Fixation times in differentiation and evolution in the presence of bottlenecks, deserts, and oases

Abstract: Cellular differentiation and evolution are stochastic processes that can involve multiple types (or states) of particles moving on a complex, high-dimensional state-space or "fitness" landscape. Cells of each specific type can thus be quantified by their population at a corresponding node within a network of states. Their dynamics across the state-space network involve genotypic or phenotypic transitions that can occur upon cell division, such as during symmetric or asymmetric cell differentiation, or upon spontaneous mutation. Waiting times between transitions can be nonexponentially distributed and reflect e.g., the cell cycle. Here, we use a multi-type branching processes to study first passage time statistics for a single cell to appear in a specific state. We present results for a sequential evolutionary process in which $L$ successive transitions propel a population from a "wild-type" state to a given "terminally differentiated," "resistant," or "cancerous" state. Analytic and numeric results are also found for first passage times across an evolutionary chain containing a node with increased death or proliferation rate, representing a desert/bottleneck or an oasis. Processes involving cell proliferation are shown to be "nonlinear" (even though mean-field equations for the expected particle numbers are linear) resulting in first passage time statistics that depend on the position of the bottleneck or oasis. Our results highlight the sensitivity of stochastic measures to cell division fate and quantify the limitations of using certain approximations and assumptions (such as fixed-population and mean-field assumptions) in evaluating fixation times.