Evolutionary genomics and population genetics of pathogenic streptococci

致病性链球菌的进化基因组学和群体遗传学

• 批准号: 7525939
• 负责人: Michael J Stanhope
• 金额: $ 46.5万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7525939
• 关键词: Address; Architecture; Bacteria; Bacterial Genome; Biological; Biological Assay; Biological Sciences; Biology; Bos taurus; Categories; Cattle; Characteristics; Class; Classification; Code; Collection; Communities; Comparative Study; Computing Methodologies; Condition; DNA; DNA Sequence; Data; Dental caries; Development; Disease; Economic Burden; Elements; Eukaryota; Eukaryotic Cell; Evolution; Exhibits; Future; Gene Transfer; Generations; Genes; Genetic Recombination; Genome; Genome Components; Genomics; Goals; Grouping; Horizontal Gene Transfer; Human; Human Genome; In Vitro; Indium; Lateral; Link; Methods; Microarray Analysis; Molecular; Molecular Evolution; Morbidity - disease rate; Numbers; Oral; Organism; Orthologous Gene; Pathogenesis; Pattern; Phenotype; Phylogenetic Analysis; Play; Population Genetics; Procedures; Process; Proteins; Purpose; RNA; Range; Recording of previous events; Regulatory Element; Research; Resources; Role; Sister; Site; Source Code; Streptococcus; Streptococcus Group B; Streptococcus mutans; Streptococcus pneumoniae; Streptococcus pyogenes; Structure; Surveys; System; Taxon; Technology; Time; Virulence; Work; base; comparative; comparison group; concept; design; disease characteristic; experience; falls; follow-up; genome sequencing; improved; in vivo; innovation; knockout gene; member; microbial genome; mortality; mutant; novel therapeutics; pathogen; pathogenic bacteria; pressure; research study; tool

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.

描述（由申请人提供）：链球菌属细菌包括一些最重要的人类病原体，引起广泛的不同疾病，并在全世界造成显著的发病率和死亡率。我们的长期目标是达到一个彻底的了解与适应性差异的分子特异性内和之间的致病菌群的链球菌。我们的中心假设是，许多基因座，位点内的位点，和非编码功能元件，被确定为在谱系特异性，或积极的选择压力，在我们的进化分析，将是关键的基因座参与的殖民化，持久性，生存，并在这些致病性链球菌引起疾病的倾向。本提案的具体目标可概括如下：1.生成和注释化脓性链球菌和变形链球菌组内9种链球菌的基因组序列数据，选择这些数据以产生涉及重要人类病原体的各种姐妹组比较，并构建链球菌基因组浏览器以呈现数据和相关的比较基因组分析。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.收集物种特异性、推定毒力和核心基因的比较序列数据，跨同一物种的菌株，用于分析选择压力和人口统计学历史，采用我们开发的基于种群遗传的新方法，以及作为本项目一部分开发的其他方法。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、变形链球菌和缓和链球菌群中的非编码功能元件进行全面调查。5.根据选择分析的结果，并对非编码功能元件进行鉴定，建立了基因敲除和位点特异突变体。变异株，并测定表型效应。从这个项目中产生的比较基因组学和分子适应的基本数据，将作为一个框架，为致病性链球菌种的新的治疗和预防策略的发展。来自这些进化分析的结果将作为未来后续、因果实验的指导，链球菌基因组浏览器将通过显示序列和功能之间关联的体外和体内研究结果而作为科学界的宝贵资源。 项目叙述：该项目将产生大量关于链球菌病原体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菌的新型治疗和预防策略的宝贵资产。