First passage on disordered intervals.

We derive unexpected first-passage properties for nearest-neighbor hopping on finite intervals with disordered hopping rates, including (a) a highly variable spatial dependence of the first-passage time, (b) huge disparities in first-passage times for different realizations of hopping rates, (c) significant discrepancies between the first moment and the square root of the second moment of the first-passage time, and (d) bimodal first-passage time distributions. Our approach relies on the backward equation, in conjunction with probability generating functions, to obtain all moments, as well as the distribution of first-passage times. Our approach is simpler than previous approaches based on the forward equation, in which computing the mth moment of the first-passage time requires all preceding moments.

Solving the time-dependent protein distributions for autoregulated bursty gene expression using spectral decomposition.

In this study, we obtain an exact time-dependent solution of the chemical master equation (CME) of an extension of the two-state telegraph model describing bursty or non-bursty protein expression in the presence of positive or negative autoregulation. Using the method of spectral decomposition, we show that the eigenfunctions of the generating function solution of the CME are Heun functions, while the eigenvalues can be determined by solving a continued fraction equation. Our solution generalizes and corrects a previous time-dependent solution for the CME of a gene circuit describing non-bursty protein expression in the presence of negative autoregulation [Ramos et al., Phys. Rev. E 83, 062902 (2011)]. In particular, we clarify that the eigenvalues are generally not real as previously claimed. We also investigate the relationship between different types of dynamic behavior and the type of feedback, the protein burst size, and the gene switching rate.

The minimal intrinsic stochasticity of constitutively expressed eukaryotic genes is sub-Poissonian.

Gene expression inherently gives rise to stochastic variation ("noise") in the production of gene products. Minimizing noise is crucial for ensuring reliable cellular functions. However, noise cannot be suppressed below a certain intrinsic limit. For constitutively expressed genes, this limit is typically assumed to be Poissonian noise, wherein the variance in mRNA numbers is equal to their mean. Here, we demonstrate that several cell division genes in fission yeast exhibit mRNA variances significantly below this limit. The reduced variance can be explained by a gene expression model incorporating multiple transcription and mRNA degradation steps. Notably, in this sub-Poissonian regime, distinct from Poissonian or super-Poissonian regimes, cytoplasmic noise is effectively suppressed through a higher mRNA export rate. Our findings redefine the lower limit of eukaryotic gene expression noise and uncover molecular requirements for achieving ultralow noise, which is expected to be important for vital cellular functions.

Recurrence and Eigenfunction Methods for Non-Trivial Models of Discrete Binary Choice.

Understanding how systems relax to equilibrium is a core theme of statistical physics, especially in economics, where systems are known to be subject to extrinsic noise not included in simple agent-based models. In models of binary choice-ones not much more complicated than Kirman's model of ant recruitment-such relaxation dynamics become difficult to determine analytically and require solving a three-term recurrence relation in the eigendecomposition of the stochastic process. In this paper, we derive a concise closed-form solution to this linear three-term recurrence relation. Its solution has traditionally relied on cumbersome continued fractions, and we instead employ a linear algebraic approach that leverages the properties of lower-triangular and tridiagonal matrices to express the terms in the recurrence relation using a finite set of orthogonal polynomials. We pay special attention to the power series coefficients of Heun functions, which are also important in fields such as quantum mechanics and general relativity, as well as the binary choice models studied here. We then apply the solution to find equations describing the relaxation to steady-state behavior in social choice models through eigendecomposition. This application showcases the potential of our solution as an off-the-shelf solution to the recurrence that has not previously been reported, allowing for the easy identification of the eigenspectra of one-dimensional, one-step, continuous-time Markov processes.

Non-equilibrium time-dependent solution to discrete choice with social interactions.

We solve the binary decision model of Brock and Durlauf (2001) in time using a method reliant on the resolvent of the master operator of the stochastic process. Our solution is valid when not at equilibrium and can be used to exemplify path-dependent behaviours of the binary decision model. The solution is computationally fast and is indistinguishable from Monte Carlo simulation. Well-known metastable effects are observed in regions of the model's parameter space where agent rationality is above a critical value, and we calculate the time scale at which equilibrium is reached using a highly accurate method based on first passage time theory. In addition to considering selfish agents, who only care to maximise their own utility, we consider altruistic agents who make decisions on the basis of maximising global utility. Curiously, we find that although altruistic agents coalesce more strongly on a particular decision, thereby increasing their utility in the short-term, they are also more prone to being subject to non-optimal metastable regimes as compared to selfish agents. The method used for this solution can be easily extended to other binary decision models, including Kirman's model of ant recruitment Kirman (1993), and under reinterpretation also provides a time-dependent solution to the mean-field Ising model. Finally, we use our time-dependent solution to construct a likelihood function that can be used on non-equilibrium data for model calibration. This is a rare finding, since often calibration in economic agent based models must be done without an explicit likelihood function. From simulated data, we show that even with a well-defined likelihood function, model calibration is difficult unless one has access to data representative of the underlying model.

Distinguishing between models of mammalian gene expression: telegraph-like models versus mechanistic models.

Two-state models (telegraph-like models) have a successful history of predicting distributions of cellular and nascent mRNA numbers that can well fit experimental data. These models exclude key rate limiting steps, and hence it is unclear why they are able to accurately predict the number distributions. To answer this question, here we compare these models to a novel stochastic mechanistic model of transcription in mammalian cells that presents a unified description of transcriptional factor, polymerase and mature mRNA dynamics. We show that there is a large region of parameter space where the first, second and third moments of the distributions of the waiting times between two consecutively produced transcripts (nascent or mature) of two-state and mechanistic models exactly match. In this region: (i) one can uniquely express the two-state model parameters in terms of those of the mechanistic model, (ii) the models are practically indistinguishable by comparison of their transcript numbers distributions, and (iii) they are distinguishable from the shape of their waiting time distributions. Our results clarify the relationship between different gene expression models and identify a means to select between them from experimental data.

Stochastic time-dependent enzyme kinetics: Closed-form solution and transient bimodality.

We derive an approximate closed-form solution to the chemical master equation describing the Michaelis-Menten reaction mechanism of enzyme action. In particular, assuming that the probability of a complex dissociating into an enzyme and substrate is significantly larger than the probability of a product formation event, we obtain expressions for the time-dependent marginal probability distributions of the number of substrate and enzyme molecules. For delta function initial conditions, we show that the substrate distribution is either unimodal at all times or else becomes bimodal at intermediate times. This transient bimodality, which has no deterministic counterpart, manifests when the initial number of substrate molecules is much larger than the total number of enzyme molecules and if the frequency of enzyme-substrate binding events is large enough. Furthermore, we show that our closed-form solution is different from the solution of the chemical master equation reduced by means of the widely used discrete stochastic Michaelis-Menten approximation, where the propensity for substrate decay has a hyperbolic dependence on the number of substrate molecules. The differences arise because the latter does not take into account enzyme number fluctuations, while our approach includes them. We confirm by means of a stochastic simulation of all the elementary reaction steps in the Michaelis-Menten mechanism that our closed-form solution is accurate over a larger region of parameter space than that obtained using the discrete stochastic Michaelis-Menten approximation.

Stochastic Modeling of Autoregulatory Genetic Feedback Loops: A Review and Comparative Study.

Autoregulatory feedback loops are one of the most common network motifs. A wide variety of stochastic models have been constructed to understand how the fluctuations in protein numbers in these loops are influenced by the kinetic parameters of the main biochemical steps. These models differ according to 1) which subcellular processes are explicitly modeled, 2) the modeling methodology employed (discrete, continuous, or hybrid), and 3) whether they can be analytically solved for the steady-state distribution of protein numbers. We discuss the assumptions and properties of the main models in the literature, summarize our current understanding of the relationship between them, and highlight some of the insights gained through modeling.

Revisiting the Reduction of Stochastic Models of Genetic Feedback Loops with Fast Promoter Switching.

Propensity functions of the Hill type are commonly used to model transcriptional regulation in stochastic models of gene expression. This leads to an effective reduced master equation for the mRNA and protein dynamics only. Based on deterministic considerations, it is often stated or tacitly assumed that such models are valid in the limit of rapid promoter switching. Here, starting from the chemical master equation describing promoter-protein interactions, mRNA transcription, protein translation, and decay, we prove that in the limit of fast promoter switching, the distribution of protein numbers is different than that given by standard stochastic models with Hill-type propensities. We show the differences are pronounced whenever the protein-DNA binding rate is much larger than the unbinding rate, a special case of fast promoter switching. Furthermore, we show using both theory and simulations that use of the standard stochastic models leads to drastically incorrect predictions for the switching properties of positive feedback loops and that these differences decrease with increasing mean protein burst size. Our results confirm that commonly used stochastic models of gene regulatory networks are only accurate in a subset of the parameter space consistent with rapid promoter switching.