Pathogenomics: Focusing studies of bacterial pathogenicity through evolutionary analysis of genomes.
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Pathogenomics: Focusing studiesof bacterial pathogenicity through evolutionary analysis of genomes
Pathogenomics
Goal:
Identify previously unrecognized mechanisms of microbial pathogenicity using a unique combination of informatics, evolutionary biology, microbiology and genetics.
Explosion of data
23 of the 37 publicly available microbial genome sequences are for bacterial pathogens
Approximately 21,000 pathogen genes with no known function!
>95 bacterial pathogen genome projects in progress …
The need for new tools
Prioritize new genes for further laboratory study
Capitalize on the existing genomic data
Bacterial Pathogenicity
Processes of microbial pathogenicity at the molecular level are still minimally understood
Pathogen proteins identified that manipulate host cells by interacting with, or mimicking, host proteins
Approach
Idea: Could we identify novel virulence factors by identifying pathogen genes more similar to host genes than you would expect based on phylogeny?
Prioritize for biological study. - Previously studied in the laboratory? - Can UBC microbiologists study it? - C. elegans homolog?
Search pathogen genes against databases. Identify those with eukaryotic similarity.
Evolutionary significance. - Horizontal transfer? Similar by chance?
Modify screening method /algorithm
Approach
Pathogens
Chlamydophila psittaci Respiratory disease, primarily in birdsMycoplasma mycoides Contagious bovine pleuropneumoniaMycoplasma hyopneumoniae Pneumonia in pigsPasteurella haemolytica Cattle shipping feverPasteurella multicoda Cattle septicemia, pig rhinitisRalstonia solanacearum Plant bacterial wiltXanthomonas citri Citrus cankerXylella fastidiosa Pierce’s Disease - grapevines
Bacterial wilt
World Research Community
ApproachPrioritized candidates
Study function of homolog in model host (C. elegans)
Study function of gene in bacterium.
Infection of mutant in model host
C. elegansDATABASE
Collaborations with others
• Fundamental research
• Interdisciplinary
• Major potential impact
• Lack of fit with alternative funding sources
Peter Wall Major Thematic Grant
Database front end
Haemophilus influenzae Rd-KW20 proteins most strongly matching eukaryotic proteins
PhyloBLAST – a tool for analysis Brinkman et al. Bioinformatics. Accepted
Eukaryote Bacteria Horizontal Transfer?
0.1Rat
Human
Escherichia coli
Caenorhabditis elegans
Pig roundworm
Methanococcus jannaschii
Methanobacterium thermoautotrophicum
Bacillus subtilis
Streptococcus pyogenes
Aquifex aeolicus
Acinetobacter calcoaceticus
Haemophilus influenzae
Chlorobium vibrioforme
E. coli Guanosine monophosphate reductase 81% similar to corresponding enzyme in humans and rats
Role in virulence not yet investigated.
Variance of the Mean %G+C for all Genes in a Genome: Correlation with bacteria’s clonal nature
nonclonal clonal
Variance of the Mean %G+C for all Genes in a Genome
Is this a measure of clonality of a bacterium?
Are intracellular bacteria more clonal because they are ecologically isolated from other bacteria?
Pathogenomics Project: Future Developments
• Identify eukaryotic motifs and domains in pathogen genes
• Identify further motifs associated with• Pathogenicity islands• Virulence determinants
• Functional tests for new predicted virulence factors
• Peter Wall Institute for Advanced Studies
• Pathogenomics group Ann M. Rose, Yossef Av-Gay, David L. Baillie, Fiona S. L.
Brinkman, Robert Brunham, Stefanie Butland, Rachel C. Fernandez, B. Brett Finlay, Hans Greberg, Robert E.W. Hancock, Steven J. Jones, Patrick Keeling, Audrey de Koning, Don G. Moerman, Sarah P. Otto, B. Francis Ouellette, Ivan Wan.
www.pathogenomics.bc.ca
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