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题名	Genetic analysis of population history and high-altitude adaptation of Sherpas living in the Himalayan region
作者	SUSHIL BHANDARI
答辩日期	2016-07
文献子类	博士
授予单位	中国科学院研究生院
授予地点	北京
导师	宿兵
关键词	Sherpa Genetic Diversity Human Migration Positive Selection High Altitude Adaptation
其他题名	喜马拉雅地区夏尔巴人群的群体历史和高原适应的遗传学研究
英文摘要	夏尔巴人群生活在喜马拉雅山地区，被誉为是高空登山者，但夏尔巴人群在何时何地人起源并且他们如何能够耐受高海拔的低氧环境仍存在争议。在本研究中，我们收集了居住在尼泊尔和中国西藏自治区的582个夏尔巴人的DNA样本。首先，我们研究了夏尔巴人群母系（线粒体DNA）与父系（Y染色体）的遗传多样性，发现他们与藏族原住民共享大多数父系与母系的世系。线粒体DNA上现存两个夏尔巴人群特有的亚单倍群（C4a3b1和A15c1）是其祖先在距今约1500年前从青藏高原穿越喜马拉雅山迁徙至尼泊尔后人群扩张的结果。我们的发现并不支持此前夏尔巴与汉族人群是藏族人群的祖先群体的理论，反而支持藏族人群是夏尔巴人群的祖先这一论点。其次，我们对夏尔巴人群进行了部分基因（EPAS1、EGLN1与TED区域）的基因型检测，这些基因此前曾报道与藏族人群的高原适应相关。我们对夏尔巴人群进行基因型检测的区域包括藏族人群富集的缺失（TED）以及30个单核苷酸多态位点（其中28个位于EPAS1基因区域，另有2个位于EGLN1基因的错义突变）。我们选择这30个单核苷酸多态位点与缺失多态位点是基于此前对藏族人群的研究，并且这些多态位点在汉族与藏族人群之间等位基因频率差异明显（FST大于0.45）。我们发现夏尔巴与藏族人群在这些位点有着相似的衍生型等位基因频率（大于51%），但在世界其他人群中其衍生型频率却非常低（小于10%）。同样，夏尔巴与藏族人群在EPAS1与EGLN1基因区域均共享明显区别于其他人群的特异单倍型。此外，基因型检测结果显示，在582份夏尔巴样本中携带藏族人群富集的缺失的频率为94%，其中73%为缺失型纯合子（拥有0个拷贝），而21%为杂合子（拥有1个拷贝）。有趣的是，非缺失型的携带者（拥有2个拷贝）在世界其他居住于平原地区的人群中的频率非常高（2792个世界范围内的样本中约占97%），但在藏族人群（大约10%）与夏尔巴人群（大约6%）中频率非常低。最后，我们进行了夏尔巴人群的表型（血红蛋白水平与血氧饱和度水平）与EPAS1,。EGLN1 和 TED区域基因型数据的关联研究。有趣的是，我们发现夏尔巴人群EPAS1基因区域内的几个单核苷酸多态位点（rs113305133、rs116611511和rs12467821）以及藏族人群富集的缺失与血红蛋白水平显著相关（p值均小于0.03）。我们观察到，夏尔巴人群中EPAS1与EGLN1基因区域内这些单核苷酸多态位点的衍生型携带者的血红蛋白浓度低于祖先型的携带者。同样，夏尔巴人群中携带TED的个体比非缺失型的携带者的血红蛋白浓度更低。综上所述，我们的研究表明EPAS1、EGLN1和TED可能在人类适应青藏高原的过程中经历了正选择。假设夏尔巴人群是近期从藏族人群衍生而来，他们从定居西藏近三万年的藏族祖先那里继承了这些适应特性。因此，这两个距今约一千五百年在夏尔巴人群中形成的线粒体DNA单倍型（C4a3b1和A15c1）并没有任何适应高原的特性。恰恰相反，夏尔巴人群和藏族人群形成了相似的适应高海拔的遗传与表型特征。; Sherpas living around the Himalayas are renowned as high-altitude mountain climbers but when and where Sherpa people originated and how they are capable of staying at less oxygen environment of high altitude remains contentious. In this study, we collected DNA samples from 582 Sherpas living in Nepal and Tibet Autonomous Region of China. Firstly, we analyzed the genetic diversity of both maternal (mitochondrial DNA) and paternal (Y chromosome) lineages in Sherpa and found they share most of their paternal and maternal lineages with indigenous Tibetans. There exist two Sherpa-specific mtDNA sub-haplogroups (C4a3b1 and A15c1) as a result of population expansion after ancestors of Sherpa migrated from Tibetan plateau to Nepal crossing the Himalayas around 1,500 years ago. In addition, our finding rejects the previous theory that Sherpa and Han Chinese served as dual ancestral populations of Tibetans, and conversely suggest that Tibetans are the ancestral populations of the Sherpas. Secondly, after knowing Sherpa as a recently derived population from Tibetans, we genotyped the key genes (EPAS1, EGLN1 and TED) in Sherpa that were reported previously in Tibetans for high altitude adaptation, including the Tibetan enriched deletion (TED) region and 30 single nucleotide polymorphisms (SNPs)(28 EPAS1 SNPs and two EGLN1 missense mutations) in Sherpas. These 30 SNPs and deletion polymorphism were selected based on previous studies of Tibetans which showed deep allelic divergence (FST>0.45) between Tibetans and Han Chinese. We found similar derived allele frequencies (>51%) among Sherpa and Tibetans, but much less derived allele frequencies (<10%) in other world populations. Similarly, there is a distinct haplotype pattern shared among Sherpa and Tibetans for EPAS1 and EGLN1, and these haplotypes are different from those of other populations. In addition, genotyping results of TED in 582 Sherpa samples showed 94%TED in Sherpa samples, including 73% homozygous deletion (Zero copy) and 21% heterozygous deletion (one copy) in Sherpa. In contrast, the non-deletion carriers (two copy samples) were seen at high frequency (around 97% of total 2,792 worldwide samples) in other lowlander populations which are rare in Tibetans(<10%) and Sherpa (<6%). Lastly, we conducted association studies between phenotypic (hemoglobin level and degree of blood oxygen saturation level) and genotyping data of EPAS1, EGLN1 and TED in Sherpa. Interestingly, we found several EPAS1 SNPs (rs113305133G, rs116611511G and rs12467821C) and TED having significant association (p value<0.03) with hemoglobin in Sherpa. We observed that Sherpa having derived allele of EPAS1 and EGLN1 SNPs had lower hemoglobin concentration than others carrying the ancestral allele. Likewise, Sherpa containing TED showed lower hemoglobin concentration in comparison with other non-deletion carriers. In summary, our studies suggest that EPAS1, EGLN1 and TED likely underwent positive selection for human adaptation in the Tibetan plateau. In case of Sherpa, who were recently derived from Tibetans, inherited these adaptive traits from their Tibetan ancestors who have been living in Tibet since about 30,000 years ago. Hence, the two population-specific mtDNA haplotypes (C4a3b1 and A15c1) in Sherpa may not have any pronounced effect for high altitude adaptation. Instead, Sherpa and Tibetans share similar genetic and phenotypic traits for high altitude adaptation.
语种	英语
学科主题	遗传学
内容类型	学位论文
源URL	[http://159.226.149.26:8080/handle/152453/11989]
专题	昆明动物研究所_比较基因组学
作者单位	中国科学院昆明动物研究所
推荐引用方式 GB/T 7714	SUSHIL BHANDARI. Genetic analysis of population history and high-altitude adaptation of Sherpas living in the Himalayan region[D]. 北京. 中国科学院研究生院. 2016.

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