MODELING AND OPTIMIZATION OF POPULATIONS SUBJECT TO TIME-DEPENDENT MUTATION

It has become clear that many organisms possess the ability to regulate their mutation rate in response to environmental conditions. So the question of finding an optimal mutation rate must be replaced by that of finding an optimal mutation schedule, We show that this task cannot be accomplished with standard population-dynamic models. We then develop a ''hybrid'' model for populations experiencing time-dependent mutation that treats population growth as deterministic but the time of first appearance of new variants as stochastic, We show that the hybrid model agrees well with a Monte Carlo simulation, From this model, we derive a deterministic approximation, a ''threshold'' model, that is similar to standard population dynamic models but differs in the initial rate of generation of new mutants. We use these techniques to model antibody affinity maturation by somatic hypermutation. We had previously shown that the optimal mutation schedule for the deterministic threshold model is phasic, with periods of mutation between intervals of mutation-free growth. To establish the validity of this schedule, we now show that the phasic schedule that optimizes the deterministic threshold model significantly improves upon the best constant-rate schedule for the hybrid and Monte Carlo models.