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CGH analysis of Candida albicans strains after in vitro evolution in the presence or absence of Fluconazole

ABSTRACT: Here we provide, for the first time, a longitudinal study of the prevalence, dynamics, and fixation of gross chromosomal rearrangements, including aneuploidy, in the presence and absence of fluconazole during a well-controlled in vitro evolution experiment. While no aneuploidy was detected in any of the no-drug control populations, in all fluconazole-treated populations analyzed, isochromosome 5L [i(5L)] appeared soon after drug exposure, was associated with increased fitness in the presence of drug, and became fixed in independent populations. In two separate cases, larger supernumerary chromosomes composed of i(5L) attached to other chromosome fragments appeared and were later lost during exposure to the drug. Other aneuploidies, particularly trisomies of the smaller chromosomes (Chr3-7), appeared throughout the evolution experiment, and the rapid accumulation of multiple aneuploid chromosomes per cell coincided with the highest resistance to fluconazole.

ORGANISM(S): Candida albicans

PROVIDER: GSE16423 | GEO | 2009/12/31

SECONDARY ACCESSION(S): PRJNA116367

REPOSITORIES: GEO

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CGH analysis of Candida albicans strains after in vitro evolution in the presence or absence of Fluconazole

Project description:Here we provide, for the first time, a longitudinal study of the prevalence, dynamics, and fixation of gross chromosomal rearrangements, including aneuploidy, in the presence and absence of fluconazole during a well-controlled in vitro evolution experiment. While no aneuploidy was detected in any of the no-drug control populations, in all fluconazole-treated populations analyzed, isochromosome 5L [i(5L)] appeared soon after drug exposure, was associated with increased fitness in the presence of drug, and became fixed in independent populations. In two separate cases, larger supernumerary chromosomes composed of i(5L) attached to other chromosome fragments appeared and were later lost during exposure to the drug. Other aneuploidies, particularly trisomies of the smaller chromosomes (Chr3-7), appeared throughout the evolution experiment, and the rapid accumulation of multiple aneuploid chromosomes per cell coincided with the highest resistance to fluconazole. All experimental strains were compared to the same reference control - sequenced strain SC5314. Some replicates are included and titled 'slide 2' for a given strain. Whole genomic DNA was used for all samples except the array labeled 'CHEFband' where we isolated DNA from a single CHEF gel band, labeled it, and hybridized it to the array.

2010-06-24 | E-GEOD-16423 | biostudies-arrayexpress

CGH analysis of Candida albicans strains

Project description:Aneuploidy and the evolution of aneuploid karyotypes of Candida albicans strains was identified using aCGH. Whole chromosome and segmental aneuploidies, (specifically on the left arm of chromosome 5 - shown to be due to isochromosome formation) are associated with the appearance of resistance to the antifungal drug fluconazole. Keywords: Comparative Genomic Hybridization

2006-06-30 | GSE4995 | GEO

CGH analysis of Candida albicans strains

2006-06-30 | E-GEOD-4995 | biostudies-arrayexpress

Gene Expression and evolution of antifungal drug resistance

Project description:We examined the gene expression changes resulting from the evolution of resistance in experimental populations of the yeast Saccharomyces cerevisiae subjected to two antifungal drugs, fluconazole (FLC) and amphotericin B (AmB). Fluconazole resistance may involve increased efflux or changes in sterol metabolism, while AmB resistance generally involves changes in sterol metabolism; for all of these types of resistance, the gene expression changes are extensive. The goal of these experiments was to test whether failure of gene expression changes all downstream of the original mutation for drug resistance would affect the ability of a mutant cell to evolve and/or to support a drug-resistant phenotype.

2008-07-28 | GSE12055 | GEO

Role of Ssd1 in modulating protein abundance in aneuploid wild yeast

Project description:We discovered that wild yeast strains can tolerate extra chromosomes, a condition known as aneuploidy, whereas well-studied laboratory strains cannot. Understanding why some cells can tolerate aneuploidy and others cannot could have far-reaching impact, as for example, 85% of solid tumors are aneuploidy and often benefit from extra chromosomes, and thus identifying mechanisms of aneuploidy sensitization could have therapeutic applications.

2020-01-17 | PXD013847 | Pride

Selection of Ethanol Tolerant Strains ofCandida albicansby Repeated Ethanol Exposure Results in Strains with Reduced Susceptibility to Fluconazole

Project description:Candida albicansis a commensal yeast that has important impacts on host metabolism and immune function, and can establish life-threatening infections in immunocompromised individuals. Previously,C. albicanscolonization has been shown to contribute to the progression and severity of alcoholic liver disease. However, relatively little is known about howC. albicansresponds to changing environmental conditions in the GI tract of individuals with alcohol use disorder, namely repeated exposure to ethanol. In this study, we repeatedly exposedC. albicansto high concentrations (10% vol/vol) of ethanol—a concentration that can be observed in the upper GI tract of humans following consumption of alcohol. Following this repeated exposure protocol, ethanol small colony (Esc) variants ofC. albicansisolated from these populations exhibited increased ethanol tolerance, altered transcriptional responses to ethanol, and cross-resistance/tolerance to the frontline antifungal fluconazole. These Esc strains exhibited chromosomal copy number variations and carried polymorphisms in genes previously associated with the acquisition of fluconazole resistance during human infection. This study identifies a selective pressure that can result in evolution of fluconazole tolerance and resistance without previous exposure to the drug.

2024-02-28 | GSE243757 | GEO

Four layer multi-omics reveals molecular responses to aneuploidy in Leishmania

Project description:Aneuploidy causes system-wide disruptions in the stochiometric balances of transcripts, proteins, and metabolites, often resulting in detrimental effects for the organism. The protozoan parasite Leishmania has an unusually high tolerance for aneuploidy, but the molecular and functional consequences for the pathogen remain poorly understood. Here, we addressed this question in vitro and present the first integrated analysis of the genome, transcriptome, proteome, and metabolome of highly aneuploid Leishmania donovani strains. Our analyses unambiguously establish that aneuploidy in Leishmania proportionally impacts the average transcript- and protein abundance levels of affected chromosomes, ultimately correlating with the degree of metabolic differences between strains. This proportionality was present in both proliferative and non-proliferative in vitro promastigotes. However, protein complex subunits and non-cytoplasmic proteins, showed dosage compensation, responding less or even not at all to aneuploidy-induced dosage changes. In contrast to other Eukaryotes, we did not observe the widespread regulation at the transcript level that typically modulates some of the negative effects of aneuploidy. Further, the majority of differentially expressed proteins between aneuploid strains were encoded by non-aneuploid chromosomes and were not driven by a significant underlying transcript change, suggesting that aneuploidy is accompanied by extensive post-transcriptional protein-level modulation. This makes Leishmania a unique Eukaryotic model for elucidating post-transcriptional protein-abundance modulation in the context of aneuploidy. Data availability:Proteomic data associated with this study are available in the PRIDE repository: accession number <a href='https://www.ebi.ac.uk/pride/archive/projects/PXD028521' rel='noopener noreferrer' target='_blank'>PXD028521</a>.

2022-09-19 | MTBLS1612 | MetaboLights

Genome-wide transcriptional response to random aneuploidy in human cells

Project description:Previous studies on transcriptional response to aneuploidy have focused on comparing model cell lines harbouring defined aneuploidy (specific chromosomes) with their parental diploid cell lines. However, the majority of tumours are composed of cancer cells with complex karyotypes (diverse chromosome assortment). Despite this fact, proven functions of random aneuploidies in promoting tumourigenesis are lacking. This prompted us to investigate the transcriptional response to heterogenous cell populations with discernible random aneuploidies.

2019-02-26 | GSE109519 | GEO

Bisulfite-Seq and RNA-seq profiling of Arabidopsis aneuploids

Project description:Aneuploidy refers to gains and/or losses of individual chromosomes from the normal chromosome set. The resulting gene dosage imbalance usually has a deleterious effect on the phenotype, as illustrated in humans by Down Syndrome (trisomy 21) and solid tumor cells, which are typically highly aneuploid. Aneuploidy has been studied for many years in plants and has been a factor contributing to plant chromosome evolution. Nevertheless, there is still relatively little information about how chromosome numerical imbalances affect the molecular constitution of cells and confer altered phenotypes. To investigate these questions we have performed comparative transcriptome (RNA-seq) and methylome (bisulfite-seq) analyses on trisomics (2n+1) of all five chromosomes of Arabidopsis thaliana as well as matched diploids, triploid and tetraploids.

2018-06-20 | GSE79676 | GEO

Mechanisms of Adaptive Evolution of Aneuploid Cells

Project description:Alteration of normal ploidy (aneuploidy) is an important mechanism of evolution of species. It has been linked to a rapid response to stress and is regarded as a hallmark of cancer. While increased genomic instability of aneuploid cells can accelerate genetic diversification and facilitate adaptation, these cells also face the adverse effects of gene imbalance, resulting in fitness cost. Here, to understand the mechanisms through which cells respond to aneuploidy and develop tolerance leading to fitness restoration, we subjected disomic (i.e. with an extra chromosome copy) strains of yeast to long-term experimental evolution, forcing disomy maintenance with selection markers. We characterized mutations, karyotype alterations and gene expression changes throughout adaptive evolution, and analyzed them to dissect the associated molecular strategies. Cells with different extra chromosomes accumulated mutations at distinct rates, and endured a diverse array of adaptive events. Despite remarkable diversity of these events, cells tended to evolve towards normal ploidy through both chromosomal DNA loss and changes in gene expression. We identified genes commonly altered during the evolution of disomic strains, and genes recurrently mutated in multiple lines. Our analyses revealed protein translation, amino acid biosynthesis, transcription regulation, stress response, and nucleotide and protein degradation as key pathways for the adaptive response to aneuploidy and identified transcription factors that mediate this response. Together, these findings define cellular strategies that underlie tolerance to aneuploidy.

2018-08-31 | GSE119272 | GEO

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