Long delay times in reaction rates increase intrinsic fluctuations

In spatially distributed cellular systems, it is often convenient to represent complicated auxiliary pathways and spatial transport by time-delayed reaction rates. Furthermore, many of the reactants appear in low numbers necessitating a probabilistic description. The coupling of delayed rates with stochastic dynamics leads to a probability conservation equation characterizing a non-Markovian process. A systematic approximation is derived that incorporates the effect of delayed rates on the characterization of molecular noise valid in the limit of long delay time. By way of a simple example, we show that delayed reaction dynamics can only increase intrinsic fluctuations about the steady state. The method is general enough to accommodate nonlinear transition rates allowing characterization of fluctuations around a delay-induced limit cycle.