On the dephasing of genetic oscillators

Significance Genetic oscillators are ubiquitous regulatory motifs in the molecular control circuits of living cells. Prominent examples include the cell cycle and cellular signaling. There are two primary sources of noise in these oscillators: the binary character of gene states and the low copy numbers of proteins. This molecular noise induces dephasing in oscillators in analogy to the way imperfections in clocks lead to disparities in time. We can study how these two distinct sources contribute to dephasing and how well it can be approximated by adding noise to a macroscopic model. Using the NFκB/IκB oscillator as an example, we find that gene noise leads to significant deviations from the often-used phenomenological models. The digital nature of genes combined with the associated low copy numbers of proteins regulating them is a significant source of stochasticity, which affects the phase of biochemical oscillations. We show that unlike ordinary chemical oscillators, the dichotomic molecular noise of gene state switching in gene oscillators affects the stochastic dephasing in a way that may not always be captured by phenomenological limit cycle-based models. Through simulations of a realistic model of the NFκB/IκB network, we also illustrate the dephasing phenomena that are important for reconciling single-cell and population-based experiments on gene oscillators.