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

Iuliana V Ene, Rhys A Farrer, Matthew P Hirakawa, Kennedy Agwamba, Christina A Cuomo, Richard J Bennett

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)E8688-E8697
JournalPNAS
Volume115
Issue number37
Early online date27 Aug 2018
DOIs
Publication statusPublished - 11 Sep 2018

Fingerprint

Diploidy
Candida albicans
Loss of Heterozygosity
Genome
Mutation Rate
Mutation
Chromosomes, Human, Pair 7
Nucleic Acid Repetitive Sequences
Trisomy
Mutagenesis
Base Pairing
Genetic Recombination
Gastrointestinal Tract
Membrane Proteins
Yeasts
Infection
Genes
In Vitro Techniques

Keywords

  • Candida albicans/genetics
  • Candidiasis/microbiology
  • Chromosomes, Fungal
  • Diploidy
  • Evolution, Molecular
  • Genome, Fungal/genetics
  • Heterozygote
  • Humans
  • Loss of Heterozygosity
  • Mutation
  • Selection, Genetic

Cite this

Ene, I. V., Farrer, R. A., Hirakawa, M. P., Agwamba, K., Cuomo, C. A., & Bennett, R. J. (2018). Global analysis of mutations driving microevolution of a heterozygous diploid fungal pathogen. PNAS, 115(37), E8688-E8697. https://doi.org/10.1073/pnas.1806002115

Global analysis of mutations driving microevolution of a heterozygous diploid fungal pathogen. / Ene, Iuliana V; Farrer, Rhys A; Hirakawa, Matthew P; Agwamba, Kennedy; Cuomo, Christina A; Bennett, Richard J.

In: PNAS, Vol. 115, No. 37, 11.09.2018, p. E8688-E8697.

Research output: Contribution to journalArticle

Ene, IV, Farrer, RA, Hirakawa, MP, Agwamba, K, Cuomo, CA & Bennett, RJ 2018, 'Global analysis of mutations driving microevolution of a heterozygous diploid fungal pathogen', PNAS, vol. 115, no. 37, pp. E8688-E8697. https://doi.org/10.1073/pnas.1806002115
Ene IV, Farrer RA, Hirakawa MP, Agwamba K, Cuomo CA, Bennett RJ. Global analysis of mutations driving microevolution of a heterozygous diploid fungal pathogen. PNAS. 2018 Sep 11;115(37):E8688-E8697. https://doi.org/10.1073/pnas.1806002115
Ene, Iuliana V ; Farrer, Rhys A ; Hirakawa, Matthew P ; Agwamba, Kennedy ; Cuomo, Christina A ; Bennett, Richard J. / Global analysis of mutations driving microevolution of a heterozygous diploid fungal pathogen. In: PNAS. 2018 ; Vol. 115, No. 37. pp. E8688-E8697.
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N2 - 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.

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