病原性细菌的物种起源：遗传学基础和获取-适应模型

Bacteria were the earliest cellular life forms in the history of the earth and are ubiquitous in all kinds of natural settings. A minority of bacteria may cause infections in humans, posing enormous threats to the human health. How have pathogenic bacteria emerged? Elucidation of this issue will help develop new strategies for the control of bacterial infections. Many lines of evidence have indicated acquisition of laterally transferred DNA to be the starting event for the origin of new pathogenic bacterial species and the ensuing accumulation of nucleotide variations in the genome, relative to those of the assumed ancestor and close relatives, as well as genomic rearrangements in certain cases, to be the adaptive processes to make the bacteria increasingly fit to the new niche during their evolution. To look into the origin and evolution of pathogenic bacterial species, we proposed an evolutionary scenario, i.e., The Adopt-Adapt Model of bacterial speciation, in which “Adopt” indicates the acquisition of laterally transferred DNA as the starting event of bacterial divergence leading to the emergence of new bacterial species and “Adapt” indicates the adaptation processes of the bacteria by nucleotide amelioration and genomic rearrangement. We hypothesize that only one of the laterally acquired DNA segments, to be systematically identified in this project, should be the postulated speciating element at the “Adopt” stage. Using representative Salmonella lineages as research models, we shall profile the laterally acquired DNA segments in the genome, prioritize them in the order of their “ages” in the genome by methods that we have recently developed, such as CTAG degeneration pattern analysis, and then investigate their potential properties in association with pathogenicity and their possible roles in initiating the speciation process. For the ensuing adaptation stages, we hypothesize that the “Adapt” processes include two categories of evolutionary events: one is the amelioration of nucleotides towards fitter genomic sequences, which we will investigate by profiling highly conserved short sequences like the tetranucleotide CTAG and delineate their species-specific degeneration patterns among closely related Salmonella lineages, and the other is the rebalancing of the genome by rearrangement through homologous recombination, which we have observed in numerous cases but will for the first time test by experiments in this project to validate the long speculated relationship between bacterial genomic rearranging and rebalancing. This proposed research project may hopefully lead to new discoveries about how pathogenic bacterial species may arise and help develop novel strategies for the control of bacterial infections.

细菌是地球历史上最早出现的有细胞形态的生命形式，在自然界中广泛存在。其中，极少数可造成人类感染，是人类健康的重大威胁。致病菌是如何出现的？这个问题的阐明，有助于人类发展新的战略控制细菌感染。大量证据表明，新致病菌起源的始发事件可能是横向转移DNA的获取，接下去细菌会在漫长的适应进程中积累遗传改变而进化为新的物种。我们于是提出获取-适应模型，拟据此对致病菌物种的起源和进化加以探讨。我们假设，致病菌基因组上数目繁多的横向转移DNA片段当中，只有一个是导致其物种起源的关键分子事件（即获取），其后的基因组变化将助力其病原性的塑造（即适应）。我们拟以沙门菌为模型，对横向转移DNA片段按龄排序，鉴定出这一假定的关键分子；同时，基于核苷酸变异有适应意义的假设，从CTAG四碱基序列的变异着手加以探讨。此外，关于细菌基因组物理平衡重建的适应意义，我们有过大量的观察和报道，但将在本项目中首次对其加以实验验证。

本项目按计划完成，为验证本团队验证前所提出关于病原性细菌的物种起源假说，提供了进一步证据，使理论模型更趋完善。我们在对Salmonella bongori 进行全基因组分析发现，其基因组编码新的VI分泌系统，并表现出特殊的基因组序列退化模式，支持非致病性祖先菌可通过获得特别的致病因子而获得病原性。我们从基因组进化角度证明，S. bongori实际上包含多个自然物种。Salmonella的VI型分泌系统具有遗传多样性和独特进化特征，其在病原体和宿主互作过程中作用不同。沙门菌多重抗生药物耐药基因虽然表型相似但进化来源却可完全不同。我们进一步验证了基因组结构重排是细菌病原性进化的关键步骤。近期对副伤寒沙门菌的基因组重排现象分析，为验证细菌病原性进化的获取-适应假说提供了进一步证据。我们以大肠杆菌为对象做平行研究，以检验在沙门菌中的发现是否有普遍性，发现人肠道内大肠杆菌的遗传多样性与结直肠癌的发生密切相关，即大肠杆菌的遗传多样性低则易患结直肠癌。本项目期间，项目负责人出版了一部系统论述致病性细菌物种起源的英文专著，由英国剑桥学术出版发行。此类著述在细菌病原学、细菌种系学、分子进化学国际研究领域没有出现过，因此代表了本领域研究的一个节点，即致病性细菌是以自然物种为进化单位的种群，为病原微生物的出现、进化、控制措施的制定，提供了独特的信息。据此，我们还推断人肠道内的各类自然物种都有其特定功能，其协作和制衡对维护人类健康和抗御疾病的发生具有重要意义，同时从人类肠道菌群中分离到多株具有强力抗癌作用细菌。癌症患者经常有肠道菌群紊乱，我们通过木脂素调整肠道菌群结构，发现患者的癌症进展得到了有效的遏制。前期研究表明肠道菌群失调会导致宿主表观遗传改变（甲基化）并促进癌前病变的发生，我们发现KAZN的表达和甲基化模式与卵巢癌的发生密切相关，并在继续探讨KAZN甲基化与肠道菌群结构的关联。

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