Cellular turnover can increase or decrease the mutant burden in expanding cell population

Expanding cell populations, such as bacterial and tumor colonies, continuously accumulate mutations as they grow. However, how mutational burden depends on cell turnover, i.e. the ratio of birth and death rates, remains poorly understood. Elucidating this relationship is crucial for predicting how populations adapt to changing environments, including during evolutionary rescue and resistance evolution. Previous theory suggested that higher turnover increases mutant abundance at a given population size, since more cell divisions are required to reach that size. Using well-mixed and spatial stochastic models, we find the relationship is more nuanced. For advantageous mutants, higher turnover does increase mutant numbers. For disadvantageous mutants, however, mutant abundance can actually decreases with turnover or exhibit non-monotonic behavior, with these somewhat counterintuitive patterns being more pronounced in spatially expanding populations. We derive explicit analytical boundaries separating different regimes and quantify the contribution of stochastic “jackpot” events to mutant burden. In spatial models, we show that the interplay between two timescales is critical: the time to reach the target population size versus the time for wild-type cells to erode disadvantageous mutant clusters. Our results reveal how basic demographic parameters influence the ability of cell populations to overcome selective barriers during growth, with implications for understanding both evolution in natural settings and disease progression.