Doctoral Degrees (Molecular Biology and Human Genetics)
Permanent URI for this collection
Browse
Browsing Doctoral Degrees (Molecular Biology and Human Genetics) by Author "Daya, Michelle"
Now showing 1 - 1 of 1
Results Per Page
Sort Options
- ItemUsing bioinformatics and biostatistics to elucidate susceptibility to tuberculosis in an admixed population(Stellenbosch : Stellenbosch University, 2015-03) Daya, Michelle; Hoal, Eileen; Van der Merwe, Lize; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences: Molecular Biology and Human GeneticsENGLISH ABSTRACT : Tuberculosis is the second leading cause of mortality from infectious disease worldwide. One of the factors involved in developing disease is the genetics of the host, yet the field of TB susceptibility genetics has not yielded the insights that were expected. The admixed South African Coloured population is the largest demographic in metropolitan areas of Cape Town that have some of the highest reported incidences of TB worldwide. The DST/NRF Centre for Biomedical TB Research at Stellenbosch University has studied a cohort of individuals from these communities for many years, in the hope of discovering novel TB susceptibility genes which may at least partly explain the exceptional rate of TB in this community. The large genotypic data sets collected by the centre are invaluable resources to aid understanding of the population genetics of the population, and to generate new hypotheses regarding genetic factors that may underpin progression to disease. Novel applications of statistical methods are used in this dissertation with a view to addressing these goals, and are presented in four research studies. An important consideration in genetic association studies of the South African Coloured population is admixture, which may confound association results. This is the subject of the first two studies. The first study describes the development of a panel of ancestry informative markers that are tailored to the complex admixture that occurred in the population. The panel can be used as a cost-effective alternative to genome-wide data to correct for the confounding effect of admixture. In the second study, the panel is used to demonstrate the importance of adjustment for ancestry in TB susceptibility genetic association studies of the South African Coloured population. A previous study identified associations between ancestry and having TB in the population, but a limited number of controls were used in that study. Ancestry informative markers were therefore used to examine the previous finding, and the substantial effect that ancestry has in the development of TB was confirmed. New hypotheses regarding genetic factors in TB susceptibility are generated in the third and fourth studies. The South African Coloured population received contributions from diverse source populations that may differ in their genetic susceptibility to TB, and the group is therefore ideally suited to the discovery of TB susceptibility genetic variants and their probable ethnic origins. Genome-wide admixture mapping was used in the third study to identify regions of the genome that may harbour such variants. The study identified a number of novel candidate TB susceptibility genes, and provided further substantiating evidence for the role of genetic loci previously implicated in the disease. The fourth study investigated the role of gene-gene interactions (epistasis), an oft-cited explanation for the missing heritability of complex disease, in the South African Coloured TB case-control cohort. A number of interesting gene-gene pairs that may jointly modify the odds of having TB were identified, and some of these findings were validated in an independent TB case-control cohort from The Gambia.