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一种媒介传播的传染病，它是由一种螺旋体细菌伯氏疏螺旋体引起的，由鹿蜱传播。莱姆病病原体至少有15种遗传上不同的克隆群在美国东北部流行，每年报告的莱姆病病例超过80%。这些克隆群在野生动物流行率和人类致病性方面存在差异。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，对17株伯氏疏螺旋体分离株进行全基因组测序，目的是确定克隆变异在环境入侵性和人类毒性方面的遗传基础。在这里，PI提出了一项研究，通过对12个最常见的克隆群体进行比较基因组分析，来完成NIAID全基因组测序计划的目标。

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.