LAUSR

The yeast Candida glabrata, an opportunistic human fungal pathogen, is the second most prevalent cause of candidiasis worldwide, with an infection incidence that has been increasing in the past decades. The completion of the C. glabrata reference genome made fundamental contributions to the understanding of the molecular basis of its pathogenic phenotypes. However, knowledge of genome-wide genetic variations among C. glabrata strains is limited. In this study, we present a population genomic study of C. glabrata based on whole genome re-sequencing of 47 clinical strains to an average coverage of ∼63×. Abundant genetic variations were identified in these strains, including single nucleotide polymorphisms (SNPs), small insertion/deletions (indels) and copy number variations (CNVs). The observed patterns of variations revealed clear population structure of these strains. Using population genetic tests, we detected fast evolution of several genes involved in C. glabrata adherence ability, such as EPA9 and EPA10. We also located genome structural variations, including aneuploidies and large fragment CNVs, in regions that are functionally related to virulence. Subtelometric regions were hotspots of CNVs, which may contribute to variation in expression of adhesin genes that are important for virulence. We further conducted a genome-wide association study that identified two SNPs in the 5'UTR region of CST6 that were associated with fluconazole susceptibility. These observations provide convincing evidence for the highly dynamic nature of the C. glabrata genome with potential adaptive evolution to clinical environments, and offer valuable resources for investigating the mechanisms underlying drug resistance and virulence in this fungal pathogen. (249 words).