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Proc Natl Acad Sci U S A. 2018 Sep 11;115(37):E8688-E8697. doi: 10.1073/pnas.1806002115. Epub 2018 Aug 27.

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

Author information

1
Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912.
2
Infectious Disease and Microbiome Program, The Broad Institute of MIT and Harvard, Cambridge, MA 02142.
3
Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912; Richard_Bennett@brown.edu.

Abstract

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 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 C. albicans microevolution, and provide a quantitative picture of genome dynamics in this heterozygous diploid species.

KEYWORDS:

Candida albicans; LOH; aneuploidy; diploid species; microevolution

PMID:
30150418
PMCID:
PMC6140516
DOI:
10.1073/pnas.1806002115
[Indexed for MEDLINE]
Free PMC Article

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