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Title: A genomic and transcriptomic study of lineage-specific variation in Mycobacterium tuberculosis
Author: Rose, G. D.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2013
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Human tuberculosis (TB) is caused by several closely related species of bacteria collectively known as the Mycobacterium tuberculosis complex (MTBC). In this thesis the identification and effect of lineage-specific genetic variation within the phylogenetic lineages of the MTBC was investigated using a combination of computational methods and high-throughput sequencing technology. Genome sequencing has now identified an extensive repertoire of single nucleotide polymorphisms (SNPs) amongst clinical isolates of the MTBC. Comparative analysis focused on the detection of all lineage-specific SNPs, providing the first glimpse of the total SNP diversity that separates the main phylogenetic lineages from each other. Bioinformatic analysis focused on SNPs more likely to contribute to functional diversity, which predicted nearly half of all SNPs in the MTBC to have functional consequences, while SNPs within regulatory proteins were over-represented. To determine whether these and other lineage- specific SNPs lead to phenotypic diversity, genome datasets were integrated with RNA- sequencing to assess their impact on the comparative transcriptome profiles of strains belonging to two MTBC lineages. Analysing the transcriptomes in the light of the underlying genetic variation found clear correlations between genotype and transcriptional phenotype. These arose by three mechanisms. First, lineage-specific changes in amino acid sequence of transcriptional regulators were associated with alterations in their ability to control gene expression. Second, changes in nucleotide sequence were associated with alteration of promoter activity and generation of novel transcriptional start sites in intergenic regions and within coding sequences. Finally, genes showing lineage-specific patterns of differential expression not linked directly to primary mutations were characterised by a striking over- representation of toxin-antitoxin pairs.
Supervisor: Young, D. B. ; Gagneux, S. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available