Drifting to victory: resolving the paradox of M.tuberculosis evolution

 描述(申请人提供)：结核分枝杆菌(M.tb)每秒感染一个新的人类宿主。目前尚不清楚为什么结核分枝杆菌是如此成功的病原体，考虑到目前对结核分枝杆菌如何进化的理解，这是意想不到的。这项研究的长期目标是确定驱动微生物种群中致病性状出现和维持的生态和进化过程。这项建议的目的是了解重组和可变结核病传播对结核分枝杆菌进化的影响。中心假设是：结核分枝杆菌进化的明显矛盾特征是由于未被认识到的隐蔽重组和结核病传播的极端变异性的影响。提出这项研究的理由是重组和生殖动力在形成遗传多样性模式方面的核心作用。将使用两个特定的目标来验证这一假设：1)表征致病分枝杆菌之间的横向基因转移(LGT)；2)量化结核病传播的可变性，并测量其对结核分枝杆菌进化的影响。在目标1中，将从分枝杆菌自然种群的高分辨率基因组数据中推断重组模式；LGT将在实验系统中进一步表征。在目标2中，将分析来自具有良好特征的结核分枝杆菌元人群的基因组和流行病学数据，以寻找结核病传播中的变异性特征。还将为结核分枝杆菌种群确定最适合的种群遗传模型，并将这些模型的参数与从流行病学数据推断的基准值进行比较。尽管结核分枝杆菌的适应性明显受到限制，但结核病持续威胁全球健康这一未被探索的悖论得到了解决，拟议的项目为当前关于结核分枝杆菌进化的观点提供了一种创新的替代方案。这项研究将更深入地了解结核分枝杆菌是如何演变的，这是理解为什么这些人群具有如此高的复原力所必需的，并最终设计出更好的控制甚至根除结核病的战略。它还将开辟新的研究途径，以确定隐蔽重组和异质传播对其他细菌病原体进化的影响。

 DESCRIPTION (provided by applicant): Mycobacterium tuberculosis (M.tb) infects a new human host every second. It is not known why M.tb is such a successful pathogen, and it is unexpected given the current understanding of how M.tb evolves. The long-term goal of this research is to identify ecological and evolutionary processes driving emergence and maintenance of pathogenic traits in microbial populations. The objective of this proposal is to understand effects of recombination and variable TB transmission on evolution of M.tb. The central hypothesis is: apparently paradoxical features of M.tb evolution are due to the unrecognized influence of cryptic recombination and extreme variability of TB transmission. The rationale for the proposed research is the central role of recombination and reproductive dynamics in shaping patterns of genetic diversity. Two specific aims will be used to test this hypothesis: 1) Characterize lateral gene transfer (LGT) among pathogenic mycobacteria; and 2) Quantify TB transmission variability and measure its effects on M.tb evolution. In Aim 1, patterns of recombination will be inferred from high resolution genomic data in natural populations of mycobacteria; LGT will be further characterized in an experimental system. In Aim 2, genomic and epidemiological data from a well-characterized M.tb meta- population will be analyzed for signatures of variability in TB transmission. Best fit population genetic models will also be identified for M.tb populations, and parameters of these models compared with benchmark values inferred from epidemiological data. By tackling the unexplored paradox of TB's persistence as a threat to global health despite apparent limitations on M.tb adaptability, the proposed project offers an innovative alternative to current perspectives on M.tb evolution. This research will provide greater insight into how M.tb evolves, which is needed to understand why these populations are so resilient, and ultimately to design better strategies of controlling or even eradicating TB. It will also open new avenues of research to identify effects of cryptic re- combination and heterogeneous transmission on evolution of other bacterial pathogens.