Comparative Genomics of Major Clonal Groups of a Lyme Disease Pathogen

描述（由申请人提供）：莱姆病是美国最流行和传播最快的病媒传染病，由螺旋体细菌伯氏疏螺旋体引起，并由鹿蜱肩突硬蜱传播。至少有15个遗传上不同的莱姆病病原体克隆群在美国东北部流行，那里每年报告的莱姆病病例超过80%。这些克隆群体在野生动物流行率和人类致病性方面有所不同。2006年，包括PI在内的六名研究人员发起了一项由NIH/NIAID资助的为期两年的项目，生产17个B的全基因组序列。分离物，目的是确定环境入侵性和人类毒力的克隆变异的遗传基础。在这里，PI提出了一项研究，通过对12个最常见的克隆组进行比较基因组分析，完成NIAID全基因组测序项目的目标。 具体目标是：首先，我们将确定菌株特异性基因组的变化，在系统发育框架。我们将鉴定和比对主要染色体、正向同源质粒和正向同源编码序列。我们将推断基于染色体DNA序列的基因组为基础的同源性，使菌株的基因组内容，基因组组织和DNA序列的差异，可以映射到不同的阶段，这些克隆群体的进化多样化。其次，我们将区分更重要的（例如，适应性的）基因组变化从较小的（例如，随机的）通过测试自然选择的影响。我们将通过序列保守性来鉴定对基因调控重要的基因间序列，即对B至关重要的基因。Burgdorferi适应（例如，赋予逃避宿主免疫的表面脂蛋白），通过比较最近分化的姐妹克隆，发现与初始适应性克隆分化相关的基因。第三，我们会发展和维持一个网站，方便公众发布B。burgdorferi比较基因组信息，如高毒力克隆群特异性的基因组变化。目前还不清楚为什么莱姆病细菌的某些菌株比其他菌株更具致病性。我们将比较高毒力和低毒力菌株的基因组，以确定致病性的基因。与病毒相关的基因组元件是设计治疗剂和疫苗的主要目标。

DESCRIPTION (provided by applicant): Lyme disease is the most prevalent and a fast spreading vector-borne infectious disease in the U.S. It is caused by a spirochetal bacterium Borrelia burgdorferi and transmitted by the deer tick Ixodes scapularis. At least 15 genetically distinct clonal groups of the Lyme disease pathogen are circulating in the northeastern U.S., where over 80% of the Lyme disease cases are reported annually. These clonal groups differ in their wildlife prevalence and human pathogenecity. In 2006, a group of six investigators including the PI have initiated a NIH/NIAID-funded 2-year project producing the whole-genome sequences of 17 B. burgdorferi isolates, with the goal of identifying the genetic basis of clone variations in environmental invasiveness and human virulence. Here, the PI proposes a study to complete the goal of the NIAID whole-genome sequencing project by performing the comparative genome analysis of 12 most common clonal groups. Specific aims are: First, we will identify strain-specific genome changes in a phylogenetic framework. We will identify and align the main chromosomes, orthologous plasmids, and orthologous coding sequences. We will infer a genome-based phylogeny based on chromosomal DNA sequences, so that the strain differences in genome content, genome organization, and DNA sequences can be mapped to different stages during the evolutionary diversification of these clonal groups. Second, we will distinguish more consequential (e.g., adaptive) genomic changes from the lesser (e.g., random) ones by testing for the influence of natural selection. We will identify intergenic sequences important for gene regulation by their sequence conservation, genes critical for B. burgdorferi adaptation (e.g., surface lipoproteins conferring escape from host immunity) by their high non-synonymous nucleotide substitution rates relative to the synonymous rates, genes associated with initial adaptive clonal divergence by comparing the most recently diverged sister clones. Third, we will develop and maintain a website to facilitate the public dissemination of B. burgdorferi comparative genome information, such as genomic changes specific to a high-virulence clonal group. It is unknown why some strains of the Lyme disease bacteria are more pathogenic than others. We will compare the genomes of high- and low-virulence strains to identify the genes contributing to pathogenecity. Virulence-related genome elements are prime targets for designing therapeutics and vaccines.