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Title: Development and application of genome-wide association studies in bacteria
Author: Earle, Sarah
ISNI:       0000 0004 7232 7600
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2017
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Since the first genome-wide association study (GWAS) applied to humans in 2005, incredible advances have been made in understanding the genetic basis underlying common human diseases and complex traits. Dramatic technological developments have enabled rapid, inexpensive whole-genome sequencing in large numbers of bacteria, creating intense interest in the large-scale application of GWAS to bacteria. However, fundamental differences between the genomes of humans and bacteria mean that although the methodological developments in the human setting are an invaluable starting point, novel methods tailored specifically to bacteria are required. This thesis concerns the development and application of GWAS in bacteria. Taking lessons from the past decade of human GWAS, I began by assessing the feasibility of GWAS in bacteria by investigating the bacterial genetic basis underlying antimicrobial resistance. I aimed to empirically test the feasibility of bacterial GWAS in light of particular challenges posed by bacteria such as strong population structure, genome-wide linkage disequilibrium and the presence of large accessory genomes. Specifically, I performed a detailed investigation into fusidic acid resistance in Staphylococcus aureus to assess the impact of controlling for population stratification in highly structured populations. This demonstrated the importance of controlling for population structure in reducing the number of false positives, but also the substantial cost in doing so. Testing for lineage-level associations enabled the inference of important lineage-level differences in phenotypes, typically discarded when controlling for population structure. I then went on to apply the methods developed to two further phenotypes. The first, carriage vs invasive disease in Neisseria meningitidis, identified the known hyperinvasive ST-11 lineage to be associated with invasive disease, and suggested that newly-reported variants in genes involved in capsule production and phase variation play an important role in the virulence potential of meningococci in natural populations. I hypothesised that a combination of two particular variants upstream of the gene encoding the virulence factor fHbp (factor H binding protein), produces a second putative FNR box, a binding site for the global transcriptional regulator FNR, which may affect expression of fHbp. Finally, I investigated wild bird vs chicken colonisation in Campylobacter jejuni and identified lineage-level associations in agreement with previously identified host-associated lineage characteristics. I hypothesised that host-associated variants downstream of the CRISPR-Cas region, in genes involved in lipooligosaccharide biosynthesis and the chemotaxis pathway, represent pathways enabling C. jejuni to survive bacteriophages encountered upon colonising a new host. To conclude, I discussed the findings of this thesis and suggested areas for future development where new technologies and methods will enable bacterial GWAS to be further advanced.
Supervisor: Wilson, Daniel Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available