A system based approch to understand human disorders using saccharomyces cerevisiae as a model organism

Abstract

Understanding the function of the genes is essential to elucidate the molecular mechanisms behind the Mendelian disorders. Conservation of the biochemical and molecular functions between organisms enables using model organisms to understand the molecular functions of disease associated genes. Studies performed with a model organism carrying a mutation in a conserved gene elucidate not only the molecular function of the gene but also the organism-level function of that gene. High degree of conservation of copper homeostasis pathway between yeast and human makes yeast an ideal model organism to study the copper-related disorders. The aim of this thesis was to provide a systems level understanding of the copper related disorders such as Wilson and Menkes diseases by making use of the yeast ortholog of the genes that were associated with these diseases. For this purpose, the genome-wide effects of the deletion of CCC2 and that of ATX1 were investigated using a systems based approach. The transcript levels were investigated in conjunction with interactome and regulome in order to further elucidate the pathways that were affected from the disturbance of copper homeostasis. The analysis of the transcriptional response to the deletion of CCC2 gene in a copper level dependent manner revealed the disturbed mechanisms due to the absence of this gene under changing copper levels. The analysis also revealed that absence of ATX1 gene and CCC2 gene resulted in different transcriptional responses. Further analyses of the reference and CCC2 deleted cells growing in copper deficient chemostat cultures engendered the differences between the effects of the short and long term exposure to high copper levels in both strains.