Characterization of non-coding regions in the human pathogen Aspergillus fumigatus and its close non-pathogenic relatives.

Abstract

Several species in the genus Aspergillus can cause invasive aspergillosis (IA) in humans, an infectious disease that is often fatal in immunocompromised individuals. With a morbidity rate of >400,000 cases per year, the mortality rate of those inflicted with IA is 50-95%. Mortality rates are even higher for patients that have also undergone an organ transplant or cancer treatment. Of the >450 species in the genus Aspergillus, Aspergillus fumigatus is responsible for > 90% of all reported IA cases. Comparative genomic analysis between A. fumigatus and closely related species revealed that most of the genes in A. fumigatus are conserved amongst nonpathogenic close relatives. For example, nearly all genes known to be genetic determinants of virulence in A. fumigatus are also found in closely related nonpathogenic species. Additionally, differences in virulence profiles are also exhibited between strains of A. fumigatus. My published work has identified large-scale, genome-wide variation in noncoding regions predicted to help regulate the expression of genes, including of genes that are known to contribute to A. fumigatus virulence between A. fumigatus and closely related species. However, how noncoding differences may influence differences in virulence between A. fumigatus strains remains not known. The goal of this thesis was to identify genomic changes in noncoding regions involved in gene regulation that contribute to the observed differences in virulence between strains of A. fumigatus and between A. fumigatus and closely relatives and elucidate how these changes may have influenced the regulation of genes, especially those involved in virulence.