Candida albicans is a commensal fungus of the human gastrointestinal tract and a prevalent opportunistic pathogen. To examine diversity within this species, extensive genomic and phenotypic analyses were performed on 21 clinical C. albicans isolates. Genomic variation was evident in the form of polymorphisms, copy number variations, chromosomal inversions, subtelomeric hypervariation, loss of heterozygosity (LOH), and whole or partial chromosome aneuploidies. All 21 strains were diploid, although karyotypic changes were present in eight of the 21 isolates, with multiple strains being trisomic for Chromosome 4 or Chromosome 7. Aneuploid strains exhibited a general fitness defect relative to euploid strains when grown under replete conditions. All strains were also heterozygous, yet multiple, distinct LOH tracts were present in each isolate. Higher overall levels of genome heterozygosity correlated with faster growth rates, consistent with increased overall fitness. Genes with the highest rates of amino acid substitutions included many cell wall proteins, implicating fast evolving changes in cell adhesion and host interactions. One clinical isolate, P94015, presented several striking properties including a novel cellular phenotype, an inability to filament, drug resistance, and decreased virulence. Several of these properties were shown to be due to a homozygous nonsense mutation in the EFG1 gene. Furthermore, loss of EFG1 function resulted in increased fitness of P94015 in a commensal model of infection. Our analysis therefore reveals intra-species genetic and phenotypic differences in C. albicans and delineates a natural mutation that alters the balance between commensalism and pathogenicity.

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SignificanceEvolution acts on mutations that naturally arise within the genome and are shaped both by intrinsic genomic features and by the cellular environment. We catalog the mutations arising in a heterozygous diploid yeast during passaging in vitro and in the mammalian host. We establish genome-wide mutation rates and reveal that “microscale” changes (base substitutions and short-track recombination events) are the primary drivers of microevolution, although chromosomal-level changes also occur in specific host environments. Our results define mutation hotspots, including those adjoining recombination tracts, and indicate that many mutations are purged from the population due to purifying selection. Together, these data provide a high-resolution picture of how the heterozygous diploid genome of a fungal pathogen undergoes evolution over short time scales.