Characterizing the contribution of mutators to mutation accumulation is essential for understanding cellular adaptation and diseases like cancer. By measuring single and double mutation rates, including point mutations, segmental duplications, and reciprocal translocations, we found that wild-type yeast colonies exhibit double mutation rates up to 17 times higher than expected from experimentally determined single mutation rates. These double mutants retained wild-type mutation rates, indicating they originated from genetically normal cells that transiently expressed a mutator phenotype. Numerical simulations suggest that transient mutator subpopulations likely consist of less than a few thousand cells, and experience high-intensity mutational bursts for less than five generations. Most double mutations accumulated sequentially across cell cycles, with simultaneous acquisition being rare and likely linked to systemic genomic instability. Additionally, we explored the genetic control of transient hypermutation and found that the excess of double mutants can be modulated by replication stress and the DNA damage tolerance pathway. Our findings suggest that transient mutators play a significant role in genomic instability and contribute to the mutational load accumulating in growing isogenic populations.

• PMID: 40490499
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Journal Article

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Agier N, Vittorelli N, Ollivier L, Chaux F, Gillet-Markowska A, O'Donnell S, Pouyet F, Fischer G, Delmas S

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