genomes with the Illumina Human-1 M high-resolution genotyping microarray and identified 139 putative copy number variable regions (CNVRs), consisting of 70 deletions, 61 duplications, and 8 multi-allelic loci. Thirty-four of the 139 CNVRs showed differential allele frequencies versus other East-Asian populations, with P values ,0.0001. These results indicated a distinct pattern of CNVR allele frequency distribution in Tibetans. The Tibetan CNVRs are enriched for genes in the disease class of human reproduction (such as genes from the DAZ, BPY2, CDY, and HLA-DQ and -DR gene clusters) and biological process categories of ‘‘response to DNA damage stimulus’’ and ‘‘DNA repair’’ (such as RAD51, RAD52, and MRE11A). These genes are related to the adaptive traits of high infant birth weight and darker skin tone of Tibetans, and may be attributed to recent local adaptation. Our results provide a different view of genetic diversity in Tibetans and new insights into their high-altitude adaptation.

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

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<i>EP300</i> contributes to high-altitude adaptation in Tibetans by regulating nitric oxide production.

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