Aneuploidy, polyploidy and loss of heterozygosity distinguish serial bloodstream isolates of Candida albicans

The opportunistic pathogen <i>Candida albicans</i> is the leading cause of invasive <i>Candida</i> infections worldwide. Genomic variation between <i>C. albicans</i> clinical isolates complicates efforts to pinpoint novel genetic variants underlying antifungal drug resistance and tolerance. Studies of serial isolates from individual patients are uncommon, limiting our understanding of genomic and phenotypic diversity during invasive <i>Candida</i> infections. We performed comparative genomic analyses of 101 <i>C</i>. <i>albicans</i> bloodstream isolates from 55 patients in the Twin Cities region of Minnesota, including serial isolates from 19 patients. We analysed the phylogenetic relationships of these isolates relative to 199 globally collected public <i>C. albicans</i> genomes. This study's regional isolates span the phylogenetic diversity of <i>C. albicans</i>; six isolates represent novel outliers to known clades. While all serial isolates from the same patient clustered together phylogenetically, we observed extensive large-scale genomic variation between serial isolates including polyploidy, aneuploidy, copy number variation, loss of heterozygosity and chromosomal rearrangements. We demonstrated how a heterozygous <i>ERG251</i> variant drives azole tolerance in a clinical isolate from a patient with a history of recurrent infections. Using serial isolates, we demonstrated that polyploidy provides an adaptive advantage in the presence of fluconazole despite the absence of overt antifungal drug resistance. Our analysis of closely matched serial isolates reveals the genomic plasticity of <i>C. albicans</i> during invasive infections and identifies variation driving antifungal drug tolerance. Our findings reveal limitations in current antifungal susceptibility testing and highlight the need to account for genomic and phenotypic variation during invasive <i>Candida</i> infections.