Evolutionary genomics and population genetics of pathogenic streptococci

描述(申请人提供)：链球菌属细菌包括一些最重要的人类病原体，可导致多种不同的疾病，并在世界各地造成显著的发病率和死亡率。我们的长期目标是彻底了解与链球菌属病原分类群内部和之间的适应性差异相关的分子特性。我们的中心假设是，在我们的进化分析中，许多基因座、基因座内的位置和非编码功能元件，在我们的进化分析中被鉴定为处于谱系特异性或正选择压力下，将是这些致病链球菌的定植、持久性、存活率和致病倾向的关键基因座。这一建议的具体目的可概括如下：1.生成和注释化脓组和变异组中9种链球菌的基因组序列数据，以使它们能够产生涉及重要人类病原体的各种姊妹组比较，并构建用于呈现数据和相关比较基因组分析的链球菌基因组浏览器。2.评估正选择和横向基因转移在不同链球菌群内物种基因组多样化中的作用。3.利用我们开发的新的基于群体遗传学的方法，以及作为本项目的一部分开发的其他方法，收集同一物种的菌株之间的物种特异性、推定毒力和核心基因的比较序列数据，以分析选择压力和人口历史。4.采用我们开发的新方法，以及作为本项目一部分开发的其他方法，对化脓性链球菌、变形链球菌和Mitis类群中的非编码功能元件进行了全面的调查。5.根据选择分析和非编码功能元件的鉴定结果，建立变形链球菌的基因敲除突变株和定点突变株，并分析其表型效应。由该项目产生的比较基因组学和分子适应方面的基本数据将作为开发针对链球菌致病物种的新的治疗和预防策略的框架。这些进化分析的结果将为未来的后续因果实验提供指导，而链球菌基因组浏览器将通过展示序列和功能之间相关性的体外和体内研究结果，为科学界提供宝贵的资源。 项目简介：这个项目将产生大量关于链球菌如何适应人类宿主的分子细节的基本信息。这些信息反过来将成为开发针对这些致病细菌的新的治疗和预防策略的宝贵资产。

DESCRIPTION (provided by applicant): The bacteria genus Streptococcus includes some of the most important human pathogens, causing a wide range of different disease, and inflicting significant morbidity and mortality throughout the world. Our long term goal is to reach a thorough understanding of the molecular specifics correlated with adaptive differences within and between the pathogenic taxa of the genus Streptococcus. Our central hypothesis is that many loci, sites within loci, and noncoding functional elements, identified as being under lineage specific, or positive selection pressure, in our evolutionary analyses, will be key loci involved in the colonization, persistence, survival, and propensity to cause disease in these pathogenic streptococci. The specific aims of this proposal can be summarized as follows: 1. Generate and annotate genome sequence data for 9 species of Streptococcus within the Pyogenes, and Mutans groups, chosen such that they will yield various sister group comparisons involving important human pathogens, and construct a Streptococcus Genome Browser for presentation of data and associated comparative genomic analyses. 2. Assess the role of positive selection and lateral gene transfer in the diversification of the genomes of the species within the different Streptococcus groups. 3. Collect comparative sequence data of species specific, putative virulence, and core genes, across strains of the same species, for the purpose of analyzing selection pressure and demographic history, employing new population genetic based methods developed by us, as well as additional methods developed as part of this project. 4. Employing new methods developed by us, as well as additional methods developed as part of this project, conduct a comprehensive survey of noncoding functional elements in the Streptococcus Pyogenes, Mutans, and Mitis groups. 5. Based on the results arising from the selection analyses, and identification of noncoding functional elements, create gene knockout and site specific mutants for S. mutans, and assay the phenotypic effects. The fundamental data on comparative genomics and molecular adaptation, arising from this project, will serve as a framework for the development of novel therapeutic and preventative strategies for pathogenic species of Streptococcus. The results from these evolutionary analyses will serve as a guide for future follow-up, cause- effect experimentation, and the Streptococcus Genome Browser will serve as a valuable resource to the scientific community by displaying results of in vitro and in vivo studies of associations between sequence and function. Project Narrative: This project will yield a great deal of fundamental information regarding the molecular details of how Streptococcus pathogens are adapted to their human hosts. This information will in turn be a valuable asset to the development of novel therapeutic and preventative strategies for these pathogenic bacteria.