1. Evolutionary Biology
  2. Genetics and Genomics
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A modified fluctuation assay reveals a natural mutator phenotype that drives mutation spectrum variation within Saccharomyces cerevisiae

  1. Pengyao Jiang
  2. Anja R Ollodart
  3. Vidha Sudhesh
  4. Alan J Herr
  5. Maitreya J Dunham
  6. Kelley Harris  Is a corresponding author
  1. University of Washington, United States
Research Article
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Cite this article as: eLife 2021;10:e68285 doi: 10.7554/eLife.68285

Abstract

Although studies of Saccharomyces cerevisiae have provided many insights into mutagenesis and DNA repair, most of this work has focused on a few laboratory strains. Much less is known about the phenotypic effects of natural variation within S. cerevisiae's DNA repair pathways. Here, we use natural polymorphisms to detect historical mutation spectrum differences among several wild and domesticated S. cerevisiae strains. To determine whether these differences are likely caused by genetic mutation rate modifiers, we use a modified fluctuation assay with a CAN1 reporter to measure de novo mutation rates and spectra in 16 of the analyzed strains. We measure a 10-fold range of mutation rates and identify two strains with distinctive mutation spectra. These strains, known as AEQ and AAR, come from the panel's 'Mosaic beer' clade and share an enrichment for C>A mutations that is also observed in rare variation segregating throughout the genomes of several Mosaic beer and Mixed origin strains. Both AEQ and AAR are haploid derivatives of the diploid natural isolate CBS 1782, whose rare polymorphisms are enriched for C>A as well, suggesting that the underlying mutator allele is likely active in nature. We use a plasmid complementation test to show that AAR and AEQ share a mutator allele in the DNA repair gene OGG1, which excises 8-oxoguanine lesions that can cause C>A mutations if left unrepaired.

Data availability

Sequencing data have been uploaded to the SRA and approved (Accession numbers PRJNA691686).

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Pengyao Jiang

    Genome Sciences, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Anja R Ollodart

    Genome Sciences, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Vidha Sudhesh

    Genome Sciences, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Alan J Herr

    Genome Sciences, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9498-0972
  5. Maitreya J Dunham

    Department of Genome Sciences, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9944-2666
  6. Kelley Harris

    Genome Sciences, University of Washington, Seattle, United States
    For correspondence
    harriske@uw.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0302-2523

Funding

National Institute of General Medical Sciences (1R35GM133428-01)

  • Kelley Harris

National Institute of General Medical Sciences (P41GM103533)

  • Maitreya J Dunham

National Institute of General Medical Sciences (R01GM118854)

  • Alan J Herr

Burroughs Wellcome Fund (Career Award at the Scientific Interface)

  • Kelley Harris

Kinship Foundation (Searle Scholarship)

  • Kelley Harris

Pew Charitable Trusts (Pew Scholarship)

  • Kelley Harris

Alfred P. Sloan Foundation (Sloan Fellowship)

  • Kelley Harris

National Human Genome Research Institute (T32HG00035)

  • Anja R Ollodart

Howard Hughes Medical Institute (Faculty Scholar Award)

  • Maitreya J Dunham

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

Reviewing Editor

  1. Magnus Nordborg, Austrian Academy of Sciences, Austria

Publication history

  1. Received: March 11, 2021
  2. Accepted: September 14, 2021
  3. Accepted Manuscript published: September 15, 2021 (version 1)

Copyright

© 2021, Jiang 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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