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Title: Redefining gene distributions in K. pneumoniae and E. coli using large public datasets
Author: Horesh, Gal
ISNI:       0000 0004 9359 6383
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2020
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The work in this thesis is concerned with characterising genes and their distributions in Escherichia coli and Klebsiella pneumoniae. While both K. pneumoniae and E. coli are found in the guts of healthy individuals, as well as in animals and in the environment, they are particularly relevant organisms to study, as they represent key players in the dissemination of drug resistance and virulence in bacterial populations. Both organisms were given the highest priority by the World Health Organisation as organisms that pose the greatest threat to human health due to high levels of drug resistance. Additionally, they are both the leading cause of life-threatening extra-intestinal disease worldwide. Finally, some E. coli variants are also a major cause of severe diarrheal disease, most commonly in the developing world. The phenomena that is driving these issues is horizontal gene transfer (HGT); the process by which new genetic material is introduced into a genome from an outside source. Drug resistance is most commonly driven by gene acquisition, and it is through the acquisition of virulence genes that K. pneumoniae and E. coli can cause disease. Indeed, HGT has been estimated to occur in high rates in K. pneumoniae and E. coli. Both are highly diverse organisms with very large gene pools and multiple co-circulating lineages. These facts make studying their gene pools on large scales highly relevant, as new genes and lineages are continuously discovered with the sequencing of new genomes. The aim of this thesis was to utilise the availability of large public genomic datasets to study the gene pools of K. pneumoniae and E. coli on a scale and resolution not previously possible. Initially, the distribution of toxin-antitoxin (TA) systems was investigated in a collection of 259 K. pneumoniae isolates. TA systems are operons where one gene encodes for a toxin which inhibits a cellular process, and the other is an antitoxin which inhibits the toxin’s activity. TA systems are relevant to study in the context of HGT as they have been shown to play a role in the maintenance of resistance and virulence genes and to contribute to antibiotic tolerance. The analysis on TA systems in K. pneumoniae revealed new insights regarding the distribution TA systems in the species. These insights were then expanded to examine the distribution of all genes of the E. coli gene pool in a collection of thousands of genomes. This analysis revealed that genes from different categories undergo different dynamics of gene gain and loss, as well as exposed E. coli lineages which may be important in their contribution to gene flow in the population. Due to the novelty and scope of the analyses presented, new computational tools and approaches were developed and are presented.
Supervisor: Thomson, Nicholas Robert ; Heinz, Eva ; Parts, Leopold Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: microbial genomics ; pan genome ; E. coli ; K. pneumoniae ; toxin-antitoxin