Abstract #18

Anti-fungal drug Resistance is associated with aneuploidy and isochromosome formation in Candida albicans. Anna Selmecki, Anja Forche, Judith Berman. Dept Genetics, Cell Biol & Dev, Univ Minnesota, Minneapolis, MN.
   In C. albicans, a pathogenic yeast, there is no known meiosis. However, diversity is generated when chromosomes undergo non-disjunction, resulting in aneuploidy. We used Comparative Genome Hybridization (CGH) arrays to identify a common segmental aneuploidy in ~20% of azole-resistant clinical C. albicans strains. This aneuploidy is due to formation of isochromosome i(5L) : a chromosome composed of two copies of the left arm of Ch5 flanking the centromere. In most strains, i(5L) is an independent chromosome while in some strains it is attached, via telomere-telomere interactions, to the left arm of an intact Ch5. We also identify a strain carrying the reciprocal i(5R) isochromosome and this strain, as expected, is not azole-resistant. This work is of interest for several reasons: 1) Strains carrying i(5L) exhibit ‘unstable’ azole resistance—a serious problem in the clinical treatment of candidemia. We show that the acquisition and loss of azole resistance in these clinical strains is associated with acquisition and loss of i(5L); 2) It suggests that companion drugs that prevent isochromosome formation or that facilitate isochromosome loss could extend the usefulness of the limited number of currently available azole anti-fungals; 3) It delimits, for the first time, a C. albicans centromere region, which is intermediate in size between the point centromeres of S. cerevisiae and the regional centromeres of S. pombe; 4) It identifies a small genomic region that is likely to be a fragile site; 5) the C. albicans mating locus is on the left arm of Ch5 and is often homozygosed in azole-resistant strains (Rustad et al, 2002), perhaps via recombination mechanisms that give rise to the isochromosome; and 6) Isochromosomes occur frequently in human cancers. Thus, in C. albicans, as in cancer cells, gross chromosomal rearrangments (e.g., isochromosomes and telomere-telomere attachments) provide a selective advantage under some growth conditions. This is the first study to show that isochromosome formation contributes to virulence in a microorganism.

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