Genetics

Edited by: Eugene Russo Reprinted with the permission of Nature and The Institute for Genomic Research Circular representation of the H. pylori chromosome. The outer concentric circle is the predicted coding region on the plus strnd; the second concentric circle is the predicted coding region on the minus strand. At the third and fourth concentric circles are insertion sequence (IS) elements (red) -- short DNA sequences in bacteria capable of transposing to a new genomic location -- and other repeats (green) on the plus and minus strands respectively. The fifth and sixth concentric circles are tRNAs (blue), rRNAs (red), and sRNAs (green) on plus and minus strands respectively. J.F. Tomb, O. White, A.R. Kerlavage, R.A. Clayton, G.G. Sutton, R.D. Fleischmann, K.A. Ketchum, H.P. Klenk, S. Gill, B.A. Dougherty, K. Nelson, J. Quackenbush, L.X. Zhou, E.F. Kirkness, S. Peterson, B. Loftus, D. Richardson, R. Dodson, H.G. Khalak, A. Glodek, K. McKenney, L.M. Fitzegerald, N. Lee, M.D. Adams, E.K. Hickey, D.E. Berg, J.D. Gocayne, T.R. Utterback, J.D. Peterson, J.M. Kelley, M.D. Cotton, J.M. Weldman, C. Fuji, C. Bowman, L. Watthey, E. Wallin, W.S. Hayes, J.M. Weidman, C. Fujii, M. Borodovsky, P.D. Karp, H.O. Smith, C.M. Fraser, J.C. Venter, "The complete genome sequence of the gastric pathogen Helicobacter pylori," Nature, 388:539-47, 1997. (Cited in more than 405 papers since publication) Comments by Jean-Francois Tomb, researcher, DuPont Research and Development, Wilmington, Del. Although many people still attribute the onset of ulcers to poor diet or stress, researchers have proven definitively that 90 percent of the painful stomach sores are actually caused by Helicobacter pylori, a bacterium that resides on the lining of the stomach. H. pylori also causes other gastric diseases and may have a role in some stomach cancers. Because H. pylori is such a prevalent cause of disease--an estimated 25 million Americans suffer from ulcers alone--scientists at The Institute for Genomic Research (TIGR) in Rockville, Md., set out to unlock its secrets by sequencing the H. pylori genome. "The decision was made because [we knew] the H. pylori genome ... would be of tremendous advantage to the research community," comments lead author Jean-Francois Tomb, who has moved from TIGR to DuPont CR&D Pharmaceuticals since the publication of this 1997 paper and has since focused on sequencing industrial microbes. TIGR has continued widespread whole genome sequencing efforts in the human and other organisms, efforts that began with Haemophilus influenzae, the first organism ever sequenced.1 Tomb suggests that his group's 1997 H. pylori paper helped to raise the level of genome interpretation. "If four years ago scientific journals would accept raw sequence and a little bit of information, that's not the case any more," says Tomb. "You've got to go in and dig more and show more value and comparative analysis." According to Tomb, these days researchers must not only identify the whole genome sequence; they must also include a thorough annotation done by a team that includes bioinformatics and genome analysis specialists. Genome Therapeutics of Waltham, Mass., had actually started to sequence H. pylori before TIGR. "There was an element of competitiveness there," says Tomb. But in the end TIGR finished ahead by a long shot. Genome Therapeutics retained its sequence even after TIGR published in order to publish a comparative analysis of two unrelated H. pylori isolates.2 Using the whole-genome shotgun random sequencing strategy, now standard, Tomb and his colleagues found that H. pylori's circular genome of 1,667,867 base pairs has well-developed systems for motility, for iron scavenging, and for DNA restriction and modification. The genome also revealed evidence of a complex interaction between host and pathogen based on the putative adhesins, lipoproteins, and other outer membrane proteins found. But, says Tomb, determining the complete genomic sequence is "only the beginning of a sustained effort to unravel the secrets of an organism." He emphasizes the difficulty of assigning gene function based solely on sequence information, a difficulty that necessitates a solid functional genomics program. Pharmaceutical companies have, though, already begun to use his team's findings and others' in attempts to devise plausible vaccines, drugs, and drug targets for H. pylori. "Within very short order ... vaccine companies can milk a lot of information," Tomb says of sequenced genomes. "Knowing the full gene complement of the genome, and knowing which gene is introduced under which condition ... in itself could lead to very rapid target identification and validation." R.D. Fleischmann et al., "Whole-genome random sequencing and assembly of haemophilus-influenzae," Science, 269:496-512, 1995. R.A. Alm et al., "Genomic-sequence comparison of two unrelated isolates of the human gastric pathogen Helicobacter pylori," Nature, 397:176-80, Jan. 14, 1999.

Genetics

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