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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Continuance Award (SC3)
Project #
5SC3GM083722-02
Application #
7597087
Study Section
Special Emphasis Panel (ZGM1-MBRS-8 (MV))
Program Officer
Rivera-Rentas, Alberto L
Project Start
2008-04-01
Project End
2012-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
2
Fiscal Year
2009
Total Cost
$114,000
Indirect Cost
Name
Hunter College
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
620127915
City
New York
State
NY
Country
United States
Zip Code
10065
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Schutzer, Steven E; Fraser-Liggett, Claire M; Qiu, Wei-Gang et al. (2012) Whole-genome sequences of Borrelia bissettii, Borrelia valaisiana, and Borrelia spielmanii. J Bacteriol 194:545-6
Casjens, Sherwood R; Mongodin, Emmanuel F; Qiu, Wei-Gang et al. (2012) Genome stability of Lyme disease spirochetes: comparative genomics of Borrelia burgdorferi plasmids. PLoS One 7:e33280
Casjens, Sherwood R; Mongodin, Emmanuel F; Qiu, Wei-Gang et al. (2011) Whole-genome sequences of two Borrelia afzelii and two Borrelia garinii Lyme disease agent isolates. J Bacteriol 193:6995-6
Xie, Xianfa; Qiu, Wei-Gang; Lipke, Peter N (2011) Accelerated and adaptive evolution of yeast sexual adhesins. Mol Biol Evol 28:3127-37
Casjens, Sherwood R; Fraser-Liggett, Claire M; Mongodin, Emmanuel F et al. (2011) Whole genome sequence of an unusual Borrelia burgdorferi sensu lato isolate. J Bacteriol 193:1489-90
Schutzer, Steven E; Fraser-Liggett, Claire M; Casjens, Sherwood R et al. (2011) Whole-genome sequences of thirteen isolates of Borrelia burgdorferi. J Bacteriol 193:1018-20
Chavadi, Sivagami Sundaram; Stirrett, Karen L; Edupuganti, Uthamaphani R et al. (2011) Mutational and phylogenetic analyses of the mycobacterial mbt gene cluster. J Bacteriol 193:5905-13
Haven, James; Vargas, Levy C; Mongodin, Emmanuel F et al. (2011) Pervasive recombination and sympatric genome diversification driven by frequency-dependent selection in Borrelia burgdorferi, the Lyme disease bacterium. Genetics 189:951-66
Wywial, Ewa; Haven, James; Casjens, Sherwood R et al. (2009) Fast, adaptive evolution at a bacterial host-resistance locus: the PFam54 gene array in Borrelia burgdorferi. Gene 445:26-37

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