Repetitive Sequences Drive Rapid Adaptation in Candida albicans
No Thumbnail Available
Genome plasticity is commonly observed during speciation, the somatic evolution of cancer, and during the rapid adaptation of fungi to novel environments. In the human fungal pathogen Candida albicans, genome plasticity resulting in copy number variations (CNVs) and loss of heterozygosity (LOH) confer increased virulence and antifungal drug resistance, yet the mechanisms and dynamics that drive these types of genome plasticity are not completely understood. In this dissertation, we build on foundational studies that identified recurrent, adaptive CNVs that occurred during antifungal drug treatment in C. albicans. We begin by describing the types of genomic diversity that is generated during adaptation in C. albicans, and the genomic structures involved in driving these large- scale, adaptive genomic changes. We identify an extensive array of long repeat sequences (65-6499 bp) that are associated with CNVs, LOH, and chromosomal inversions during the acute stages of adaptation to azole antifungal drugs. Additionally, we describe the occurrence of complex CNVs that are associated with a decreased sensitivity to multiple azole antifungal drugs. We describe how these complex CNVs are generated via an intra- chromosomal recombination event between two, distinct long inverted repeat sequences, leading to the formation of a dicentric chromosome. The copy number of these CNVs is rapidly expandable in the presence of antifungal drug, due to successive rounds of the breakage-fusion-bridge cycle and homologous repair. Importantly, we describe how removal from antifungal drug promotes rapid loss of the complex CNVs, resulting in the ancestral genotype and azole antifungal drug susceptibility These findings, while focused on fungal adaptation, have broad implications in understanding how genome plasticity contributes to rapid adaptation during the development of human diseases.
Copyright is retained by the Author. A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.