No description available.

Thesis (Ph. D.)--Carleton University, 1992. / Also available in electronic format on the Internet.

Thesis--Universiteit van Amsterdam.

Inaug.-dis.--Jena. / Lebenslauf.

Mutations affecting the mitochondrial electron transport chain cause numerous neurodegenerative disorders in humans and affect longevity in other organisms. A natural model system to study the relationship between mitochondrial function and aging within an evolutionary or population genetic context has been lacking. Natural populations of Caenorhabditis briggsae nematodes were recently found to harbor mitochondrial genetic variation with likely functional consequences for aging. Specifically, C. briggsae isolates containing high frequencies of a deletion mutation affecting the mitochondrial NADH dehydrogenase 5 (ND5) gene were found to have reduced reproductive fitness and lifespan and elevated levels of mutagenic superoxide. Here, rates of growth and aging and aerobic respiratory capacity were evaluated in several isolates spanning the range of mitochondrial genetic variation in this species. There is considerable variation among isolates for all measured traits, although the observed relationships between isolate-specific trait means and ND5 deletion frequency did not always conform to my expectations. In an effort to determine whether the among-isolate phenotypic variation is due to mitochondrial rather than to nuclear genetic variation, inter-population hybrids of C. briggsae were created and compared to the progenitor isolates. Surprisingly, evidence for paternal mitochondrial inheritance was detected in many of these hybrid lines. Where mitochondrial genomes were maternally inherited as expected, intergenomic epistasis appears to contribute to fitness, longevity, and aging in this species.

No description available.

The genetic basis of the different cancer phenotypes has been a continuous and accelerating subject of investigation. Data accumulated thanks to recently introduced genome-wide scanning technologies have revealed that human diversity and diseases susceptibility is also greatly influenced by structural alterations in the human genome, such as DNA copy number variants (CNVs) and copy number alterations (CNAs), which influence gene expression in both healthy and pathological cells. Our research aims to investigate the influence of structural alterations on gene expression in cancer cells using SNP microarray data. Specifically, we focus on analyzing DNA copy number alternations (CNAs), which can significantly influence gene expression in cancer cells. Several cancer-predisposing mutations affect genes that are responsible for maintaining the integrity of the chromosomes during cell division, which can result in translocations, gains or losses of large parts of chromosome. To our knowledge, there have been no publications that link whole-genome copy number alterations in cancer to gene expression variations using the full range of possibilities offered by SNP arrays. The accurate use of SNP arrays in the analysis of cancer has been difficult due to tumour purity, tumour heterogeneity, aneuploidy/polyploidy and complex patterns of CNA and loss-of-heterozygosity (LOH). In our work, we use and further extend a recently developed novel tool for tumour genome profiling called OncoSNP (Yau, Mouradov et al. 2010), in order to resolve some of those problems and accurately estimate copy number alterations (CNA) and loss-of-heterozygosity (LOH) from SNP array data in cancer cell samples. The methods developed in this thesis tackle the problem of cancer genomic investigation by developing and validating an extension (DPS smoothing) of a new method (OncoSNP). This approach is used in the analysis of global expression versus CNA patterns in experimental systems and large clinical datasets. We analyse various cancer SNP and gene expression arrays of increasing complexity and heterogeneity, starting with a dataset of head and neck squamous cell carcinoma (HNSCC) cell lines, followed by leukaemia samples and finally a large breast cancer dataset. The central findings of our research are multifold. In the HNSCC dataset we find that the level of genetic instability is not indicative of the pathological state; i.e. there are premalignant lesions displaying extensive mutations. However some genetic features are typical of certain lesion type; e.g. we consistently observe copy loss in the short arm of chromosome 3 in carcinoma. The pattern of homozygous deletion in the dataset reveals common deletion of cancer related genes, especially CDK4 (pI6). Furthermore we notice a significant positive correlation between the copy number and the expression on a systematic level. In Leukaemia, we do not observe extended uniparental disomy as previously published (Akagi, Shih et al. 2009) and expected. However large alterations (whole arm amplification) are observed in individual patients: copy loss in chromosome 7 (2 patients), copy gain in chromosome 8 (3 patients) as well as common alterations around the centromeres and telomeres. In the breast cancer dataset significantly different level of mutations were observed in the different subtypes in the cohort. Furthermore 499 genes were identified with significant correlation between their gene expression (GE) and underlying genomic alterations (either copy number (CN) or loss-of-heterozygosity (LOH)). Performing hierarchical clustering on the cohort using the 499 correlated genes enabled us to recover the subtypes' separation previously based on gene expression alone.

Ph.D., Faculty of Science, University of the Witwatersrand, 2011 / The ABCB1 gene encodes P-glycoprotein, a transmembrane protein that regulates the efflux of drugs in the cells and may affect the response to antiretroviral drugs. ABCB1 polymorphisms affect the function or expression of P-gp. The 3435T allele has been associated with decreased protein production, but is in linkage disequilibrium with other polymorphisms. HIV is prevalent in Southern Africa, and characterization of ABCB1 variation may provide insight into its role in antiretroviral immune response. The aim was to determine if there was any association between ABCB1 variation, relative mRNA levels and immune response. Seven known polymorphisms were characterized for linkage disequilibrium and haplotype analysis, regions upstream of the gene were sequenced for bioinformatic analysis, the relative amounts of mRNA were determined, and CD4+ and viral load data was analyzed for association. Sequencing revealed six novel variations: T-137G, C-233T and G-298A upstream of exon 1, T108G and G153A in exon 2, and A111G in intron 26. The frequencies of the -129T (0.85), 1236T (0.70), 2677G (0.77), IVS 25+3050G (0.86), IVS 25+5231T (0.51), 3435C (0.88) and IVS 26+80T (0.89) polymorphisms were different and LD was lower compared to other populations. The haplotype frequencies were different to other populations and the genetic structure was probably a result of multiple recombination or mutation events. The viral load counts at the second measurement after baseline (time point 2) were significantly different from baseline for the 2677GG and 2677GA genotypes, and the -129T allele was associated with a lower proportional decrease in viral load at 8 the second measurement. The IVS 25+3050GG, 3435CC and IVS 26+80TT genotypes have been associated with lower mean relative mRNA levels. In conclusion, the genetic structure of the southern African populations is different from other populations and that genetic association and functional studies derived from other populations would be irrelevant in this population. A larger sample size and functional studies would be required to attempt to resolve the molecular mechanisms of the ABCB1 gene and to confirm the findings of association between ABCB1 polymorphisms and immune response.

Thesis (Ph.D.)--University of Delaware, 2009. / Principal faculty advisor: Patrick M. Gaffney, College of Earth, Ocean, & Environment. Includes bibliographical references.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1955. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 121-123).