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.

doi:10.1073/pnas.1806002115

Cited by 123 publications

(194 citation statements)

References 102 publications

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“…Allelic imbalance 279 in the trisomic strains may also affect cell wall architecture and/or composition, which would then alter 280 immune recognition by the host. Accordingly, the amount of exposed β-glucan on the surface of fungal 281 cells was strongly predictive of competitive fitness in the mouse GI tract (Ene et al 2018). Furthermore, 282 fungal cell wall architecture, rather than cell wall composition, determines the ability of fungi to colonize 283 the GI tract (Sem et al 2016).…”

mentioning

confidence: 99%

Selection of Candida albicans Trisomy during Oropharyngeal Infection Results in a Commensal-Like Phenotype

Forche

Solis

Swidergall

et al. 2019

Preprint

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When the fungus Candida albicans proliferates in the oropharyngeal cavity during experimental oropharyngeal candidiasis (OPC), it undergoes large-scale genome changes at a much higher frequency than when it grows in vitro. Previously, we identified a specific whole chromosome amplification, trisomy of Chr 6 (Chr6x3), that was highly overrepresented among strains recovered from the tongues of mice with OPC. To determine the functional significance of this trisomy, we assessed the virulence of two Chr6 trisomic strains and a Chr5 trisomic strain in the mouse model of OPC. We also analyzed the expression of virulence-associated traits in vitro. All three trisomic strains exhibited characteristics of a commensal during OPC in mice. They achieved the same oral fungal burden as the diploid progenitor strain but caused significantly less weight loss and elicited a significantly lower inflammatory host response. In vitro, all three trisomic strains had reduced capacity to adhere to and invade oral epithelial cells and increased susceptibility to neutrophil killing. Whole genome sequencing of pre-and post-infection isolates found that the trisomies were usually maintained. Most post-infection isolates also contained de novo point mutations, but these were not conserved. While in vitro growth assays did not reveal phenotypes specific to de novo point mutations, they did reveal novel phenotypes specific to each lineage. These data reveal that during OPC, clones that are trisomic for Chr5 or Chr6 are selected and they facilitate a commensallike phenotype.

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mentioning

confidence: 99%

Selection of Candida albicans Trisomy during Oropharyngeal Infection Results in a Commensal-Like Phenotype

Forche

Solis

Swidergall

et al. 2019

Preprint

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“…The comparison of heterozygosity patterns between different species is often hampered by the use of different methodologies and criteria to define heterozygous and homozygous regions in different studies. For instance, while studies performed so far on C. albicans distinguished heterozygous from LOH regions based on SNP density within windows of 5kb (Ene et al 2018;Wang, Bennett, and Anderson 2018;Hirakawa et al 2015), 10kb (Ropars et al 2018), or even 100kb length (Bensasson et al 2019), studies performed on hybrids defined these blocks based on the distance between heterozygous positions (Pryszcz et al 2014;Pryszcz et al 2015;Mixão et al 2019). This last approach makes the boundaries between heterozygous and LOH blocks more flexible and precise and avoids averaging levels of heterozygosity when a window spans both homozygous and heterozygous regions.…”

Section: Heterozygosity Patterns In C Albicans Are Comparable To Thomentioning

confidence: 99%

“…between different strains (Ropars et al 2018;Wang, Bennett, and Anderson 2018). Furthermore, they have reported that the fraction of the genome covered by heterozygous regions can vary between 48% to 89%, depending on the strain, and that these heterozygous tracts are separated by regions of loss of heterozygosity (LOH) (Ene et al 2018;Ropars et al 2018;Wang, Bennett, and Anderson 2018;Bensasson et al 2019). Moreover, it has been shown that the accumulation of mutations and the exchange of genomic material between strains are the main forces shaping C. albicans genome (Wang, Bennett, and Anderson 2018).…”

mentioning

confidence: 99%

Genomic evidence for a hybrid origin of the yeast opportunistic pathogenCandida albicans

Mixão

Gabaldón

2019

Preprint

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AbstractOpportunistic yeast pathogens are of increasing medical concern. Candida albicans, the species with the highest incidence, is a natural commensal of humans that can adopt a pathogenic behaviour. This species is highly heterozygous, is an obligate diploid, and cannot undergo meiosis, adopting instead a parasexual cycle. The origin of these traits is unknown and we hypothesize they could result from ancestral hybridization. We tested this idea by analyzing available genomes of C. albicans isolates and comparing them to those of hybrid and non-hybrid strains of other Candida species. Our results show compelling evidence that C. albicans is an evolved hybrid, with levels and patterns of ancestral heterozygosity that cannot be fully explained under the paradigm of vertical evolution. Although the level of inferred divergence between the putative parental lineages (2.8%) is not clearly beyond current species boundaries in Saccharomycotina, we show here that all analyzed C. albicans strains derive from a single hybrid ancestor, which diverged by extensive loss of heterozygosis. This finding has important implications for our understanding of C. albicans evolution, including the loss of the sexual cycle, the origin of the association with humans, and the evolution of virulence traits.

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“…While point mutations are quite rare in C. albicans, large-scale genomic rearrangements occur more frequently and are easily detected (Forche et al 2011;Hickman et al 2015;Ene et al 2018). To determine how exposure to antifungal drugs impacts the rate of large-scale rearrangements in diploid and tetraploid C. albicans, we measured the rate of GAL1 loss-ofheterozygosity in both ploidy states.…”

Section: Tetraploid Mutation Rates Are Differentially Impacted By Antmentioning

confidence: 99%

Ploidy determines the consequences of antifungal-induced mutagenesis in Candida albicans, a human fungal pathogen

Avramovska

2019

Preprint

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Organismal ploidy state and environmental stress impact the mutational spectrum and the mutational rate. The human fungal pathogen Candida albicans, serves as a clinically relevant model for studying the interaction between eukaryotic ploidy and stress-induced mutagenesis. In this study, we compared the rates and types of genome perturbations in diploid and tetraploid C. albicans following exposure to two classes of antifungal drugs, azoles and echinocandins. We measured mutations at three different scales: point mutation, loss-ofheterozygosity (LOH), and genome size changes in cells treated with fluconazole and caspofungin. We find that caspofungin induced higher rates of mutation than fluconazole, likely an indirect result from the stress associated with cell wall perturbations rather than an inherent genotoxicity. Furthermore, we found disproportionately elevated rates of LOH and genome size changes in response to both antifungals in tetraploid C. albicans compared to diploid C.albicans, suggesting that the magnitude of stress-induced mutagenesis results from an interaction between ploidy state and the environment. These results have both clinical and evolutionary implications for how fungal pathogens generate mutations in response to antifungal drug stress, and may facilitate the emergence of antifungal resistance.

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

Cited by 123 publications

References 102 publications

Selection of Candida albicans Trisomy during Oropharyngeal Infection Results in a Commensal-Like Phenotype

Selection of Candida albicans Trisomy during Oropharyngeal Infection Results in a Commensal-Like Phenotype

Genomic evidence for a hybrid origin of the yeast opportunistic pathogenCandida albicans

Ploidy determines the consequences of antifungal-induced mutagenesis in Candida albicans, a human fungal pathogen

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