Mutation rate balances the need to protect genome integrity with the advantage of evolutionary innovations. Microorganisms increase their mutation rate when stressed, perhaps addressing the growing need for evolutionary innovation. Such a strategy, however, is only beneficial under moderate stresses that allow cells to divide and realize their mutagenic potential. In contrast, severe stresses rapidly kill the majority of the population with the exception of a small minority of cells that are in a phenotypically distinct state termed persistence. Although persisters were discovered many decades ago, the stochastic event triggering persistence is poorly understood. We report that spontaneous DNA damage triggers persistence in Saccharomyces cerevisiae by activating the general stress response, providing protection against a range of harsh stress and drug environments. We further show that the persister subpopulation carries an increased load of genetic variants in the form of insertions, deletions or large structural variations, which are unrelated to their stress survival. This coupling of DNA damage to phenotypic persistence may increase genetic diversity specifically in severe stress conditions, where diversity is beneficial but the ability to generate de novo mutations is limited.
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We thank our group members for discussions and comments. We thank the Weizmann Institute of Science Flow Cytometry unit for support and O. Golani for help with the cell segmentation macro. This work was supported by the Minerva Center, European Research Council and the Israel Science Foundation. K.B. was supported by the European Molecular Biology Organization long-term fellowship.
The authors declare no competing financial interests.
Supplementary figures 1–8, Supplementary note on variant calling. (PDF 14154 kb)
DNA damage precedes Hsp12 induction. (AVI 616 kb)
Emergence of drug-tolerant, DANN-damage-induced extreme cells in an unperturbed population A. (AVI 1644 kb)
Emergence of drug-tolerant, DANN-damage-induced extreme cells in an unperturbed population B. (AVI 5424 kb)
Emergence of drug-tolerant, DANN-damage-induced extreme cells in an unperturbed population C. (AVI 4773 kb)
HO-induced DSBs trigger persistence A. (AVI 502 kb)
HO-induced DSBs trigger persistence B. (AVI 1188 kb)
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Yaakov, G., Lerner, D., Bentele, K. et al. Coupling phenotypic persistence to DNA damage increases genetic diversity in severe stress. Nat Ecol Evol 1, 0016 (2017). https://doi.org/10.1038/s41559-016-0016
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