| 题名 | 链球菌属基因组进化的生物信息学研究 |
| 作者 | 高晓阳 |
| 学位类别 | 博士 |
| 答辩日期 | 2015 |
| 授予单位 | 中国科学院大学 |
| 授予地点 | 北京 |
| 导师 | 李文均 |
| 关键词 | 链球菌属 物种组 比较基因组学 系统发育 毒力因子 |
| 学位专业 | 理学博士 |
| 中文摘要 | 链球菌属是厚壁菌门中物种最为丰富类群之一，包含着大量人畜共患的重要病原菌。链球菌常引发人和动物化脓性感染，造成极高的发病率和死亡率，严重影响着人类健康并带来巨大的农业经济损失。随着分类学的快速发展，链球菌属经历了大量的修订，并将该属中多数物种划分到不同物种组。然而，链球菌属的分类目前还未研究清楚，进化机制等研究还未有深入涉及。同时，关于物种组的认识仍停留在表型特征，它们的进化机制尚不清楚。另外，前期研究大多针对单种或几个种的比较基因组分析，缺乏基于属水平上的进化历史和毒性抗性研究。随着链球菌基因组数据不断涌现，将为链球菌进化机制探索和多样性研究提供新的见解，为链球菌遗传分子生物学及遗传进化的深入研究提供新的途径，并有助于链球菌引发疾病问题的深入思考。鉴于链球菌危害性和重要性，借助生物信息理论和方法认识链球菌属基因组进化和毒性抗性特征显得尤为重要。本论文运用生物信息相关方法，从基因组水平上，对链球菌基因组动态，群体遗传结构，系统发育关系，毒力因子分布和进化等方面展开分析，以其理解链球菌属基因组进化历史。主要研究结果如下： (1) 基因组动态模拟分析表明在链球菌属水平和物种组水平下的泛基因组，核心基因组及特有基因有相同变化趋势。属水平下，泛基因组变化趋势符合一个增长型复合函数： ；核心基因组变化趋势符合一个衰减指数函数： 。从理论上证实了目前链球菌属的泛基因组处于开放状态；同时也说明现在泛基因组大小是被低估了，随着新种的发现和越来越多的链球菌基因组被测序，还会挖掘出链球菌的新基因。核心基因组所对应的基因簇在整个同源簇占主要部分，其中检测到一些基因是链球菌属所特有，为其适应性进化提供线索。 (2) 鉴于基因组水平下的群体遗传结构分析，本论文认为链球菌属以2个谱系处理最为合适，能较好反映该属内群体间的自然关系。谱系1包括化脓组、牛组，变异组和唾液组；谱系2包括轻型组，咽峡炎组和未知组。链球菌属系统发育关系和群体遗传结构分析结果具有一致性，即来自同一物种组的不同物种均聚在一起，并且系统树有2大分支组成。由于水平基因转移影响，变异组中的链球菌形成2个分支。群体遗传结构中的杂交现象印证了系统发育研究中出现的复系。 (3) 在链球菌基因组依次扫描中，检测到大量毒力基因和组特异抗生素耐药基因。粘附因子、免疫逃逸因子和压力因子占较大比例；物种组间未发现明显的组特异毒力因子。pavA，srtA，slrA，plr/gapA，eno，htrA/degP，tig/ropA这些广泛分布的毒力因子相关基因的进化和物种组的进化保持一致。另外，抗生素耐药性基因识别过程中发现138株链球菌均含有基因bacA和pbp2x，大部分物种含有pmrA基因。在物种组水平，耐药基因分布具有一定特异性。变异组的所有菌株几乎均含有bcrA基因；化脓组的大部分菌株含有vanug基因。另外，通过病原宿主交互作用分析，发现链球菌GNO1基因突变株和URE1基因突变株类表型特征主要为毒性降低。该论文研究中，由表型特征所提出的物种组，通过基因组分析发现它们在链球菌进化过程中扮演重要角色。链球菌由于基因组较小并且整个属的泛基因组处于开放状态，一定程度上反映了链球菌存在频繁基因交流，这有利于它适应新宿主环境并快速定殖。另外，链球菌属基因组进化轨迹和各个物种组的进化轨迹是一致的。猪链球菌因种内表型差异性而未被划入现有物种组，通过链球菌属系统发育关系和群体遗传结构分析，表明猪链球菌是和咽峡炎组及轻型组来自同一个谱系。通过上述生物信息学分析，将有助于深入了解链球菌基因组的动态变化及其进化历史，并为预防和控制链球菌疫病提供理论依据，同时也为大规模病原菌基因组数据的分析方法提供借鉴。随着今后研究的深入，链球菌的进化历史将会更加清晰，能够不断为临床监控与防治提供一定理论依据。 |
| 英文摘要 | The genus Streptococcus is the most aboundant group in the phylum Firmicute, which composes diverse and significant zoonotic pathogens. They are responsible for serious infections to human and animals, and substantial economic losses to agriculture. Genus Streptococcus has gone through considerable taxonomic revision and the majority of streptococci were placed into “species groups” due to increasing improvements of systematic bacteriology. The taxonomy of Streptococcus is still not very clear, and its evolutionary mechanism is still not well resolved. Additionally, understanding of species groups remains on phenotypic traits and their evolutionary implications are not clear presently. Besides, previous studies mainly focused on comparative genomic analyses of a single species or several species, lacking of evolutionary process and virulence studies at genus level. As streptococcal genomes are increasingly sequenced and reported, which may provide new insights into Streptococcus genetic evolutionary and biodiversity researches, contributing to the deeply thought through Streptococcus diseases of human and animals. In view of threat and harm of Streptococcus to animal husbandry and public health, it is necessary to understand Streptococcus genome evolution and virulence and antiboitic resistance features. In this research, comparative genomic approaches were used to yield a better understanding of the evolution of Streptococcus through genome dynamics, population structure, phylogenies and virulence factor distribution of species groups. The major results were summarized as follows: (1) Genome dynamics analyses indicated that the changing trends of sizes of pan-genome, core genome and unique genes at the species group level were respectively consistent with the ones at the genus level. The change trend of pan-genome size meets a increasing compound fountion: ; the change trend of core genome size meets a decreasing fountion: . These analyses theoretically verified the open status of Streptococcus pan-genome. Also, those results illustrated that pan-genome was underestimated, new genes appears with more streptococcal strains sequenced and more species discovered. Core genome played an important part in homologous clusters; as well, Streptococcus-specific genes might provide clues for adaptative evolution. (2) Population structure inferenced from genomic data suggested that there were two distinct lineages within the genus, closing to the nature relationships of Streptococcus populations. One included Pyogenic, Bovis, Mutans and Salivarius groups; and the other included Mitis, Anginosus and Unknown groups. The phylogenetic dendrograms also revealed two main clades, which were in accordance with population structure analyses, and species within the same species group clustered together. Due to horizontal gene transfer, Mutans group had a split lineage and contained two clades. The polyphyly profiles also were evidenced by the hybridazation of population structure. (3) During the scanning of streptococcal genomes, an abundant of virulence factors and antibiotic resistence related genes were detected. Adhesin, immune evasion and stress protein virulence factors accounted for a large proportion; distribution of streptococcal virulence factors has no obvious patterns among the species groups. And evolution of some common virulence factors, e.g., pavA, srtA, slrA, plr/gapA, eno, htrA/degP, tig/ropA, was congruous with the evolution of species groups, according to phylogenetic inference. Additonally, all the strains had bacA and pbp2x gene, and most of the strains had pmrA gene. Streptococcal speices groups possess group-specific antibiotic resistance genes, almost all of strains of Mutans group have bcrA gene while most strains of Pyogenic group have vanug gene. And virulence of GNO1 mutant and URE1 mutant of Streptococcus was reduced obviouly, on the basis of analyses of pathogen host interaction In this study, the proposed streptococcal species groups were reasonable, which played significant roles in evolution from the viewpoints of comparative genomics. The small genome size and open pan-genome of Streptococcus imply frequently gene exchanges to benefit their novel habits and colonization. Evolution of genus Streptococcus is congruent with the individual evolutionary trajectories of different species groups. Evolutionary trajectories are congruent between genus Streptococcus and individuals of species groups. S. suis was unassigned for phenotypic difference, but it might originated from the same lineage with species of Anginosus group. The results and conclusions will help to understand of streptococcal genome dynamic change and its evolution process, also provide theoretical basis for the prevention and control of Streptococus disease. Furthermore, this study will provide useful data for analyzing large-scale genomes of pathgenic bacteria. With development of research, the evolution details of Streptococus will be clear and be benefit to clinical control and monitoring in the near future. |
| 语种 | 中文 |
| 学科主题 | 生态学 |
| 内容类型 | 学位论文 |
| 源URL | [http://ir.xjlas.org/handle/365004/14916]  |
| 专题 | 新疆生态与地理研究所_研究系统_空间对地观测与系统模拟研究室 |
| 作者单位 | 中科院新疆生态与地理研究所 |
| 推荐引用方式 GB/T 7714 | 高晓阳. 链球菌属基因组进化的生物信息学研究[D]. 北京. 中国科学院大学. 2015. |
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