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Proc Natl Acad Sci U S A DOI:10.1073/pnas.1806002115

Global analysis of mutations driving microevolution of a heterozygous diploid fungal pathogen.

Publication TypeJournal Article
Year of Publication2018
AuthorsEne, IV, Farrer, RA, Hirakawa, MP, Agwamba, K, Cuomo, CA, Bennett, RJ
JournalProc Natl Acad Sci U S A
Date Published2018 09 11
KeywordsCandida albicans, Candidiasis, Chromosomes, Fungal, Diploidy, Evolution, Molecular, Genome, Fungal, Heterozygote, Humans, Loss of Heterozygosity, Mutation, Selection, Genetic

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 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 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 recombination-induced 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 microevolution, and provide a quantitative picture of genome dynamics in this heterozygous diploid species.


Alternate JournalProc Natl Acad Sci U S A
PubMed ID30150418
PubMed Central IDPMC6140516
Grant ListHHSN272200900018C / AI / NIAID NIH HHS / United States
R21 AI112363 / AI / NIAID NIH HHS / United States
R21 AI122011 / AI / NIAID NIH HHS / United States
R21 AI139592 / AI / NIAID NIH HHS / United States
/ / Wellcome Trust / United Kingdom
F31 DE023726 / DE / NIDCR NIH HHS / United States
U19 AI110818 / AI / NIAID NIH HHS / United States
R01 AI081704 / AI / NIAID NIH HHS / United States