EGLN1基因的序列多态性与藏族人群高原低氧适应的遗传学机制
文献类型：学位论文
| 作者 | 向坤 |
| 学位类别 | 博士 |
| 答辩日期 | 2015-05 |
| 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 | 藏族人群 高原低氧适应 EGLN1基因 rs186996510 |
| 其他题名 | Sequence polymorphisms of EGLN1 and genetic mechanism of adaptation to high altitude hypoxia in Tibetans |
| 中文摘要 | 高海拔极端环境对人类的选择压力包括寒冷、强紫外照射以及低氧，其中低氧是唯一人类无法借助传统工具或技术完全克服的环境压力。虽然最初对高海拔地区人群的研究主要集中在安第斯山脉的高原人群，但近年来研究者开始关注藏族人群对高原低氧环境的适应。 近年对藏族人群全基因组的研究试图找出基因组中的关键基因，以解释藏族人群适应高原低氧环境的表型性状与其遗传之间的关系。研究者用不同的方法对比藏族人群与平原人群(例如汉族)的基因组，发现EPAS1与EGLN1这两个位于低氧代谢通路上的关键基因在藏族人群中存在群体特异的序列变异和显著的正选择信号，提示它们对藏族的高原低氧适应可能有重要的贡献。 我们对46个藏族个体的EGLN1基因区域进行重测序，发现该基因区域有在藏族人群中有两个改变氨基酸的单核苷酸多态性位点，其中一个改变第4个氨基酸，另一个改变第127个氨基酸。改变第4个氨基酸的位点rs186996510(D4E)的衍生型在藏族人群中频率较高(约为63.27%)，而在世界代表人群中的频率均不足2.5%。改变第127个氨基酸的位点rs12097901(S127C)的衍生型在藏族人群中频率较低(约为20.65%)，而在世界代表人群中的频率介于52.06%至92.35%之间。同时，基于频率的遗传差异度FST的计算结果表明汉藏之间在位点rs186996510的差异度约为0.709，是EGLN1基因所处的1号染色体汉藏之间平均差异(0.0102)的近70倍，而在位点rs12097901的差异度约为0.1891。基于EGLN1单倍型的网络结构图分析结果与用Fay and Wu的中性检验方法分析得到的结果相一致，它们都表明藏族人群中存在群体特异的单倍型，这提示我们该区域具有达尔文正选择的信号。 我们对大样本量靶位点基因分型的结果显示，rs186996510(D4E)的衍生型频率与海拔具有一定的正相关，这进一步说明该位点对藏族人群的高原低氧环境适应性可能具有贡献。基因型-表型相关性分析的结果表明，藏族男性个体中两个改变氨基酸的位点与血红蛋白浓度具有显著的相关性。这一结果提示我们，该位点可能对藏族适应高原低氧环境具有潜在的功能效应。多态位点rs186996510(D4E)所处的位置编码EGLN1的第4个氨基酸，靠近基因编码蛋白质的N端，但并不在目前已知的3个功能域的范围内。我们通过比对多个物种的该蛋白氨基酸序列发现，祖先型对应的天冬氨酸在不同物种之间都非常保守，这提示我们天冬氨酸在功能上对EGLN1所编码的蛋白PHD2非常重要，而由天冬氨酸突变为谷氨酸有可能使蛋白PHD2在功能上发生改变。 我们进一步对受选择的等位基因的起源时间及其选择强度进行计算的结果表明，其起源于距今大约8400年前。该起源时间的估算结果比此前估算EPAS1受到选择的时间(距今大约18000年)晚了近1万年。有两种可能形成这样的差异：一种可能是这两个基因的突变型是随着人群迁徙分两次进入现今的藏族人群；还有一种可能，两个基因的适应型突变最初都被带入青藏高原，只是自然选择发生在不同的时期。 |
| 英文摘要 | Extreme environment of high altitude for humans contains cold, high UV, as well as hypoxia, of which hypoxia is the only environmental stress for human because it cannot be overcome by traditional tools or technology. Although early studies on high altitude populations were focused on Andeans, Tibetan populations attract scientists’ extended attention recently. Recent studies on Tibetans tried to identify key genes from their genome, in order to explain biological characteristics of Tibetans adapting to high altitude and their heredity. These studies used different methodologies to compare the Tibetan genome with genomes of populations in plain area, such as the Han Chinese, finding out that EPAS1 and EGLN1, which are in the pathway relative regions, were under positive selection with population-specific sequence variations in Tibetans, suggesting that they are important for high-altitude hypoxic adaptation of Tibetans. We conducted resequencing of the entire genomic region of EGLN1 within 46 Tibetans and found two SNPs (single nucleotide polymorphisms) which belong to nonsynonymous mutations, with one changing 4th amino acid while the other changing 127th. The derived allele of rs186996510 (D4E) which changes 4th amino acid, was quite frequent in Tibetans with the frequency about 63.27%, while quite rare in other populations with the frequency less than 2.5%. The derived allele of rs12097901 (S127C) which changes 127th amino acid, was not frequent in Tibetans with the frequency about 20.65%, while the frequency in other populations were from 52.06% to 92.35%. Meanwhile, the results of FST which reflects diversity between populations based on allele frequency, showed that FST between Tibetans and Han Chinese on rs186996510 (D4E) was 0.709, nearly 70-folds more than the average (FST = 0.0102) of Chromosome 1 between Tibetans and Han Chinese., while the result on rs12097901 was just 0.1891. We performed a neutrality test using the method by Fay and Wu and constructed Network based on haplotypes of EGLN1, both of the results showed that there was an excess of major haplotypes in Tibetans, suggesting a signal of Darwinian positive selection in this region. Genotyping of Tag SNPs in Extensive Tibetan showed that a significant correlation between the frequency of derived allele on rs186996510 (D4E) in Tibetan populations and altitudes, as an implication of its contribution to high-altitude hypoxic adaptation in Tibetans. We conducted genetic association analyses and two SNPs showed nominally significant association with hemoglobin levels in Tibetan males, which suggesting that rs186996510 may play a role on high-altitude hypoxic adaptation in Tibetans as a functional mutation.As an amino acid changing mutation, rs186996510 (D4E) islocated at the N-terminal of the EGLN1 protein but not in the three known functional domains. However, a protein sequence alignment among distantly related species revealed that the ancestral amino acid (D) is a phylogenetically conserved residue, suggesting that this amino acid siteis functionally important for EGLN1, and the D to E mutation may cause protein functional change. We assessed the intensity and age of selection on EGLN1 in Tibetans, and the result showed that the age of selection was about 8,400 years before. The estimated age of selection on the C alleleof rs186996510 falls in the early Neolithic (~8,400 years ago), which is much younger than the estimated selection age of EPAS1 (~18,000 years ago). There are two possible scenarios explaining the difference: first, the adaptive mutations of EGLN1 and EPAS1 were brought onto the Himalayas at different times; second, the adaptive mutations of EGLN1 and EPAS1 might be brought onto the Himalayas at the same time during the Upper Paleolithic, but selection might have occurred at different times on these two genes. |
| 语种 | 中文 |
| 源URL | [http://159.226.149.26:8080/handle/152453/10189]  |
| 专题 | 昆明动物研究所_比较基因组学 |
| 推荐引用方式 GB/T 7714 | 向坤. EGLN1基因的序列多态性与藏族人群高原低氧适应的遗传学机制[D]. 北京. 中国科学院研究生院. 2015. |
入库方式： OAI收割
来源：昆明动物研究所
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