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      The Parasexual Cycle in Candida albicans Provides an Alternative Pathway to Meiosis for the Formation of Recombinant Strains

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          Candida albicans has an elaborate, yet efficient, mating system that promotes conjugation between diploid a and α strains. The product of mating is a tetraploid a/α cell that must undergo a reductional division to return to the diploid state. Despite the presence of several “meiosis-specific” genes in the C. albicans genome, a meiotic program has not been observed. Instead, tetraploid products of mating can be induced to undergo efficient, random chromosome loss, often producing strains that are diploid, or close to diploid, in ploidy. Using SNP and comparative genome hybridization arrays we have now analyzed the genotypes of products from the C. albicans parasexual cycle. We show that the parasexual cycle generates progeny strains with shuffled combinations of the eight C. albicans chromosomes. In addition, several isolates had undergone extensive genetic recombination between homologous chromosomes, including multiple gene conversion events. Progeny strains exhibited altered colony morphologies on laboratory media, demonstrating that the parasexual cycle generates phenotypic variants of C. albicans. In several fungi, including Saccharomyces cerevisiae and Schizosaccharomyces pombe, the conserved Spo11 protein is integral to meiotic recombination, where it is required for the formation of DNA double-strand breaks. We show that deletion of SPO11 prevented genetic recombination between homologous chromosomes during the C. albicans parasexual cycle. These findings suggest that at least one meiosis-specific gene has been re-programmed to mediate genetic recombination during the alternative parasexual life cycle of C. albicans. We discuss, in light of the long association of C. albicans with warm-blooded animals, the potential advantages of a parasexual cycle over a conventional sexual cycle.

          Author Summary

          Candida albicans is an important human fungal pathogen that has an unconventional sexual cycle. Efficient mating requires that diploid cells of opposite mating type first switch from the more common “white” phase to the “opaque” phase and then undergo cell fusion. The resulting tetraploid strains can return to the diploid state via a non-meiotic parasexual program of concerted chromosome loss. We used SNP and comparative genome hybridization to analyze the progeny resulting from this parasexual cycle and found a range of genetically diverse strains with altered phenotypes. In addition, in a subset of these strains, genetic recombination was found to have taken place between homologous chromosomes. This recombination was dependent on Spo11, a conserved protein required for the introduction of DNA double-strand breaks in the chromosomes of eukaryotes that undergo conventional meiosis. Thus, Spo11 is required for genetic recombination and the generation of increased genetic diversity during the C. albicans parasexual cycle.


          The opportunistic pathogen Candida albicans has a cryptic parasexual mating cycle involving epigenetic switching and chromosome loss. This study demonstrates that genetic recombination occurs during the mating cycle and that this requires the activity of Spo11, a protein necessary for meiotic recombination in other eukaryotes.

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            Genetic manipulation of Candida albicans is constrained by its diploid genome and asexual life cycle. Recessive mutations are not expressed when heterozygous and undesired mutations introduced in the course of random mutagenesis cannot be removed by genetic back-crossing. To circumvent these problems, we developed a genotypic screen that permitted identification of a heterozygous recessive mutation at the URA3 locus. The mutation was introduced by targeted mutagenesis, homologous integration of transforming DNA, to avoid introduction of extraneous mutations. The ura3 mutation was rendered homozygous by a second round of transformation resulting in a Ura- strain otherwise isogenic with the parental clinical isolate. Subsequent mutation of the Ura- strain was achieved by targeted mutagenesis using the URA3 gene as a selectable marker. URA3 selection was used repeatedly for the sequential introduction of mutations by flanking the URA3 gene with direct repeats of the Salmonella typhimurium hisG gene. Spontaneous intrachromosomal recombination between the flanking repeats excised the URA3 gene restoring a Ura- phenotype. These Ura- segregants were selected on 5-fluoroorotic acid-containing medium and used in the next round of mutagenesis. To permit the physical mapping of disrupted genes, the 18-bp recognition sequence of the endonuclease I-SceI was incorporated into the hisG repeats. Site-specific cleavage of the chromosome with I-SceI revealed the position of the integrated sequences.
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                Author and article information

                Role: Academic Editor
                PLoS Biol
                PLoS Biology
                Public Library of Science (San Francisco, USA )
                May 2008
                6 May 2008
                : 6
                : 5
                [1 ] Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota, United States of America
                [2 ] Department of Molecular Microbiology and Immunology, Brown University, Providence, Rhode Island, United States of America
                [3 ] Departments of Biochemistry and Biophysics and Microbiology and Immunology, University of California San Francisco, San Francisco, California, United States of America
                Duke University, United States of America
                Author notes
                * To whom correspondence should be addressed. E-mail: Richard_Bennett@ 123456brown.edu
                07-PLBI-RA-3563R3 plbi-06-05-04
                Copyright: © 2008 Forche et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 14
                Research Article
                Genetics and Genomics
                Infectious Diseases
                Custom metadata
                Forche A, Alby K, Schaefer D, Johnson AD, Berman J, et al. (2008) The parasexual cycle in Candida albicans provides an alternative pathway to meiosis for the formation of recombinant strains. PLoS Biol 6(5): e110. doi:10.1371/journal.pbio.0060110

                Life sciences


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