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

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.

The following data sets were generated
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.

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.

Metrics

  • 6,566
    views
  • 717
    downloads
  • 96
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

https://doi.org/10.7554/eLife.45954

Further reading

    1. Chromosomes and Gene Expression
    2. Evolutionary Biology
    Gülnihal Kavaklioglu, Alexandra Podhornik ... Christian Seiser
    Research Article

    Repression of retrotransposition is crucial for the successful fitness of a mammalian organism. The domesticated transposon protein L1TD1, derived from LINE-1 (L1) ORF1p, is an RNA-binding protein that is expressed only in some cancers and early embryogenesis. In human embryonic stem cells, it is found to be essential for maintaining pluripotency. In cancer, L1TD1 expression is highly correlative with malignancy progression and as such considered a potential prognostic factor for tumors. However, its molecular role in cancer remains largely unknown. Our findings reveal that DNA hypomethylation induces the expression of L1TD1 in HAP1 human tumor cells. L1TD1 depletion significantly modulates both the proteome and transcriptome and thereby reduces cell viability. Notably, L1TD1 associates with L1 transcripts and interacts with L1 ORF1p protein, thereby facilitating L1 retrotransposition. Our data suggest that L1TD1 collaborates with its ancestral L1 ORF1p as an RNA chaperone, ensuring the efficient retrotransposition of L1 retrotransposons, rather than directly impacting the abundance of L1TD1 targets. In this way, L1TD1 might have an important role not only during early development but also in tumorigenesis.

    1. Chromosomes and Gene Expression
    Shihui Chen, Carolyn Marie Phillips
    Research Article

    RNA interference (RNAi) is a conserved pathway that utilizes Argonaute proteins and their associated small RNAs to exert gene regulatory function on complementary transcripts. While the majority of germline-expressed RNAi proteins reside in perinuclear germ granules, it is unknown whether and how RNAi pathways are spatially organized in other cell types. Here, we find that the small RNA biogenesis machinery is spatially and temporally organized during Caenorhabditis elegans embryogenesis. Specifically, the RNAi factor, SIMR-1, forms visible concentrates during mid-embryogenesis that contain an RNA-dependent RNA polymerase, a poly-UG polymerase, and the unloaded nuclear Argonaute protein, NRDE-3. Curiously, coincident with the appearance of the SIMR granules, the small RNAs bound to NRDE-3 switch from predominantly CSR-class 22G-RNAs to ERGO-dependent 22G-RNAs. NRDE-3 binds ERGO-dependent 22G-RNAs in the somatic cells of larvae and adults to silence ERGO-target genes; here we further demonstrate that NRDE-3-bound, CSR-class 22G-RNAs repress transcription in oocytes. Thus, our study defines two separable roles for NRDE-3, targeting germline-expressed genes during oogenesis to promote global transcriptional repression, and switching during embryogenesis to repress recently duplicated genes and retrotransposons in somatic cells, highlighting the plasticity of Argonaute proteins and the need for more precise temporal characterization of Argonaute-small RNA interactions.