Conditional Moment Closure Schemes for Studying Stochastic Dynamics of Genetic Circuits.

Inside individual cells, stochastic expression drives random fluctuations in gene product copy numbers, which corrupts functioning of both natural and synthetic genetic circuits. Dynamic models of genetic circuits are formulated stochastically using the chemical master equation framework. Since obtaining probability distributions can be computationally expensive in these models, noise is typically investigated through lower-order statistical moments (mean, variance, correlation, skewness, etc.) of mRNA/proteins levels. However, due to the nonlinearities in genetic circuits, this moment dynamics is typically not closed, in the sense that the time derivative of the lower-order statistical moments depends on high-order moments. Moment equations are closed by expressing higher-order moments as nonlinear functions of lower-order moments, a technique commonly referred to as moment closure. We provide a new moment closure scheme for studying stochastic dynamics of genetic circuits, where genes randomly toggle between transcriptionally active and inactive states. The method is based on conditioning protein levels on active states of genes and then expressing higher-order moments as functions of lower-order conditional moments. The conditional closure scheme is illustrated on different circuit motifs and found to outperform existing closure techniques. Rapid computation of stochasticity through closure methods will enable improved characterization and design of synthetic circuits that exhibit robust performance in spite of noisy expression of underlying genes.