No abstract

First, we revisit the stochastic Luria-Delbrück model: a classic two-type branching process which describes cell proliferation and mutation. We prove limit theorems and exact results for the mutation times, clone sizes, and number of mutants. Second, we extend the framework to consider mutations at multiple sites along the genome. The number of mutants in the two-type model characterises the mean site frequency spectrum in the multiple-site model. Our predictions are consistent with previously published cancer genomic data. MSC 2010 subject classifications: Primary 60J80; secondary 60J28, 92D10, 92D20

Stochastic models of sequential mutation acquisition are widely used to quantify cancer and bacterial evolution. Across manifold scenarios, recurrent research questions are: how many cells are there with n alterations, and how long will it take for these cells to appear. For exponentially growing populations, these questions have been tackled only in special cases so far. Here, within a multitype branching process framework, we consider a general mutational path where mutations may be advantageous, neutral or deleterious. In the biologically relevant limiting regimes of large times and small mutation rates, we derive probability distributions for the number, and arrival time, of cells with n mutations. Surprisingly, the two quantities respectively follow Mittag-Leffler and logistic distributions regardless of n or the mutations’ selective effects. Our results provide a rapid method to assess how altering the fundamental division, death, and mutation rates impacts the arrival time, and number, of mutant cells. We highlight consequences for mutation rate inference in fluctuation assays.