Genomes, pangenomes and drug resistance in Candida parapsilosis

Candida parapsilosis is an increasingly common human fungal pathogen responsible for widespread infections in hospital environments, and incidences of acquired resistance to antifungal drugs is becoming worryingly frequent. In this thesis, I discuss genome variation between isolates of C. parapsilosis using both reference-based and reference-free methodology in an attempt to distinguish causative variants associated with antifungal resistance and other growth conditions. In Chapter 2, I use reference-based analyses in two studies to uncover variants associated with antifungal drug resistance. In the first study, I identify increased expression of drug transporters CDR1B and MDR1 associated with azole resistance through gain-offunction and copy number mutations. In the second study, I identify changes in drug targets ERG11 and FKS1 associated with azole and echinocandin resistance respectively and discuss their relationship to an ongoing hospital outbreak of multi-drug-resistant infections. In Chapter 3, I use a reference-free pangenome approach to describing genomic variation across 372 isolates of C. parapsilosis. This approach describes the total gene content across all isolates and presents genome variation in the form of presences and absences between isolates. Here I identify that variation in gene content is driven primarily through tandem duplication and fusion of homologous neighbouring genes, predominantly within the Major Facilitator Superfamily of transporters. I also discuss pitfalls in referencebased methodology by identifying truncated reference loci that do not represent all isolates. In Chapter 4, I depart from C. parapsilosis and discuss genome variation across the Hanseniaspora genus of yeasts using both reference-based and reference-free methodology in the process of describing the newly sequenced species Hanseniaspora menglaensis. In this analysis, I discuss variation in mating locus structure and mitochondrion topology across lineages of Hanseniaspora.