SCIENCE

SRI International, an independent nonprofit research and development organization, today announced it has performed a series of important computational analyses that report the complete genome sequence of Francisella tularensis, a bacterium that causes tularemia, or "rabbit fever" in animals and humans. An article about the findings is published in the February 2005 issue of Nature Genetics and appeared online January 9, 2005. The research findings increase the understanding of how highly virulent human pathogens evolve and could expedite strategies to combat them. In addition, the study will specifically support work on improved countermeasures against tularemia. "Enzymes in metabolic pathways are the most frequent type of anti-microbial drug target. The first phase of our work involved predicting the metabolic pathways of Francisella," said Peter Karp, Ph.D., director of SRI International's Bioinformatics Research Group. "We found an unexpectedly high proportion of pathways that had been disrupted by pseudogenes, explaining the fastidious nutritional requirements of the bacterium. In the second pathway analysis, we identified 74 candidate genes that filled holes in the predicted pathways, thus increasing the completeness of the genome annotation." Pathway holes are biochemical steps in metabolic pathways for which no enzyme has been identified in the organism's genome. Classical genome analysis typically fails to identify the functions of up to half the genes in a bacterial genome. SRI's pathway hole filling algorithm, developed jointly by Drs. Peter Karp and Michelle Green of SRI, found high probability candidates for 74 of the 390 pathway holes in Francisella, and lower probability candidates for many others. The predicted metabolic pathways of Francisella, as well as its genome and predicted operons, are available through the FrantCyc database on the SRI Web site at URL BioCyc.org. The BioCyc database collection includes Pathway/Genome Databases for virtually all Category A, B, and C agents, including Bacillus anthracis (anthrax), Rickettsia prowazekii (typhus), and Vibrio cholerae (cholera). Each database includes the genome annotated with predicted metabolic pathways and operons of the organism. This collection constitutes a unique resource for biodefense research because of the important role of metabolic enzymes in drug discovery. SRI researchers collaborated with a large, interdisciplinary team on the Francisella tularensis project. The team included researchers from the Swedish Defense Research Agency, Umea, Sweden; the Defence Science and Technology Laboratory in Salisbury, U.K.; and the Lawrence Livermore National Laboratory in Livermore, Calif.