藏族人群中GCH1基因的适应性选择及其对高原低氧适应的贡献

发布时间：2019-03-12 09:59

【摘要】：藏族群体是高海拔低氧极端环境成功适应和遗传机制研究的很好的范例。与移居到高海拔低氧环境条件下的低海拔人群相比较,藏族群体经过长期的低氧环境适应,进化出了许多重要的适应性性状,较高的肺容量和较好的肺功能,较好的肺扩散能力和肺通气,低的血红蛋白水平,较高的血氧饱和度,低的肺动脉高压,高的一氧化氮水平和低的婴儿出生体重减少率。由于藏族人群在高海拔低氧条件下长时间的自然选择才产生了这些遗传性状,导致了他们的基因组发生了遗传变化。藏族群体对于高海拔低氧环境适应的复杂性状是由许多基因参与的。其中,EPAS1和EGLN1是低氧通路上游的关键调控基因,它们在藏族低氧适应中发挥重要作用,在藏族群体中,对于血红蛋白水平产生一个钝化作用。EGLN1基因负调控EPAS1基因表达来维持正常的血红蛋白水平。除以上两个关键基因,在藏族群体中存在另一个候选基因有助于低氧遗传适应。在本研究中,我们报道了一个低氧候选基因GCH1(GTP-环化水解酶I),参与维持NOS功能和正常的血压,在藏族群体中存在许多潜在的适应性变异。我们完成了GCH1基因整个区域(60.8kb)和该基因上下游各10kb的重测序。共重测序了50个非近亲的藏族个体,并结合之前发表的数据,完成了分子进化和多个生理性状相关性分析,包括血红蛋白浓度,血氧饱和度,肺动脉压和一氧化氮浓度。在测序的藏族群体中,我们在GCH1基因上总共鉴定出384个序列变异,我们发现49个变异在群体之间(藏族和汉族)存在显著的遗传分化(Fst0.2),而且,这些高Fst的变异也表现出了高的iHS和XPEHH。这些结果表明了在藏族群体的GCH1基因上存在一个明显的达尔文自然选择信号。通过检验9个GCH1的tagSNPs(标签单核苷酸变异),我们发现在藏族群体中,这些变异与多个生理性状存在相关性,包括血红蛋白浓度、血液一氧化氮、肺动脉压和血氧饱和度。总之,我们验证了GCH1基因在藏族群体中受到了明显的达尔文正选择。我们在高海拔藏族群体和低海拔群体中鉴定了许多存在深度遗传分化的遗传变异。GCH1已知功能表明,它潜在的主要参与藏族群体高海拔低氧适应肺血管调控。
[Abstract]:The Tibetan population is a good example of the successful adaptation of the high-altitude and low-altitude environment and the research of the genetic mechanism. Compared with the low-altitude population moving to the high altitude and low-altitude environment, the Tibetan population has developed many important adaptive characters, higher lung capacity and better lung function, better lung diffusion capacity and lung ventilation after long-term low-oxygen environmental adaptation. Low hemoglobin levels, higher blood oxygen saturation, low pulmonary hypertension, high nitric oxide levels, and low birth weight reduction rates for infants. Due to the long-term natural selection of the Tibetan population under high altitude and low-oxygen conditions, these genetic traits have been produced, leading to a genetic change in their genome. The complex characters of the Tibetan population for high altitude and low-oxygen environment adaptation are involved in many genes. EAS1 and EGLN1 are the key regulatory genes upstream of the hypoxia pathway, which play an important role in the Tibetan hypoxia adaptation. The EGLN1 gene negatively regulates the expression of the EPAS1 gene to maintain a normal hemoglobin level. In addition to the above two key genes, there is another candidate gene in the Tibetan population to help the low-oxygen genetic adaptation. In this study, we reported a low-oxygen candidate GCH1 (GTP-cyclohydrolase I), which was involved in the maintenance of NOS function and normal blood pressure, and there were many potential adaptive variations in the Tibetan population. We completed the entire region of the GCH1 gene (60.8 kb) and the 10 kb resequencing at the upstream and downstream of the gene. A total of 50 non-close-related Tibetan individuals were sequenced and combined with previously published data to complete molecular evolution and a number of physiological traits-related analyses, including hemoglobin concentration, blood oxygen saturation, pulmonary arterial pressure, and nitric oxide concentration. In the Tibetan population of the sequencing, we identified a total of 384 sequence variations on the GCH1 gene, and we found that 49 variation had significant genetic differentiation among the population (Tibetan and Han) (Fst0.2), and the variation of these high Fst also showed high iHS and XPEHH. These results show that there is a clear Darwinian natural selection signal on the GCH1 gene of the Tibetan population. By examining the tagSNPs of 9 GCH1 (label monucleotide variations), we found that in the Tibetan population, these variations are associated with multiple physiological traits, including hemoglobin concentration, blood nitric oxide, pulmonary arterial pressure, and blood oxygen saturation. In conclusion, we have verified that the GCH1 gene has been selected by Darwinian in the Tibetan population. In that high-altitude Tibetan and low-altitude group, we identified many genetic variation with deep genetic differentiation. The known function of GCH1 indicates that it is mainly involved in the high-altitude hypoxia-adapted pulmonary vascular regulation in the Tibetan population.
【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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