Comparative Genomics of Major Clonal Groups of a Lyme Disease Pathogen

莱姆病病原体主要克隆群的比较基因组学

基本信息

批准号：
7429047
负责人：
WEIGANG QIU
金额：
$ 11.4万
依托单位：
HUNTER COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7429047
关键词：
Affect Antigens Bacteria Bioinformatics Black-legged Tick Borrelia Borrelia burgdorferi Borrelia burgdorferi Group Case Study Centers for Disease Control and Prevention (U.S.)Characteristics Chromosome Mapping Chromosomes Code Collaborations Communities Complex DNA Sequence Data Deer Tick Depth Development Disease Elements Evolution Functional RNA Funding Gene Expression Regulation Gene Family Genes Genetic Genome Genomics Goals Homologous Gene Human Imagery Immunity Individual Infection Inflammatory Informatics Intergenic Sequence Internet Invasive Joints Lead Lipoproteins Lyme Disease Maps Molecular Mutation National Institute of Allergy and Infectious Disease Natural Selections Neuraxis North America Nucleotides Numbers Open Reading Frames Order Spirochaetales Outcome Pathogenesis Phenotype Phylogenetic Analysis Phylogeny Plasmids Population Prevalence Qualifying Range Rate Regulator Genes Relative (related person)Research Research Infrastructure Research Personnel Retrieval Score Sequence Alignment Single Nucleotide Polymorphism Sister Skin Specificity Staging Sum Surface Testing Ticks Tissues United States Variant Vector-transmitted infectious disease Vertebral column Vertebrates Virulence Width Work Yang base career college comparative design gene conservation genome sequencing geographic difference improved pathogen preference success therapeutic vaccine tool development

项目摘要

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.

描述（由申请人提供）：莱姆病是美国最流行且传播最快的媒介传播传染病。它由螺旋体细菌伯氏疏螺旋体引起，并由鹿蜱肩胛硬蜱传播。至少 15 个遗传上不同的莱姆病病原体克隆群正在美国东北部流行，每年报告的莱姆病病例中有超过 80% 都在该地区。这些克隆群体在野生动物患病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 2 年的项目，生产 17 种伯氏疏螺旋体分离株的全基因组序列，目的是确定环境侵袭性中克隆变异的遗传基础和人类毒力。在此，PI 提出一项研究，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 全基因组测序项目的目标。具体目标是：首先，我们将在系统发育框架中识别菌株特异性基因组变化。我们将鉴定并比对主要染色体、直系同源质粒和直系同源编码序列。我们将根据染色体DNA序列推断出基于基因组的系统发育学，以便将基因组内容、基因组组织和DNA序列方面的菌株差异映射到这些克隆群体进化多样化过程中的不同阶段。其次，我们将通过测试自然选择的影响来区分更重要（例如适应性）的基因组变化与较小（例如随机）的基因组变化。我们将通过其序列保守性来鉴定对基因调控重要的基因间序列，通过其相对于同义率的高非同义核苷酸取代率来鉴定对伯氏疏螺旋体适应至关重要的基因（例如，赋予逃避宿主免疫的表面脂蛋白），与通过比较最近分歧的姐妹克隆来确定初始适应性克隆分歧。第三，我们将开发和维护一个网站，以方便公众传播伯氏疏螺旋体比较基因组信息，例如高毒力克隆群特有的基因组变化。目前尚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。我们将比较高毒力菌株和低毒力菌株的基因组，以确定有助于致病性的基因。毒力相关的基因组元件是设计治疗方法和疫苗的主要目标。