Spectral theory of stochastic gene expression: a Hilbert space framework

Abstract

A survey of the literature reveals notable discrepancies among the purported exact results for the spectra of stochastic gene expression models. For self-repressing gene circuits, previous studies ([Phys. Rev. Lett. 99, 108103 (2007)], [Phys. Rev. E 83,062902 (2011)], [J. Chem. Phys. 160, 074105 (2024)], and [bioRxiv 2025.02.05.635946 (2025)]) have provided different exact solutions for the eigenvalues of the generator matrix. In this work, we propose a unified Hilbert space framework for the spectral theory of stochastic gene expression. Based on this framework, we analytically derive the spectra for models of constitutive, bursty, and autoregulated gene expression. The eigenvalues and eigenvectors obtained are then used to construct an exact spectral representation of the time-dependent distribution of gene product numbers. The spectral gap between the zero eigenvalue and the first nonzero eigenvalue, which reflects the relaxation rate of the system towards its steady state, is then compared with the prediction of the deterministic model, and we find that deterministic modeling fails to capture the relaxation rate when autoregulation is strong. In particular, our results demonstrate that for infinite-dimensional operators such as in stochastic gene expression models, many conclusions in linear algebra do not apply, and one must rely on the modern theory of functional analysis.