Using the Genome to Understand Pathogenicity

  • Dawn Field
  • Jennifer Hughes
  • E. Richard Moxon
Part of the Methods in Molecular Biology™ book series (MIMB, volume 266)


Genome sequencing, the determination of the complete complement of DNA in an organism, is revolutionizing all aspects of the biological sciences. Genome sequences make available for scientific scrutiny the complete genetic capacity of an organism. With respect to microbes, this means we now have the unprecedented opportunity to investigate the molecular basis of commensal and virulence behavior. We now have genome sequences for a wide range of bacterial pathogens (obligate, facultative, and opportunistic); this has facilitated the discovery of many previously unidentified determinants of pathogenicity and has provided novel insights into what creates a pathogen. In-depth analyses of bacterial genomes are also providing new perspectives on bacterial physiology, molecular adaptation to a preferred niche, and genomic susceptibility to the uptake of foreign DNA, three key factors that can play a significant role in determining whether a species, or a strain, will have pathogenic potential.

Key Words

Genome pathogenicity comparative genomics virulence determinants orphan genes physiology ecological niche adaptation horizontal gene transfer bacterial evolution 


  1. 1.
    Wassenaar, T. M. and Gaastra, W. (2001) Bacterial virulence: can we draw the line? FEMS Microbiol. Lett. 201, 1–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Moxon, R. and Tang, C. (2000) Challenge of investigating biologically relevant functions of virulence factors in bacterial pathogens. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 355, 643–656.PubMedCrossRefGoogle Scholar
  3. 3.
    Groisman, E. A. and Ochman, H. (1997) How Salmonella became a pathogen. Trends Microbiol. 5, 343–349.PubMedCrossRefGoogle Scholar
  4. 4.
    Groisman, E. A. and Ochman, H. (1994) How to become a pathogen. Trends Microbiol. 2, 289–294.PubMedCrossRefGoogle Scholar
  5. 5.
    Fleischmann, R. D., Adams, M. D., White, O., Clayton, R. A., Kirkness, E. F., Kerlavage, A. R., et al. (1995) Whole-genome random sequencing and assembly of Haemophilus influenzae Rd. Science 269, 496–512.PubMedCrossRefGoogle Scholar
  6. 6.
    Fraser, C. M., Norris, S. J., Weinstock, G. M., White, O., Sutton, G. G., Dodson, R., et al. (1998) Complete genome sequence of Treponema pallidum, the syphilis spirochete. Science 281, 375–388.PubMedCrossRefGoogle Scholar
  7. 7.
    Nowak, R. (1995) Bacterial genome sequence bagged. Science 269, 468–470.PubMedCrossRefGoogle Scholar
  8. 8.
    Bentley, S. D., Chater, K. F., Cerdeno-Tarraga, A. M., Challis, G. L., Thomson, N. R., James, K. D., et al. (2002) Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2). Nature 417, 141–147.PubMedCrossRefGoogle Scholar
  9. 9.
    Goffeau, A., Barrell, B. G., Bussey, H., Davis, R. W., Dujon, B., Feldmann, H., et al. (1996) Life with 6000 genes. Science 546, 63–67.Google Scholar
  10. 10.
    Bernal, A., Ear, U., and Kyrpides, N. (2001) Genomes OnLine Database (GOLD): a monitor of genome projects world-wide. Nucleic Acids Res. 29, 126–127.PubMedCrossRefGoogle Scholar
  11. 11.
    Cole, S. T., Eiglmeier, K., Parkhill, J., James, K. D., Thomson, N. R., Wheeler, P. R., et al. (2001) Massive gene decay in the leprosy bacillus. Nature 409, 1007–1011.PubMedCrossRefGoogle Scholar
  12. 12.
    Read, T. D., Brunham, R. C., Shen, C., Gill, S. R., Heidelberg, J. F., White, O., et al. (2000) Genome sequences of Chlamydia trachomatis MoPn and Chlamydia pneumoniae AR39. Nucleic Acids Res. 28, 1397–1406.PubMedCrossRefGoogle Scholar
  13. 13.
    Chambaud, I., Heilig, R., Ferris, S., Barbe, V., Samson, D., Galisson, F., et al. (2001) The complete genome sequence of the murine respiratory pathogen Mycoplasma pulmonis. Nucleic Acids Res. 29, 2145–2153.PubMedCrossRefGoogle Scholar
  14. 14.
    McClelland, M., Sanderson, K. E., Spieth, J., Clifton, S. W., Latreille, P., Courtney, L., et al. (2001) Complete genome sequence of Salmonella enterica serovar Typhimurium LT2. Nature 413, 852–856.PubMedCrossRefGoogle Scholar
  15. 15.
    Field, D., Hood, D., and Moxon, R. (1999) Contribution of genomics to bacterial pathogenesis. Curr. Opin. Genet. Dev. 9, 700–703.PubMedCrossRefGoogle Scholar
  16. 16.
    Kalman, S., Mitchell, W., Marathe, R., Lammel, C., Fan, J., Hyman, R. W., et al. (1999) Comparative genomes of Chlamydia pneumoniae and C. trachomatis. Nat. Genet. 21, 385–389.PubMedCrossRefGoogle Scholar
  17. 17.
    Blattner, F. R., Plunkett, G., 3rd, Bloch, C. A., Perna, N. T., Burland, V., Riley, M., et al. (1997) The complete genome sequence of Escherichia coli K-12. Science 277, 1453–1474.PubMedCrossRefGoogle Scholar
  18. 18.
    Perna, N. T., Plunkett, G., 3rd, Burland, V., Mau, B., Glasner, J. D., Rose, D. J., et al. (2001) Genome sequence of enterohaemorrhagic Escherichia coli O157:H7. Nature 409, 529–533.PubMedCrossRefGoogle Scholar
  19. 19.
    Hayashi, T., Makino, K., Ohnishi, M., Kurokawa, K., Ishii, K., Yokoyama, K., et al. (2001) Complete genome sequence of enterohemorrhagic Escherichia coli O157:H7 and genomic comparison with a laboratory strain K-12. DNA Res. 8, 11–22.PubMedCrossRefGoogle Scholar
  20. 20.
    Moxon, R. and Rappuoli, R. (2002) Bacterial pathogen genomics and vaccines. Br. Med. Bull. 62, 45–58.PubMedCrossRefGoogle Scholar
  21. 21.
    Pizza, M., Scarlato, V., Masignani, V., Giuliani, M. M., Arico, B., Comanducci, M., et al. (2000) Identification of vaccine candidates against serogroup B meningococcus by whole-genome sequencing. Science 287, 1816–1820.PubMedCrossRefGoogle Scholar
  22. 22.
    Tettelin, H., Saunders, N. J., Heidelberg, J., Jeffries, A. C., Nelson, K. E., Eisen, J. A., et al. (2000) Complete genome sequence of Neisseria meningitidis serogroup B strain MC58. Science 287, 1809–1815.PubMedCrossRefGoogle Scholar
  23. 23.
    Fraser, C. M., Gocayne, J. D., White, O., Adams, M. D., Clayton, R. A., Fleischmann, R. D., et al. (1995) The minimal gene complement of Mycoplasma genitalium. Science 270, 397–403.PubMedCrossRefGoogle Scholar
  24. 24.
    Hutchison, C. A., Peterson, S. N., Gill, S. R., Cline, R. T., White, O., Fraser, C. M., et al. (1999) Global transposon mutagenesis and a minimal Mycoplasma genome. Science 286, 2165–2169.PubMedCrossRefGoogle Scholar
  25. 25.
    Fleischmann, R. D., Alland, D., Eisen, J. A., Carpenter, L., White, O., Peterson, J., et al. (2002) Whole-genome comparison of Mycobacterium tuberculosis clinical and laboratory strains. J. Bact. 184, 5479–5490.PubMedCrossRefGoogle Scholar
  26. 26.
    Joyce, E. A., Chan, K., Salama, N. R., and Falkow, S. (2002) Redefining bacterial populations: a post-genomic reformation. Nat. Rev. Genet. 3, 462–473.PubMedGoogle Scholar
  27. 27.
    Heidelberg, J. F., Eisen, J. A., Nelson, W. C., Clayton, R. A., Gwinn, M. L., Dodson, R. J., et al. (2000) DNA sequence of both chromosomes of the cholera pathogen Vibrio cholerae. Nature 406, 477–483.PubMedCrossRefGoogle Scholar
  28. 28.
    Lan, R. and Reeves, P. R. (2000) Intraspecies variation in bacterial genomes: the need for a species genome concept. Trends Microbiol. 8, 396–401.PubMedCrossRefGoogle Scholar
  29. 29.
    Lan, R. and Reeves, P. R. (2001) When does a clone deserve a name? A perspective on bacterial species based on population genetics. Trends Microbiol. 9, 419–424.PubMedCrossRefGoogle Scholar
  30. 30.
    Miller, W. (2001) Comparison of genomic DNA sequences: solved and unsolved problems. Bioinformatics 17, 391–397.PubMedCrossRefGoogle Scholar
  31. 31.
    Overbeek, R., Fonstein, M., D’Souza, M., Pusch, G. D., and Maltsev, N. (1999) The use of gene clusters to infer functional coupling. Proc. Natl. Acad. Sci. USA 96, 2896–2901.PubMedCrossRefGoogle Scholar
  32. 32.
    Stover, C. K., Pham, X. Q., Erwin, A. L., Mizoguchi, S. D., Warrener, P., Hickey, M. J., et al. (2000) Complete genome sequence of Pseudomonas aeruginosa PA01, an opportunistic pathogen. Nature 406, 959–964.PubMedCrossRefGoogle Scholar
  33. 33.
    Bayliss, C. D., Field, D., and Moxon, E. R. (2001) The simple sequence contingency loci of Haemophilus influenzae and Neisseria meningitidis. J. Clin. Invest. 107, 657–662.PubMedCrossRefGoogle Scholar
  34. 34.
    Schilling, C. H., Covert, M. W., Famili, I., Church, G. M., Edwards, J. S., and Palsson, B. O. (2002) Genome-scale metabolic model of Helicobacter pylori 26695. J. Bacteriol. 184, 4582–4593.PubMedCrossRefGoogle Scholar
  35. 35.
    Edwards, J. S. and Palsson, B. O. (2000) The Escherichia coli MG1655 in silico metabolic genotype: its definition, characteristics, and capabilities. Proc. Natl. Acad. Sci. USA 97, 5528–5533.PubMedCrossRefGoogle Scholar
  36. 36.
    Oliver, S. G. (1996) From DNA sequence to biological function. Nature 379, 597–600.PubMedCrossRefGoogle Scholar
  37. 37.
    Fischer, D. and Eisenberg, D. (1999) Finding families for genomic ORFans. Bioinformatics 15, 759–762.PubMedCrossRefGoogle Scholar
  38. 38.
    Doolittle, R. F. (2002) Biodiversity: microbial genomes multiply. Nature 416, 697–700.PubMedCrossRefGoogle Scholar
  39. 39.
    Salama, N., Guillemin, K., McDaniel, T. K., Sherlock, G., Tompkins, L., and Falkow, S. (2000) A whole-genome microarray reveals genetic diversity among Helicobacter pylori strains. Proc. Natl. Acad. Sci. USA 97, 14,668–14,673.PubMedCrossRefGoogle Scholar
  40. 40.
    Huynen, M. A., Diaz-Lazcoz, Y., and Bork, P. (1997) Differential genome display. Trends Genet. 13, 389–390.PubMedCrossRefGoogle Scholar
  41. 41.
    Casjens, S. (1998) The diverse and dynamic structure of bacterial genomes. Annu. Rev. Genet. 32, 339–377.PubMedCrossRefGoogle Scholar
  42. 42.
    Tamas, I., Klasson, L. M., Sandstrom, J. P., and Andersson, S. G. (2001) Mutualists and parasites: how to paint yourself into a (metabolic) corner. FEBS Lett. 498, 135–139.PubMedCrossRefGoogle Scholar
  43. 43.
    Andersson, J. O. and Andersson, S. G. (1999) Insights into the evolutionary process of genome degradation. Curr. Opin. Genet. Dev. 9, 664–671.PubMedCrossRefGoogle Scholar
  44. 44.
    Andersson, S. G., Zomorodipour, A., Andersson, J. O., Sicheritz-Ponten, T., Alsmark, U. C., Podowski, R. M., et al. (1998) The genome sequence of Rickettsia prowazekii and the origin of mitochondria. Nature 396, 133–140.PubMedCrossRefGoogle Scholar
  45. 45.
    Ochman, H., Lawrence, J. G., and Groisman, E. A. (2000) Lateral gene transfer and the nature of bacterial innovation. Nature 405, 299–304.PubMedCrossRefGoogle Scholar
  46. 46.
    Eisen, J. A. (2000) Horizontal gene transfer among microbial genomes: new insights from complete genome analysis. Curr. Opin. Genet. Dev. 10, 606–611.PubMedCrossRefGoogle Scholar
  47. 47.
    Nelson, K. E., Clayton, R. A., Gill, S. R., Gwinn, M. L., Dodson, R. J., Haft, D. H., et al. (1999) Evidence for lateral gene transfer between Archaea and bacteria from genome sequence of Thermotoga maritime. Nature 399, 323–329.PubMedCrossRefGoogle Scholar
  48. 48.
    Smoot, J. C., Barbian, K. D., Van Gompel, J. J., Smoot, L. M., Chaussee, M. S., Sylva, G. L., et al. (2002) Genome sequence and comparative microarray analysis of serotype M18 group A Streptococcus strains associated with acute rheumatic fever outbreaks. Proc. Natl. Acad. Sci. USA 99, 4668–4673.PubMedCrossRefGoogle Scholar
  49. 49.
    Knapp, S., Hacker, J., Jarchau, T., and Goebel, W. (1986) Large, unstable inserts in the chromosome affect virulence properties of uropathogenic Escherichia coli O6 strain 536. J. Bacteriol. 168, 22–30.PubMedGoogle Scholar
  50. 50.
    Finlay, B. B. and Falkow, S. (1997) Common themes in microbial pathogenicity revisited. Microbiol. Mol. Biol. Rev. 61, 136–169.PubMedGoogle Scholar
  51. 51.
    Graham, D. E., Overbeek, R., Olsen, G. J., and Woese, C. R. (2000) An archaeal genomic signature. Proc. Natl. Acad. Sci. USA 97, 3304–3308.PubMedCrossRefGoogle Scholar
  52. 52.
    Weinstock, G. M. (2000) Genomics and bacterial pathogenesis. Emerg. Infect. Dis. 6, 496–504.PubMedCrossRefGoogle Scholar
  53. 53.
    Chizhikov, V., Rasooly, A., Chumakov, K., and Levy, D. D. (2001) Microarray analysis of microbial virulence factors. Appl. Environ. Microbiol. 67, 3258–3263.PubMedCrossRefGoogle Scholar
  54. 54.
    Mitchell, T. J. (1998) Molecular basis of virulence. Arch. Dis. Child. 78, 197–199; discussion 99–200.PubMedCrossRefGoogle Scholar
  55. 55.
    Fraser, C. M., Casjens, S., Huang, W. M., Sutton, G. G., Clayton, R., Lathigra, R., et al. (1997) Genomic sequence of a Lyme disease spirochaete, Borrelia burgdorferi. Nature 390, 580–586.PubMedCrossRefGoogle Scholar
  56. 56.
    Cole, S. T., Brosch, R., Parkhill, J., Garnier, T., Churcher, C., Harris, D., et al. (1998) Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393, 537–544.PubMedCrossRefGoogle Scholar
  57. 57.
    Wizemann, T. M., Heinrichs, J. H., Adamou, J. E., Erwin, A. L., Kunsch, C., Choi, G. H., et al. (2001) Use of a whole genome approach to identify vaccine molecules affording protection against Streptococcus pneumoniae infection. Infect. Immun. 69, 1593–1598.PubMedCrossRefGoogle Scholar
  58. 58.
    De Bolle, X., Bayliss, C. D., Field, D., van de Ven, T., Saunders, N. J., Hood, D. W., et al. (2000) The length of a tetranucleotide repeat tract in Haemophilus influenzae determines the phase variation rate of a gene with homology to type III DNA methyltransferases. Mol. Microbiol. 35, 211–222.PubMedCrossRefGoogle Scholar
  59. 59.
    Moxon, E. R., Rainey, P. B., Nowak, M. A., and Lenski, R. E. (1994) Adaptive evolution of highly mutable loci in pathogenic bacteria. Curr. Biol. 4, 24–33.PubMedCrossRefGoogle Scholar
  60. 60.
    Hood, D. W., Deadman, M. E., Jennings, M. P., Bisercic, M., Fleischmann, R. D., Venter, J. C., et al. (1996) DNA repeats identify novel virulence genes in Haemophilus influenzae. Proc. Natl. Acad. Sci. USA 93, 11,121–11,125.PubMedCrossRefGoogle Scholar
  61. 61.
    Weiser, J. N. (2000) The generation of diversity by Haemophilus influenzae. Trends Microbiol. 8, 433–435.PubMedCrossRefGoogle Scholar
  62. 62.
    Tomb, J. F., White, O., Kerlavage, A. R., Clayton, R. A., Sutton, G. G., Fleischmann, R. D., et al. (1997) The complete genome sequence of the gastric pathogen Helicobacter pylori. Nature 388, 539–547.PubMedCrossRefGoogle Scholar
  63. 63.
    Parkhill, J., Wren, B. W., Mungall, K., Ketley, J. M., Churcher, C., Basham, D., et al. (2000) The genome sequence of the food-borne pathogen Campylobacter jejuni reveals hypervariable sequences. Nature 403, 665–668.PubMedCrossRefGoogle Scholar
  64. 64.
    Parkhill, J., Achtman, M., James, K. D., Bentley, S. D., Churcher, C., Klee, S. R., et al. (2000) Complete DNA sequence of a serogroup A strain of Neisseria meningitidis Z2491. Nature 404, 502–506.PubMedCrossRefGoogle Scholar
  65. 65.
    Tettelin, H., Nelson, K. E., Paulsen, I. T., Eisen, J. A., Read, T. D., Peterson, S., et al. (2001) Complete genome sequence of a virulent isolate of Streptococcus pneumoniae. Science 293, 498–506.PubMedCrossRefGoogle Scholar
  66. 66.
    Dziejman, M., Balon, E., Boyd, D., Fraser, C. M., Heidelberg, J. F., and Mekalanos, J. J. (2002) Comparative genomic analysis of Vibrio cholerae: genes that correlate with cholera endemic and pandemic disease. Proc. Natl. Acad. Sci. USA 99, 1556–1561.PubMedCrossRefGoogle Scholar
  67. 67.
    Dorrell, N., Mangan, J. A., Laing, K. G., Hinds, J., Linton, D., Al-Ghusein, H., et al. (2001) Whole genome comparison of Campylobacter jejuni human isolates using a low-cost microarray reveals extensive genetic diversity. Genome Res. 11, 1706–1715.PubMedCrossRefGoogle Scholar
  68. 68.
    Behr, M. A., Wilson, M. A., Gill, W. P., Salamon, H., Schoolnik, G. K., Rane, S., et al. (1999) Comparative genomics of BCG vaccines by whole-genome DNA microarray. Science 284, 1520–1523.PubMedCrossRefGoogle Scholar
  69. 69.
    Riley, M. (1993) Functions of the gene products of Escherichia coli. Microbiol. Rev. 57, 862–952.PubMedGoogle Scholar
  70. 70.
    Fraser, C. M., Eisen, J., Fleischmann, R. D., Ketchum, K. A., and Peterson, S. (2000) Comparative genomics and understanding of microbial biology. Emerg. Infect. Dis. 6, 505–512.PubMedCrossRefGoogle Scholar
  71. 71.
    Shimizu, T., Ohtani, K., Hirakawa, H., Ohshima, K., Yamashita, A., Shiba, T., et al. (2002) Complete genome sequence of Clostridium perfringens, an anaerobic flesh-eater. Proc. Natl. Acad. Sci. USA 99, 996–1001.PubMedCrossRefGoogle Scholar
  72. 72.
    Kapatral, V., Anderson, I., Ivanova, N., Reznik, G., Los, T., Lykidis, A., et al. (2002) Genome sequence and analysis of the oral bacterium Fusobacterium nucleatum strain ATCC 25586. J. Bact. 184, 2005–2018.PubMedCrossRefGoogle Scholar
  73. 73.
    Smith, H. O., Tomb, J. F., Dougherty, B. A., Fleischmann, R. D., and Venter, J. C. (1995) Frequency and distribution of DNA uptake signal sequences in the Haemophilus influenzae Rd genome. Science 269, 538–540.PubMedCrossRefGoogle Scholar
  74. 74.
    Frank, A. C., Amiri, H., and Andersson, S. G. (2002) Genome deterioration: loss of repeated sequences and accumulation of junk DNA. Genetica 115, 1–12.PubMedCrossRefGoogle Scholar
  75. 75.
    Kuroda, M., Ohta, T., Uchiyama, I., Baba, T., Yuzawa, H., Kobayashi, I., et al. (2001) Whole genome sequencing of meticillin-resistant Staphylococcus aureus. Lancet 357, 1225–1240.PubMedCrossRefGoogle Scholar
  76. 76.
    Glaser, P., Frangeul, L., Buchrieser, C., Rusniok, C., Amend, A., Baquero, F., et al. (2001) Comparative genomics of Listeria species. Science 294, 849–852.PubMedGoogle Scholar
  77. 77.
    Thompson, J. N. (1999) The evolution of species interactions. Science 284, 2116–2118.PubMedCrossRefGoogle Scholar
  78. 78.
    Stein, L. (2002) Creating a bioinformatics nation. Nature 417, 119–120.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2004

Authors and Affiliations

  • Dawn Field
    • 1
  • Jennifer Hughes
    • 2
  • E. Richard Moxon
    • 3
    • 4
  1. 1.Oxford Centre for Ecology and HydrologyOxford
  2. 2.Department of Ecology and Evolutionary BiologyBrown UniversityProvidence
  3. 3.Molecular Infectious Diseases GroupWeatherall Institute of Molecular MedicineOxfordUK
  4. 4.University of Oxford Department of PaediatricsJohn Radcliffe HospitalOxfordUK

Personalised recommendations