本文選題：幽門螺桿菌 + 比較基因組　； 參考：《中國疾病預防控制中心》2017年博士論文

【摘要】：幽門螺桿菌(Helicobacter pylori,縮寫為H.pylori或HP)是一種定植于人體胃部的病原菌,可引起慢性胃炎、消化性潰瘍,并與胃癌發(fā)生密切相關。人體一旦感染HP如不經規(guī)范治療可終生帶菌,因此HP常被作為一種可靠的生物標識來推測人類種群結構與歷史遷徙。據推算,HP已伴隨人類走出非洲向全球各地遷移、共進化了六萬年以上,逐步形成了與人類種群相對應的七個群。以往的HP種群結構研究主要是基于7個管家基因序列多態(tài)性,不能準確反映我國HP的種群結構。本研究通過整合國際公共數據及對我國八個地區(qū)分離自不同消化道疾病、不同民族菌株的基因組測序,建立了包括491株全球HP的分層基因組數據集,其中包括107株東亞HP、65株中國HP。分析了中國HP的基因組特征及其在東亞、全球范圍內的基因交流情況,以及中國HP種群中新發(fā)現的前噬菌體基因組特點。利用三代測序技術針對胃內多重感染相關的7個克隆構建了基因組完成圖,并評價了三代與二代測序數據對于噬菌體預測的準確性。從群體和個體角度分析了 HP前噬菌體與宿主的共進化規(guī)律。第一部分:中國幽門螺桿菌比較基因組分析65株中國HP共鑒定出3072個泛基因,其中核心基因1147個,附屬基因1925個,菌株特異基因0～47個。拼接序列經reads校正獲得237250個核心基因組SNPs。不同菌株間顯示出高度的遺傳異質性,發(fā)現兩個DNA轉移相關Ⅳ型分泌系統(tǒng)是塑造中國菌株遺傳多樣性的主要因素。從85個毒力基因中發(fā)現76個序列較保守,主要編碼尿素酶、鞭毛蛋白、Cag致病島及VacA毒素。6個外膜蛋白編碼基因存在較大變異,其中sabA、sabB將中國菌株分成了 2個距離較遠的進化支,表明在中國不同人群中HP通過不同的表面抗原識別模式逃避宿主免疫。分層分析初步發(fā)現在整個種群水平上HP具有高度開放的基因庫,鑒定出697個核心基因,為進一步篩選種屬鑒定相關特異基因奠定基礎。中國HP的序列多樣性不能直接預測宿主疾病結局,反映了疾病發(fā)生過程中宿主免疫、胃內微環(huán)境、宿主外環(huán)境等多種其他因素與HP交互作用的復雜性。第二部分:中國幽門螺桿菌種群結構分析利用群體結構分析軟件Chromopainter、fineSTRUCTURE和系統(tǒng)發(fā)育樹,在中國HP中初步發(fā)現地域聚集性特征。在云南少數民族菌株中發(fā)現民族聚集性特點。從東亞亞群(hspEAsia)中鑒定出16個亞組,其中10個亞組為中國HP。中、日、韓、馬來西亞華裔HP各亞組間基因交流頻繁,遺傳關系緊密,與其它亞群基因交流較少;在全球HP層面上的基因流分析發(fā)現東亞亞群、美洲印第安亞群、南印度群及歐洲群各自具有相對獨立的基因庫。這些地域特異性的亞組可能經歷遺傳漂變和瓶頸效應。根據HP與宿主平行共進化的特點,推測中國HP種群結構的形成可能與近代歷史上的人群遷徙有關。對中國HP群體結構的初步鑒定使得未來開展中國HP與胃癌的GWAS研究中能夠從地域、民族角度準確界定同質人群,扣除人群遺傳背景的干擾,具有重要公共衛(wèi)生意義。第三部分:中國幽門螺桿菌前噬菌體遺傳多樣性分析HP噬菌體研究在國際上報道很少,對其遺傳特點及在HP中的作用認識十分有限。本研究首次在中國HP基因組中發(fā)現完整的前噬菌體YN4-84P,與最近日本分離的溶源性噬菌體KHP30基因組高度相似,但編碼門戶蛋白的基因被iS605插入,可能影響其生物合成。中國HP、全球整個種群HP的噬菌體攜帶率分別為13.07%和8.2%。噬菌體可能在塑造HP種群多樣性方面發(fā)揮一定作用,且參與HP與人類的共進化。發(fā)現前噬菌體中攜帶黏附定植相關外膜蛋白基因,未發(fā)現毒素基因和耐藥基因。通過對一名慢性胃炎病人分離7個克隆的基因組完成圖分析,發(fā)現噬菌體與HP基因組具有一致的分化模式。評價了基于二代和三代測序數據進行前噬菌體預測的準確性。
[Abstract]:Helicobacter pylori (Helicobacter pylori, abbreviated as H.pylori or HP) is a pathogenic bacteria colonized in the stomach of the human body, which can cause chronic gastritis, peptic ulcers, and is closely related to gastric cancer. Once the human body is infected with HP without standard treatment, it can be used for life, so HP is often used as a reliable biomarker to speculate on the human population. It is reckon that HP has been associated with the migration of human beings out of Africa to all over the world, and has evolved over sixty thousand years and has gradually formed seven groups corresponding to the human population. The previous study on the structure of HP population is based on the polymorphism of 7 housekeeping gene sequences, which can not accurately reflect the population structure of our country's HP. The international public data and the genome sequencing of eight regions of our country, which are isolated from different digestive tract diseases and different ethnic strains, have set up a stratified genome data set including 491 global HP, including 107 East Asian HP and 65 Chinese HP. to analyze the genomic characteristics of Chinese HP and its genetic exchange in East Asia and around the world. The characteristics of the newly discovered phage genome in the HP population of China. The genome completion map was constructed by three generation sequencing technology for 7 clones associated with intragastric multiple infection, and the accuracy of the three and two generation sequencing data for phage prediction was evaluated. The co evolution of the pre HP phage with the host from the group and the individual angles was analyzed. The first part: 65 Chinese HP strains of Helicobacter pylori were analyzed. 3072 pan genes were identified, including 1147 core genes, 1925 accessory genes and 0~47 strain specific genes. The splice sequence was corrected by reads to obtain the high genetic heterogeneity among the different strains of SNPs., and found two The DNA transfer related type IV secretory system was the main factor in the genetic diversity of the Chinese strain. 76 of the 85 virulence genes were found to be more conservative. The main coding genes encoding urease, flagellin, Cag pathogenicity island and VacA toxin.6 outer membrane protein were large variation, and sabA and sabB divided the Chinese strain into 2 distances. The distant evolutionary branch indicates that HP is escaping from host immunity through different surface antigen recognition patterns in different populations of China. Stratification analysis has preliminarily found that HP has a highly open gene pool at the whole population level, and 697 core genes are identified, which lays the foundation for further screening of specific genes for identification of the species. The sequence of HP in China is diverse. Sex does not directly predict the outcome of the host disease, reflecting the complexity of host immunity, microenvironment in the stomach, and the external environment of the host in the course of the disease. The second part: the structure analysis of Helicobacter pylori in China, Chromopainter, fineSTRUCTURE and phylogenetic tree, are used in the analysis of the structure of Helicobacter pylori strains in China. The characteristics of regional aggregation were found in the national HP. 16 subgroups were identified in the ethnic minority strains in Yunnan. From the East Asian subgroup (hspEAsia), 16 subgroups were identified, of which 10 subgroups were in the Chinese HP., Japan, Korea, and Malaysia Chinese Asian HP subgroups with frequent genetic exchanges, and less genetic communication with other subgroups; Genetic flow analysis at the global HP level shows that East Asia subsets, Indian subgroups, southern India groups and European groups have relatively independent gene banks. These regional specific subgroups may experience genetic drift and bottleneck effects. According to the characteristics of parallel coevolution between HP and host, it is presumed that the formation of Chinese HP population structure may be in modern times. The preliminary identification of the population migration in history. The preliminary identification of the HP population structure in China makes it possible to define the homogenous population from the region and the national angle in the GWAS study of HP and gastric cancer in the future, and to deduct the interference of the genetic background of the population. Third parts: the genetic diversity of the phage before Helicobacter pylori in China. HP phage analysis is rarely reported in the world and has limited understanding of its genetic characteristics and its role in HP. This study was the first to discover the complete pre phage YN4-84P in the Chinese HP genome, which is highly similar to that of the soluble phage KHP30 genome isolated from recent Japan, but the gene encoding the portal protein is inserted by iS605 and may be inserted. The bacteriophages of HP in the whole population of China HP, 13.07% and 8.2%. phages, may play a role in shaping the diversity of HP population, and participate in the co evolution of HP and human. The former phage found that the adhesion and colonization related epicin gene was carried in the pre phage, and the toxin gene and the drug resistance gene were not found. The genome completion map analysis of 7 clones isolated from a chronic gastritis patient showed that the phage has a consistent pattern of differentiation with the HP genome. The accuracy of pre phage prediction based on the two and three generation sequencing data was evaluated.
【學位授予單位】：中國疾病預防控制中心
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R378

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