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Title: Genomic variation and evolution of Salmonella enterica serovars Typhi and Paratyphi A
Author: Holt, K. E.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2009
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In this thesis, comparative genomic analysis was used to detect variation within the Typhi and Paratyphi A populations, and to compare the evolution of these two pathogens. There was evidence in both populations of ongoing accumulation of inactivating mutations which result in loss of gene function. Detailed comparison of this functional gene loss in Typhi and Paratyphi A revealed that many of the same genes were inactivated in both serovars, but the mutations occurred independently and were not the result of horizontal transfer of DNA between their genomes. Comparative analysis found that the same type of plasmid was present in both serovars, carrying identical DNA sequences encoding resistance to the drugs used to treat typhoid fever. This demonstrates that the evolution of drug resistance in both serovars is tightly linked. Very closely related sequences were also found in other human bacterial pathogens, highlighting how easily drug resistance can spread. Single nucleotide variants (SNPs) identified in Typhi and in the drug resistance plasmids were used to develop a high-throughput SNP typing assay with which to study Typhi populations. The SNP typing assay was used to interrogate a global collection of Typhi, as well as local Typhi populations from areas where typhoid is endemic, including regions of Vietnam, Nepal, India and Kenya. The analysis linked strain type with plasmid type for the first time, and demonstrated multiple independent acquisitions of distinct drug resistance plasmids over the past 40 years, culminating in the current dominance of a single plasmid type. Analysis of recent Typhi populations circulating in endemic areas showed that the same Typhi clone now dominates all of these regions, although local diversification has resulted in subtle differences between the populations. Importantly, the dominant Typhi clone was closely associated with the dominant plasmid type, suggesting that the success of the clone and plasmid may have been intimately linked.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available