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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.

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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.

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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).

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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.

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Correspondence to Kathryn E Holt.

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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

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