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Comparative Pathogen Genomics Create Buzz at Genomes 2004

Hinxton, UK, April 16 (GenomeWeb News) - Same species, different genome: this is the surprising finding from analyses of closely related strains of bacteria, reported in several different presentations at this week's Genomes 2004 conference organized by the Institute for Genomic Research and the Wellcome Trust, and held here at the Wellcome Trust Genome Center.


"Comparative genomics is the news of the day-particularly [that] between closely related strains," said George Weinstock, of Baylor College of Medicine. "It's news to a lot of people that so much information is coming out of comparisons of such closely related strains."


Weinstock presented this afternoon in the circular Francis Crick auditorium on his multi-pronged comparison of Treponema pallidum strains. Among the numerous strains of the spirochete, he compared the subspecies pallidum, which causes human syphilis; the subspecies pertenue, which causes the non-venereal skin disease yaws; and T. paraluiscuniculi, a closely-related species that causes syphilis in rabbits. The subspecies pallidum and pertenue differed in four different genes, and a few hundred SNPs - out of 1.1 mb genomes - while T. paraluiscuniculi was missing several more genes found in the two strains of T. palladium. These genes were generally found within pathogenicity islands - discrete blocks within the genome that seem to be particularly suited to gene transfer between organisms.


Weinstock also discussed ongoing comparisons between T. palladium and T. denticola - a related oral spirochete that causes periodontal disease - which he and colleagues at TIGR have recently sequenced.


In another example of complex genomic comparisons, Siv Andersson, of UppsalaUniversityin Sweden, presented yesterday morning on a comparison of the newly completed genomes of Bortonella quintana and a closely related pathogen, Bortonella henselae. B. Quintana, a louse-borne pathogen, causes trench fever, an illness that gets its name from its prevalence among soldiers in World War I. B. henselae, which is carried by cats, causes "cat scratch fever," the symptoms of which include tumor-like skin lesions and liver and spleen tumors, and which is spread through feline-human contact. Both pathogens can cause serious disease in immuno-compromised patients such as those with HIV.


The relationship between the genomes of these two pathogens proved analogous to that between two other previously-sequenced pathogens: Rickettsia prowazekii, the louse-borne agent that causes typhus, and Rickettsia conorii, which causes Mediterranean fever, according to Andersson. Just as the genome of R. prowazekii appeared to be a subset of the R. conorii genome, the genes of B. Quintana made up a subset of the B. henselae genome - pointing to an evolutionary relationship between the two, she showed.


Another central theme of the conference was that of horizontal gene transfer between organisms, said Vivek Kapur, of the Universityof Minnesota, one of the conference organizers. "It is very gratifying to see that both the exception to this rule and this rule [are] being validated in many other organisms" in addition to the early examples of this phenomenon.


One presentation by Jorg Hacker of the Universityof Wurzburg, which focused on Escherichia coli comparative genomics, found abundant evidence of transfer of pathogenicity islands between strains of this species and numerous other pathogens. 


In another, Lisa Herron-Olsen, one of Kapur's graduate students at the Universityof Minnesota, compared 10 strains of bovine and human Staphylococcus aureus, including two strains she and colleagues sequenced: RF122, a strain associated with the skin condition bovine mastitis, and MSA553, an isolate that causes toxic shock syndrome in humans. Just as Weinstock found significant genomic differences in Treponema spirochetes that caused different diseases, Herron-Olsen found that the sequences of outer membrane protein genes in the bovine strains of S. aureus were significantly different thanthose in the human strains, and that the virulence genes, especially the pathogenicity islands and phages, also differed between bovine and human strains. Herron-Olsen concluded that Staph is a "plug-n-play" organism, in which certain genes for toxins, adherence factors, antibiotic resistance, altered regulation, and all-round general nuisance, can be "installed" and deleted as different strains adapt to their specific hosts.


Presentations like Herron-Olson's demonstrate the level of analysis that the next generation of genomic scientists, enabled with a growing toolkit of sequenced genomes, will be able to conduct. While this may be the year of multiple genome comparisons, chats with some of the 300 participants at this conference revealed that things will only get more complex. With the completed genome of the Falciparum plasmodium, the most virulent malaria parasite; a draft of Anopheles gambiae, the mosquito vector; and the completed human genome all available, researchers can now do a three-way host-vector-parasite genome comparison to gain better insights into the molecular mechanisms of the disease. In fact, some conference participants said they were already thinking about it. More straightforward comparative analyses involving bacterial pathogen genomes and those of their human hosts are already in the works.


Even with "simple" comparisons of newly sequenced genomes, many researchers will have their hands full.


"Every year, I think 'it has topped out and will start to get less interesting," said Weinstock. "But it's a very vital field. Every year I see new things."


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