This is the final published version, available from the National Academy of Sciences via the DOI in this recordThe sequence reported in this paper has been deposited in the NCBI
Sequence Read Archive, https://www.ncbi.nlm.nih.gov/bioproject (BioProject ID
PRJNA345600).Candida albicans is a heterozygous diploid yeast that is a commensal
of the human gastrointestinal tract and a prevalent opportunistic
pathogen. Here, whole-genome sequencing was performed on multiple C. albicans isolates passaged both in vitro and in vivo to characterize the complete spectrum of mutations arising in laboratory
culture and in the mammalian host. We establish that, independent
of culture niche, microevolution is primarily driven by de novo base
substitutions and frequent short-tract loss-of-heterozygosity events.
An average base-substitution rate of ∼1.2 × 10−10 per base pair per
generation was observed in vitro, with higher rates inferred during
host infection. Large-scale chromosomal changes were relatively rare,
although chromosome 7 trisomies frequently emerged during passaging in a gastrointestinal model and was associated with increased
fitness for this niche. Multiple chromosomal features impacted mutational patterns, with mutation rates elevated in repetitive regions,
subtelomeric regions, and in gene families encoding cell surface proteins involved in host adhesion. Strikingly, de novo mutation rates
were more than 800-fold higher in regions immediately adjacent to
emergent loss-of-heterozygosity tracts, indicative of recombinationinduced mutagenesis. Furthermore, genomes showed biased patterns
of mutations suggestive of extensive purifying selection during passaging. These results reveal how both cell-intrinsic and cell-extrinsic
factors influence C. albicans microevolution, and provide a quantitative picture of genome dynamics in this heterozygous diploid species.National Institute of Health (NIH)Burroughs Wellcome FundSigma Delta Epsilon-Graduate Women in ScienceWellcome Trust/Massachusetts Institute of TechnologyNational Institute of Allergy and Infectious Diseases, NIH, Department of Health and Human Service
