藏族人群中低氧适应相关基因EP300的变异模式及其对高原低氧环境适应的遗传贡献

发布时间：2018-08-16 15:37

【摘要】：青藏高原是人类居住的最极端的环境之一,藏族人群通过长期的达尔文进化选择,在生理和遗传上对高原独特的低氧生境表现出良好的适应。藏族人群对低氧的适应是一个动态多基因调控的过程。本研究通过对80个无亲缘关系的藏族个体EP300(108.93k)基因进行重测序,并进行了SNP位点的鉴定和基于等位基因频率和单倍型中性选择信号检测、功能预测、遗传关联等分析,结果显示藏族人群与低海拔人群(汉族、欧洲人群和非洲人群)相比有一组变异位点表现出等位基因频率分歧。以千人基因组为参考基因组对EP300基因进行SNP鉴定,经过质量控制后,得到185个可用后续分析的SNP位点。基于等位基因频率和单倍型的中性检验结果表明,有34个SNP位点FST大于全基因组平均分歧值(0.03),XPEHH2,说明EP300受到了达尔文选择。利用CADD数据库对149个位点进行基于GERP的序列保守性、转录因子结合区域、剪切基序、组蛋白甲基化/三甲基化修饰位点和DNA酶I超敏感剪切位点等功能预测,发现除了2个非同义突变都位于非编码区,14个SNP位点高度保守(GREP++5.0),还有多个位点与H3K4Me1/H3K4Me3修饰相关,表明他们可能参与了组蛋白的修饰和染色体重塑以及启动子的活性相关。我们利用血液eQTL数据库对EP300基因SNP位点进行了分析。其中有6个TagSNP位点中有三个位点(rs2076578,rs5758251 and rs2143694)与EP300的表达水平表现出强烈的相关性(P v值分别1.64×10-54,3.63×10-54和3.26×10-54),这也说明EP300可能在藏族人群适应低氧的遗传机制中扮演者重要的角色。遗传关联分析结果表明EP300与藏族血液中一氧化氮(NO)含量相关,说明EP300可能通过调节NO的水平来帮助藏族人群适应高原低氧环境。
[Abstract]:Qinghai-Xizang Plateau is one of the most extreme environments inhabited by human beings. The Tibetan people have shown good physiological and genetic adaptation to the plateau's unique hypoxic habitat through long-term Darwinian evolutionary selection. Adaptation to hypoxia in Tibetan populations is a dynamic polygenic process. In this study, EP300 (108.93k) genes of 80 unrelated Tibetan individuals were sequenced, and SNP loci were identified and analyzed based on allele frequency and haplotype neutral selection signal detection, functional prediction and genetic association. The results showed that there were different alleles in a group of mutation loci between Tibetan and low altitude population (Han, European and African). The EP300 gene was identified by SNP with thousands of human genomes as reference. After quality control, 185 SNP loci were obtained which could be used for subsequent analysis. The results of neutral test based on allelic frequency and haplotype showed that 34 SNP loci had higher FST than the whole genome average divergence value (0.03) XPEH2, indicating that EP300 was selected by Darwin. The CADD database was used to predict the function of 149 sites based on GERP sequence conserved, transcription factor binding region, shearing motif, histone methylation / trimethylation modification site and DNA enzyme I hypersensitive shear site. It was found that except for 2 nonsynonymous mutations, 14 SNP loci were highly conserved (GREP 5.0), and many other sites were related to H3K4Me1/H3K4Me3 modification, suggesting that they may be involved in the modification of histone, chromosome remodeling and promoter activity. We used blood eQTL database to analyze the SNP locus of EP300 gene. Three of the six TagSNP loci (rs2076578rs5758251 and rs2143694) showed strong correlation with the expression of EP300, and the (P v values were 1.64 脳 10-54 and 3.26 脳 10-54, respectively, indicating that EP300 may play an important role in the genetic mechanism of adaptation to hypoxia in Tibetan population. The results of genetic association analysis showed that EP300 was related to the content of nitric oxide (NO) in Tibetan blood, suggesting that EP300 might help Tibetan people adapt to hypoxia environment by regulating the level of no.
【学位授予单位】：甘肃农业大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R339.5

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