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

Proc Natl Acad Sci U S A
Authors
Keywords
Abstract

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.

Year of Publication
2018
Journal
Proc Natl Acad Sci U S A
Volume
115
Issue
37
Pages
E8688-E8697
Date Published
2018 09 11
ISSN
1091-6490
DOI
10.1073/pnas.1806002115
PubMed ID
30150418
PubMed Central ID
PMC6140516
Links
Grant list
HHSN272200900018C / 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