Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

High-throughput sequencing provides insights into genome variation and evolution in Salmonella Typhi

Abstract

Isolates of Salmonella enterica serovar Typhi (Typhi), a human-restricted bacterial pathogen that causes typhoid, show limited genetic variation. We generated whole-genome sequences for 19 Typhi isolates using 454 (Roche) and Solexa (Illumina) technologies. Isolates, including the previously sequenced CT18 and Ty2 isolates, were selected to represent major nodes in the phylogenetic tree. Comparative analysis showed little evidence of purifying selection, antigenic variation or recombination between isolates. Rather, evolution in the Typhi population seems to be characterized by ongoing loss of gene function, consistent with a small effective population size. The lack of evidence for antigenic variation driven by immune selection is in contrast to strong adaptive selection for mutations conferring antibiotic resistance in Typhi. The observed patterns of genetic isolation and drift are consistent with the proposed key role of asymptomatic carriers of Typhi as the main reservoir of this pathogen, highlighting the need for identification and treatment of carriers.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Phylogenetic tree based on SNP data.
Figure 2: Trajectory of dN/dS over time.
Figure 3: Distribution of number of SNPs per gene.
Figure 4: Accumulation of gene-inactivating mutations in Typhi lineages.

References

  1. 1

    Parry, C.M., Hien, T.T., Dougan, G., White, N.J. & Farrar, J.J. Typhoid fever. N. Engl. J. Med. 347, 1770–1782 (2002).

    CAS  Article  PubMed  Google Scholar 

  2. 2

    Coburn, B., Grassl, G.A. & Finlay, B.B. Salmonella, the host and disease: a brief review. Immunol. Cell Biol. 85, 112–118 (2007).

    Article  PubMed  Google Scholar 

  3. 3

    Parkhill, J. et al. Complete genome sequence of a multiple drug resistant Salmonella enterica serovar Typhi CT18. Nature 413, 848–852 (2001).

    CAS  Article  PubMed  Google Scholar 

  4. 4

    Pickard, D. et al. Composition, acquisition, and distribution of the Vi exopolysaccharide-encoding Salmonella enterica pathogenicity island SPI-7. J. Bacteriol. 185, 5055–5065 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5

    Roumagnac, P. et al. Evolutionary history of Salmonella Typhi. Science 314, 1301–1304 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6

    Chau, T.T. et al. Antimicrobial drug resistance of Salmonella enterica serovar Typhi in Asia and molecular mechanism of reduced susceptibility to the fluoroquinolones. Antimicrob. Agents Chemother. 51, 4315–4323 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  7. 7

    Le, T.A. et al. Clonal expansion and microevolution of quinolone-resistant Salmonella enterica serotype Typhi in Vietnam from 1996 to 2004. J. Clin. Microbiol. 45, 3485–3492 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8

    Deng, W. et al. Comparative genomics of Salmonella enterica serovar Typhi strains Ty2 and CT18. J. Bacteriol. 185, 2330–2337 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9

    Hall, N. Advanced sequencing technologies and their wider impact in microbiology. J. Exp. Biol. 210, 1518–1525 (2007).

    CAS  Article  PubMed  Google Scholar 

  10. 10

    Pearson, T. et al. Phylogenetic discovery bias in Bacillus anthracis using single-nucleotide polymorphisms from whole-genome sequencing. Proc. Natl. Acad. Sci. USA 101, 13536–13541 (2004).

    CAS  Article  PubMed  Google Scholar 

  11. 11

    Baker, S. et al. High-throughput genotyping of Salmonella Typhi allows geographical assignment of haplotypes and pathotypes within an urban district of Jakarta, Indonesia. J. Clin. Microbiol. 46, 1741–1746 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12

    Rocha, E.P.C. et al. Comparisons of dN/dS are time dependent for closely related bacterial genomes. J. Theor. Biol. 239, 226–235 (2006).

    CAS  Article  Google Scholar 

  13. 13

    Turner, A.K., Nair, S. & Wain, J. The acquisition of full fluoroquinolone resistance in Salmonella Typhi by accumulation of point mutations in the topoisomerase targets. J. Antimicrob. Chemother. 58, 733–740 (2006).

    CAS  Article  PubMed  Google Scholar 

  14. 14

    Haraga, A., Ohlson, M.B. & Miller, S.I. Salmonellae interplay with host cells. Nat. Rev. Microbiol. 6, 53–66 (2008).

    CAS  Article  PubMed  Google Scholar 

  15. 15

    Falush, D. & Bowden, R. Genome-wide association mapping in bacteria? Trends Microbiol. 14, 353–355 (2006).

    CAS  Article  PubMed  Google Scholar 

  16. 16

    Didelot, X., Achtman, M., Parkhill, J., Thomson, N.R. & Falush, D. A bimodal pattern of relatedness between the Salmonella Paratyphi A and Typhi genomes: convergence or divergence by homologous recombination? Genome Res. 17, 61–68 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17

    Thomson, N. et al. The role of prophage-like elements in the diversity of Salmonella enterica serovars. J. Mol. Biol. 339, 279–300 (2004).

    CAS  Article  PubMed  Google Scholar 

  18. 18

    Vernikos, G.S. & Parkhill, J. Interpolated variable order motifs for identification of horizontally acquired DNA: revisiting the Salmonella pathogenicity islands. Bioinformatics 22, 2196–2203 (2006).

    CAS  Article  PubMed  Google Scholar 

  19. 19

    Boyd, E.F., Porwollik, S., Blackmer, F. & McClelland, M. Differences in gene content among Salmonella enterica serovar Typhi isolates. J. Clin. Microbiol. 41, 3823–3828 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20

    Nair, S. et al. Salmonella enterica serovar Typhi strains from which SPI7, a 134-kilobase island with genes for Vi exopolysaccharide and other functions, has been deleted. J. Bacteriol. 186, 3214–3223 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21

    Bueno, S.M. et al. Precise excision of the large pathogenicity island, SPI7, in Salmonella enterica serovar Typhi. J. Bacteriol. 186, 3202–3213 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22

    Bertram, G., Innes, S., Minella, O., Richardson, J.P. & Stansfield, I. Endless possibilities: translation termination and stop codon recognition. Microbiology 147, 255–269 (2001).

    CAS  Article  PubMed  Google Scholar 

  23. 23

    Thomson, N.R. et al. The complete genome sequence and comparative genome analysis of the high pathogenicity Yersinia enterocolitica strain 8081. PLoS Genet. 2, e206 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  24. 24

    Parkhill, J. et al. Comparative analysis of the genome sequences of Bordetella pertussis, Bordetella parapertussis and Bordetella bronchiseptica. Nat. Genet. 35, 32–40 (2003).

    Article  PubMed  Google Scholar 

  25. 25

    Cole, S.T. et al. Massive gene decay in the leprosy bacillus. Nature 409, 1007–1011 (2001).

    CAS  Article  PubMed  Google Scholar 

  26. 26

    Andersson, J.O. & Andersson, S.G.E. Genome degradation is an ongoing process in Rickettsia. Mol. Biol. Evol. 16, 1178–1191 (1999).

    CAS  Article  PubMed  Google Scholar 

  27. 27

    Hiller, N. L. et al. Comparative genomic analyses of seventeen Streptococcus pneumoniae strains: insights into the pneumococcal supragenome. J. Bacteriol. 189, 8186–8195 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28

    Tettelin, H. et al. Genome analysis of multiple pathogenic isolates of Streptococcus agalactiae: implications for the microbial “pan-genome”. Proc. Natl. Acad. Sci. USA 102, 13950–13955 (2005).

    CAS  Article  PubMed  Google Scholar 

  29. 29

    Octavia, S. & Lan, R. Single nucleotide polymorphism typing and genetic relationships of Salmonella enterica serovar Typhi isolates. J. Clin. Microbiol. 45, 3795–3801 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30

    Saurin, W., Hofnung, M. & Dassa, E. Getting in or out: early segregation between importers and exporters in the evolution of ATP-binding cassette (ABC) transporters. J. Mol. Evol. 48, 22–41 (1999).

    CAS  Article  PubMed  Google Scholar 

  31. 31

    Webber, M.A. & Piddock, L.J. The importance of efflux pumps in bacterial antibiotic resistance. J. Antimicrob. Chemother. 51, 9–11 (2003).

    CAS  Article  PubMed  Google Scholar 

  32. 32

    Suerbaum, S. et al. Free recombination within Helicobacter pylori. Proc. Natl. Acad. Sci. USA 95, 12619–12624 (1998).

    CAS  Article  PubMed  Google Scholar 

  33. 33

    Gomes, J.P. et al. Evolution of Chlamydia trachomatis diversity occurs by widespread interstrain recombination involving hotspots. Genome Res. 17, 50–60 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34

    Gey Van Pittius, N.C. et al. Evolution and expansion of the Mycobacterium tuberculosis PE and PPE multigene families and their association with the duplication of the ESAT-6 (esx) gene cluster regions. BMC Evol. Biol. 6, 95 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  35. 35

    Vaishnavi, C. et al. Epidemiology of typhoid carriers among blood donors and patients with biliary, gastrointestinal and other related diseases. Microbiol. Immunol. 49, 107–112 (2005).

    CAS  Article  PubMed  Google Scholar 

  36. 36

    Levine, M.M., Black, R.E. & Lanata, C. Precise estimation of the number of chronic carriers of Salmonella typhi in Santiago, Chile, an endemic area. J. Infect. Dis. 146, 724–726 (1982).

    CAS  Article  PubMed  Google Scholar 

  37. 37

    Lewis, M.D. et al. Typhoid fever: a massive, single-point source, multidrug-resistant outbreak in Nepal. Clin. Infect. Dis. 40, 554–561 (2005).

    Article  PubMed  Google Scholar 

  38. 38

    Sears, S.D., Ferreccio, C. & Levine, M.M. The use of Moore swabs for isolation of Salmonella typhi from irrigation water in Santiago, Chile. J. Infect. Dis. 149, 640–642 (1984).

    CAS  Article  PubMed  Google Scholar 

  39. 39

    Cho, J.C. & Kim, S.J. Viable, but non-culturable, state of a green fluorescence protein-tagged environmental isolate of Salmonella typhi in groundwater and pond water. FEMS Microbiol. Lett. 170, 257–264 (1999).

    CAS  Article  PubMed  Google Scholar 

  40. 40

    Sokurenko, E.V., Gomulkiewicz, R. & Dykhuizen, D.E. Source-sink dynamics of virulence evolution. Nat. Rev. Microbiol. 4, 548–555 (2006).

    CAS  Article  PubMed  Google Scholar 

  41. 41

    Kurtz, S. et al. Versatile and open software for comparing large genomes. Genome Biol. 5, R12 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the Wellcome Trust. M.A. and C.J.M. are supported in Ireland by grant 05/FE1/B882 from the Scientific Foundation Ireland and C.J.M. was supported in Berlin by a Wellcome Trust grant to J. Farrar. We gratefully acknowledge the support of the Sanger Institute core sequencing and informatics groups. Isolates were provided by the Oxford University Clinical Research Unit (CT18, J185SM, AG3); B. Holmes at the National Collection of Type Cultures (M223); the Wellcome Trust Sanger Institute (404ty, Ty2); and F.-X.W. (all other isolates).

Author information

Affiliations

Authors

Contributions

G.D., J.P., M.A., P.R. and J.W. designed the study; F.-X.W. and C.D. contributed isolates for analysis; I.G. and R.R. performed 454 and Solexa sequencing; K.E.H. and S.B. performed validation experiments; D.J.M. co-supervises the PhD studies of K.E.H. and contributed to experimental design; K.E.H. and C.J.M. analysed data and K.E.H., J.P., P.R. and G.D. wrote the manuscript.

Corresponding author

Correspondence to Kathryn E Holt.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3, Supplementary Tables 1 and 3, Supplementary Methods, Supplementary Note (PDF 1448 kb)

Supplementary Table 2 (XLS 1029 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Holt, K., Parkhill, J., Mazzoni, C. et al. High-throughput sequencing provides insights into genome variation and evolution in Salmonella Typhi. Nat Genet 40, 987–993 (2008). https://doi.org/10.1038/ng.195

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing