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Exposure to the oral host niche yields rapid phenotypic and genotypic diversification in Candida albicans

View ORCID ProfileA. Forche, G. Cromie, A.C. Gerstein, N. V. Solis, Z. Pisithkul, W. Srifa, E. Jeffery, View ORCID ProfileS.G. Filler, View ORCID ProfileA.M. Dudley, J. Berman
doi: https://doi.org/10.1101/254201
A. Forche
1Department of Biology, Bowdoin College, Brunswick, ME USA
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  • For correspondence: aforche@bowdoin.edu
G. Cromie
2Pacific Northwest Research Institute, Seattle, WA, USA
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A.C. Gerstein
3Department of Microbiology & Immunology, University of Minnesota, Minneapolis MN USA
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N. V. Solis
4Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA USA; Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA USA
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Z. Pisithkul
1Department of Biology, Bowdoin College, Brunswick, ME USA
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W. Srifa
1Department of Biology, Bowdoin College, Brunswick, ME USA
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E. Jeffery
2Pacific Northwest Research Institute, Seattle, WA, USA
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S.G. Filler
4Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA USA; Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA USA
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A.M. Dudley
2Pacific Northwest Research Institute, Seattle, WA, USA
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J. Berman
5School of Molecular Cell Biology & Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
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Abstract

In vitro studies suggest that stress may generate random standing variation, and that different cellular and ploidy states may evolve more rapidly under stress. Yet this idea has not been tested with pathogenic fungi growing within their host niche in vivo. Here, we analyzed the generation of both genotypic and phenotypic diversity during exposure of Candida albicans to the mouse oral cavity. Ploidy, aneuploidy, loss of heterozygosity (LOH) and recombination were determined using flow cytometry and ddRADseq. Colony phenotypic changes (CPs) in size and filamentous growth were evident without selection, and were enriched among colonies selected for LOH of the GAL1 marker. Aneuploidy and LOH occurred on all chromosomes (Chrs), with aneuploidy more frequent for smaller Chrs and whole Chr LOH more frequent for larger Chrs. Large genome shifts in ploidy to haploidy often maintained one or more heterozygous disomic Chrs, consistent with random Chr missegregation events. Most isolates displayed several different types of genomic changes, suggesting that the oral environment rapidly generates diversity de novo. In sharp contrast, following in vitro propagation isolates were not enriched for multiple LOH events, except in those that underwent haploidization and/or had high levels of Chr loss. The frequency of events was overall 100 times higher for C. albicans populations following in vivo passage compared to in vitro. These hyperdiverse in vivo isolates likely provide C. albicans with the ability to adapt rapidly to the diversity of stress environments it encounters inside the host.

Author summary Adaption is a continuous dynamic process that requires genotypic and phenotypic variation. Here we studied the effects of a single passage in a mouse oropharyngeal model of infection on the appearance of diversity in C. albicans, a common commensal of the human oral cavity and GI tract. We found that variation could be rapidly detected following oral colonization, with the frequency of genome change being considerably higher with pre-selection for recombination and colony phenotypic changes. Importantly, one third of all isolates had multiple genome changes, significantly higher than expected by chance alone. We suggest that some cells in the population are naturally hypervariable and that they are a major source of diversity upon which selection can act in stressful conditions in vivo and in vitro.

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Posted January 25, 2018.
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Exposure to the oral host niche yields rapid phenotypic and genotypic diversification in Candida albicans
A. Forche, G. Cromie, A.C. Gerstein, N. V. Solis, Z. Pisithkul, W. Srifa, E. Jeffery, S.G. Filler, A.M. Dudley, J. Berman
bioRxiv 254201; doi: https://doi.org/10.1101/254201
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Exposure to the oral host niche yields rapid phenotypic and genotypic diversification in Candida albicans
A. Forche, G. Cromie, A.C. Gerstein, N. V. Solis, Z. Pisithkul, W. Srifa, E. Jeffery, S.G. Filler, A.M. Dudley, J. Berman
bioRxiv 254201; doi: https://doi.org/10.1101/254201

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