A transient burst of mutations occurs during the normal development of yeast colonies

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Abstract Characterizing the pace of mutation accumulation is crucial for understanding how populations adapt to their environment and for unraveling the intricate dynamics between gradual processes and more sudden burst-like events occurring during cancer development. We engineered the genome of Saccharomyces cerevisiae to measure the rates of single and double mutations, including point mutations, segmental duplications and reciprocal translocations. We found that during the development of wild-type yeast colonies, double mutations occur at rates that are up to 17-fold higher than those expected on the basis of single mutation rates. We found that this excess of double mutations is partially dependent on the ELG1/ATAD5 clamp unloader. Additionally, the double mutants retain wild-type mutation rates, suggesting that they originated from genetically wild-type cells that transiently expressed a mutator phenotype. Numerical simulations based on the experimentally measured mutation rates, confirmed that the excess of double mutations can be accounted for by subpopulations of transient mutators within the colony. These subpopulations would be limited to less than a few thousand cells and temporarily adopt mutation rates multiplied by hundreds or thousands for less than five generations. We found that the majority of double mutations would accumulate sequentially in different cell cycles. The simultaneous acquisition of both mutations during the same cell cycle would be rare and possibly associated with systemic genomic instability. In conclusion, our results suggest that transient hypermutators play a major role in genomic instability and contribute significantly to the mutational load naturally accumulating during the growth of isogenic cell populations. Significance statement Understanding the pace at which mutations accumulate is of paramount importance in the field of genome dynamics and evolution. In our study, we unveiled a surprising burst of mutations within growing yeast colonies, occurring independently of external stressors. This discovery indicates that, during short intervals, a small subset of cells within the colonies undergoes a mutational overdrive. Notably, these mutator cells do not represent genetically stable mutators with mutations in genes associated with genome stability. Instead, they stem from a strong mutator phenotype that was transiently expressed in genetically wild-type cells. This phenomenon, previously underestimated or even overlooked, holds significant importance and may have far-reaching implications, particularly in the context of cancer development.

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