1. Chromosomes and Gene Expression
  2. Genetics and Genomics

Genome plasticity in Candida albicans is driven by long repeat sequences

  1. Robert T Todd
  2. Tyler D Wikoff
  3. Anja Forche
  4. Anna Selmecki  Is a corresponding author
  1. Creighton University Medical School, United States
  2. Bowdoin College, United States
https://doi.org/10.7554/eLife.45954
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Cite this article
  1. Robert T Todd
  2. Tyler D Wikoff
  3. Anja Forche
  4. Anna Selmecki
(2019)
Genome plasticity in Candida albicans is driven by long repeat sequences
eLife 8:e45954.
https://doi.org/10.7554/eLife.45954
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Abstract

Genome rearrangements resulting in copy number variation (CNV) and loss of heterozygosity (LOH) are frequently observed during the somatic evolution of cancer and promote rapid adaptation of fungi to novel environments. In the human fungal pathogen Candida albicans, CNV and LOH confer increased virulence and antifungal drug resistance, yet the mechanisms driving these rearrangements are not completely understood. Here, we unveil an extensive array of long repeat sequences (65-6499bp) that are associated with CNV, LOH, and chromosomal inversions. Many of these long repeat sequences are uncharacterized and encompass one or more coding sequences that are actively transcribed. Repeats associated with genome rearrangements are predominantly inverted and separated by up to ~1.6Mb, an extraordinary distance for homology-based DNA repair/recombination in yeast. These repeat sequences are a significant source of genome plasticity across diverse strain backgrounds including clinical, environmental, and experimentally evolved isolates, and previously uncharacterized variation in the reference genome.

Data availability

All data generated and analyzed during this study are included in the manuscript and supporting files. Source data files have a been provided for Figure 1, Figure 1-figure supplement 1, Figure 2, Figure 2-figure supplement 2, Figure 2-figure supplement 3, Figure 6, and Figure 6-figure supplement 1.All genomic data are deposited in SRA under accession PRJNA510147.

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The following previously published data sets were used

Article and author information

Author details

  1. Robert T Todd

    Department of Medical Microbiology and Immunology, Creighton University Medical School, Omaha, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4522-7124

  2. Tyler D Wikoff

    Department of Medical Microbiology and Immunology, Creighton University Medical School, Omaha, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Anja Forche

    Department of Biology, Bowdoin College, Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Anna Selmecki

    Department of Medical Microbiology and Immunology, Creighton University Medical School, Omaha, United States
    For correspondence
    annaselmecki@creighton.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3298-2400

Funding

Nebraska LB692 New Initiatives Grants (LB692 NE Tobacco Settlement Biomedical Research Development New Initiative Grant)

  • Anna Selmecki

Nebraska Established Program to Stimulate Competitive Research (EPSCoR First Award)

  • Anna Selmecki

Nebraska Department of Health and Human Services (LB506-2017-55)

  • Anna Selmecki

Creighton University (CURAS Faculty Faculty Research Fund)

  • Anna Selmecki

National Center for Research Resources (P20RR018788 sub award)

  • Anna Selmecki

National Institutes of Health (R15 AI090633)

  • Anja Forche

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Kevin J Verstrepen, VIB-KU Leuven Center for Microbiology, Belgium

Publication history

  1. Received: February 10, 2019
  2. Accepted: June 7, 2019
  3. Accepted Manuscript published: June 7, 2019 (version 1)
  4. Version of Record published: June 24, 2019 (version 2)

Copyright

© 2019, Todd et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Robert T Todd
  2. Tyler D Wikoff
  3. Anja Forche
  4. Anna Selmecki
(2019)
Genome plasticity in Candida albicans is driven by long repeat sequences
eLife 8:e45954.
https://doi.org/10.7554/eLife.45954

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Further reading

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    Previously, we identified long repeat sequences that are frequently associated with genome rearrangements, including copy number variation (CNV), in many diverse isolates of the human fungal pathogen Candida albicans (Todd et al., 2019). Here, we describe the rapid acquisition of novel, high copy number CNVs during adaptation to azole antifungal drugs. Single-cell karyotype analysis indicates that these CNVs appear to arise via a dicentric chromosome intermediate and breakage-fusion-bridge cycles that are repaired using multiple distinct long inverted repeat sequences. Subsequent removal of the antifungal drug can lead to a dramatic loss of the CNV and reversion to the progenitor genotype and drug susceptibility phenotype. These findings support a novel mechanism for the rapid acquisition of antifungal drug resistance and provide genomic evidence for the heterogeneity frequently observed in clinical settings.

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