Single cell functional genomics reveals the importance of mitochondria in cell-to-cell phenotypic variation

  1. Riddhiman Dhar
  2. Alsu M Missarova
  3. Ben Lehner  Is a corresponding author
  4. Lucas B Carey  Is a corresponding author
  1. Center for Genomic Regulation, Spain
  2. Universitat Pompeu Fabra, Spain

Abstract

Mutations frequently have outcomes that differ across individuals, even when these individuals are genetically identical and share a common environment. Moreover, individual microbial and mammalian cells can vary substantially in their proliferation rates, stress tolerance, and drug resistance, with important implications for the treatment of infections and cancer. To investigate the causes of cell-to-cell variation in proliferation, we used a high-throughput automated microscopy assay to quantify the impact of deleting >1,500 genes in yeast. Mutations affecting mitochondria were particularly variable in their outcome. In both mutant and wild-type cells mitochondrial membrane potential - but not amount - varied substantially across individual cells and predicted cell-to-cell variation in proliferation, mutation outcome, stress tolerance, and resistance in a clinically used anti-fungal drug. These results suggest an important role for cell-to-cell variation in the state of an organelle in single cell phenotypic variation.

Data availability

RNA-sequencing data that support the findings of this study have been deposited in NCBI GEO with the accession code GSE104343

The following data sets were generated

Article and author information

Author details

  1. Riddhiman Dhar

    Systems Biology Program, Center for Genomic Regulation, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4642-0492
  2. Alsu M Missarova

    Systems Biology Program, Center for Genomic Regulation, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9472-2095
  3. Ben Lehner

    Systems Biology Program, Center for Genomic Regulation, Barcelona, Spain
    For correspondence
    lehner.ben@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8817-1124
  4. Lucas B Carey

    Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
    For correspondence
    lucas.carey@upf.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7245-6379

Funding

H2020 European Research Council (616434)

  • Ben Lehner

AXA Research Fund

  • Ben Lehner

Ministerio de Economía y Competitividad (BFU2011-26206)

  • Ben Lehner

Bettencourt Schueller Foundation

  • Ben Lehner

Ministerio de Economía y Competitividad (BFU2015-68351-P))

  • Lucas B Carey

AGAUR

  • Ben Lehner
  • Lucas B Carey

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

  • Riddhiman Dhar

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

Reviewing Editor

  1. Naama Barkai, Weizmann Institute of Science, Israel

Publication history

  1. Received: June 4, 2018
  2. Accepted: January 13, 2019
  3. Accepted Manuscript published: January 14, 2019 (version 1)
  4. Version of Record published: February 7, 2019 (version 2)

Copyright

© 2019, Dhar 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. Riddhiman Dhar
  2. Alsu M Missarova
  3. Ben Lehner
  4. Lucas B Carey
(2019)
Single cell functional genomics reveals the importance of mitochondria in cell-to-cell phenotypic variation
eLife 8:e38904.
https://doi.org/10.7554/eLife.38904
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