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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

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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.

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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.

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