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

Proceedings of the National Academy of Sciences of the United States of America
Iuliana V EneRichard J Bennett

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...Continue Reading

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Citations

Sep 8, 2019·Nature Communications·Claude LemieuxJean-François Pombert
Sep 29, 2019·Nature Communications·Matthew Z AndersonRichard J Bennett
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Aug 6, 2020·Journal of Fungi·Callum J O'KaneEdel M Hyland
Jan 2, 2020·Journal of Fungi·Shen-Huan Liang, Richard J Bennett
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Methods Mentioned

BETA
PCR
genotyping

Software Mentioned

KASP
Picard
Genome Analysis Toolkit
Integrative Genomics Viewer ( IGV )
Pilon
Samtools
Haplotype Caller ( Genome Analysis Toolkit )
Burrows Aligner

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