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PMID: 19876375 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Acquisition of aneuploidy provides increased fitness during the evolution of antifungal drug resistance.

PLoS genetics ·Vol. 5 ·No. 10 ·2009-10-00 ·Pages e1000705

Selmecki AM, Dulmage K, Cowen LE, Anderson JB, Berman J

Abstract

The evolution of drug resistance is an important process that affects clinical outcomes. Resistance to fluconazole, the most widely used antifungal, is often associated with acquired aneuploidy. Here we provide a longitudinal study of the prevalence and dynamics of gross chromosomal rearrangements, including aneuploidy, in the presence and absence of fluconazole during a well-controlled in vitro evolution experiment using Candida albicans, the most prevalent human fungal pathogen. While no aneuploidy was detected in any of the no-drug control populations, in all fluconazole-treated populations analyzed an isochromosome 5L [i(5L)] appeared soon after drug exposure. This isochromosome was associated with increased fitness in the presence of drug and, over time, became fixed in independent populations. In two separate cases, larger supernumerary chromosomes composed of i(5L) attached to an intact chromosome or chromosome fragment formed during exposure to the drug. Other aneuploidies, particularly trisomies of the smaller chromosomes (Chr3-7), appeared throughout the evolution experiment, and the accumulation of multiple aneuploid chromosomes per cell coincided with the highest resistance to fluconazole. Unlike the case in many other organisms, some isolates carrying i(5L) exhibited improved fitness in the presence, as well as in the absence, of fluconazole. The early appearance of aneuploidy is consistent with a model in which C. albicans becomes more permissive of chromosome rearrangements and segregation defects in the presence of fluconazole.

MeSH Terms
Aneuploidy Candida albicans/drug effects,genetics Chromosomes, Fungal Drug Resistance, Fungal/drug effects Evolution, Molecular Fluconazole/pharmacology Genetic Fitness/drug effects Humans
Chemicals
Fluconazole
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Selmecki Anna M
Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota, USA.
Dulmage Keely
Cowen Leah E
Anderson James B
Berman Judith
Conflict of Interest

The authors have declared that no competing interests exist.

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Article Info
Journal
PLoS genetics
Abbr.
PLoS Genet
ISSN
1553-7404
DOI
10.1371/journal.pgen.1000705
Published
2009-10-00
Epub
2009-00-30
Pages
e1000705
Language
English
Region
United States
NLM ID
101239074
PMCID
PMC2760147
Subset
IM
Grants
NIAID NIH HHS · R01 AI075096 · United States
NIAID NIH HHS · R01AI0624273 · United States
NIAID NIH HHS · R01AI075096 · United States
CIHR · MOP-86452 · Canada
External Links
PubMed source DOI: 10.1371/journal.pgen.1000705 PMC Full Text View journal details
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