Optimal first-passage time in gene regulatory networks

The inherent probabilistic nature of the biochemical reactions, and low copy number of species can lead to stochasticity in gene expression across identical cells. As a result, after induction of gene expression, the time at which a specific protein count is reached is stochastic as well. Therefore events taking place at a critical protein level will see stochasticity in their timing. First-passage time (FPT), the time at which a stochastic process hits a critical threshold, provides a framework to model such events. Here, we investigate stochasticity in FPT. Particularly, we consider events for which controlling stochasticity is advantageous. As a possible regulatory mechanism, we also investigate effect of auto-regulation, where the transcription rate of gene depends on protein count, on stochasticity of FPT. Specifically, we investigate for an optimal auto-regulation which minimizes stochasticity in FPT, given fixed mean FPT and threshold. For this purpose, we model the gene expression at a single cell level. We find analytic formulas for statistical moments of the FPT in terms of model parameters. Moreover, we examine the gene expression model with auto-regulation. Interestingly, our results show that the stochasticity in FPT, for a fixed mean, is minimized when the transcription rate is independent of protein count. Further, we discuss the results in context of lysis time of an \textit{E. coli} cell infected by a $\lambda$ phage virus. An optimal lysis time provides evolutionary advantage to the $\lambda$ phage, suggesting a possible regulation to minimize its stochasticity. Our results indicate that there is no auto-regulation of the protein responsible for lysis. Moreover, congruent to experimental evidences, our analysis predicts that the expression of the lysis protein should have a small burst size.Comment: 8 pages, 3 figures, Submitted to Conference on Decision and Control 201

Comprehensive review of models and methods for inferences in bio-chemical reaction networks

The key processes in biological and chemical systems are described by networks of chemical reactions. From molecular biology to biotechnology applications, computational models of reaction networks are used extensively to elucidate their non-linear dynamics. The model dynamics are crucially dependent on the parameter values which are often estimated from observations. Over the past decade, the interest in parameter and state estimation in models of (bio-) chemical reaction networks (BRNs) grew considerably. The related inference problems are also encountered in many other tasks including model calibration, discrimination, identifiability, and checking, and optimum experiment design, sensitivity analysis, and bifurcation analysis. The aim of this review paper is to examine the developments in literature to understand what BRN models are commonly used, and for what inference tasks and inference methods. The initial collection of about 700 documents concerning estimation problems in BRNs excluding books and textbooks in computational biology and chemistry were screened to select over 270 research papers and 20 graduate research theses. The paper selection was facilitated by text mining scripts to automate the search for relevant keywords and terms. The outcomes are presented in tables revealing the levels of interest in different inference tasks and methods for given models in the literature as well as the research trends are uncovered. Our findings indicate that many combinations of models, tasks and methods are still relatively unexplored, and there are many new research opportunities to explore combinations that have not been considered—perhaps for good reasons. The most common models of BRNs in literature involve differential equations, Markov processes, mass action kinetics, and state space representations whereas the most common tasks are the parameter inference and model identification. The most common methods in literature are Bayesian analysis, Monte Carlo sampling strategies, and model fitting to data using evolutionary algorithms. The new research problems which cannot be directly deduced from the text mining data are also discussed

On moments and timing: stochastic analysis of biochemical systems

Singh, AbhyudaiAt the level of individual living cells, key species such as genes, mRNAs, and proteins are typically present in small numbers. Consequently, the biochemical reactions involving these species are inherently noisy and result in considerable cell-to-cell variability. This thesis outlines two mathematical tools to quantify stochasticity in these biochemical reaction systems: (i) a novel computational method that provides exact lower and upper bounds on statistical moments of population counts of important species, and (ii) a first-passage time framework to study noise in the timing of a cellular event that occurs when population count of an underlying regulatory protein attains a critical threshold. ☐ The method to compute bounds on moments builds upon the well-known linear dynamical system that describes the time evolution of statistical moments. However, except for some ideal cases, this dynamical system is not closed in the sense that lower-order moments depend upon some higher-order moments. To overcome this issue, our method exploits the fact that statistical moments of a random variable must satisfy constraints that are compactly represented through the positive semidefiniteness of moment matrices. We find lower and upper bounds on a moment of interest via a semidefinite program that includes linear constraints obtained from moment dynamics, along with semidefinite constraints on moment matrices. We further show that these bounds improve as the size of the semidefinite program is increased by including dynamics of more moments as well as constraints involving them. We also extend the scope of this method for stochastic hybrid systems, which are a more general class of stochastic systems that integrate discrete and continuous dynamics. ☐ The second tool proposed in this thesis - a first-passage time framework to study event timing - is based on the premise that several cellular events in living cells occur upon attainment of critical levels by corresponding regulatory proteins. Two particular examples that we study here are the lysis of a bacterial cell infected by the virus bacteriophage lambda and the cell-division in exponentially growing bacterial cells. We provide analytical calculations for the first-passage time distribution and its moments for both these examples. We show that the first-passage time statistics can be used to explain several experimentally observed behaviors in both these systems. Finally, the thesis discusses potential directions for future research.University of Delaware, Department of Electrical and Computer EngineeringPh.D

On moments and timing: stochastic analysis of biochemical systems

Singh, AbhyudaiAt the level of individual living cells, key species such as genes, mRNAs, and proteins are typically present in small numbers. Consequently, the biochemical reactions involving these species are inherently noisy and result in considerable cell-to-cell variability. This thesis outlines two mathematical tools to quantify stochasticity in these biochemical reaction systems: (i) a novel computational method that provides exact lower and upper bounds on statistical moments of population counts of important species, and (ii) a first-passage time framework to study noise in the timing of a cellular event that occurs when population count of an underlying regulatory protein attains a critical threshold. ☐ The method to compute bounds on moments builds upon the well-known linear dynamical system that describes the time evolution of statistical moments. However, except for some ideal cases, this dynamical system is not closed in the sense that lower-order moments depend upon some higher-order moments. To overcome this issue, our method exploits the fact that statistical moments of a random variable must satisfy constraints that are compactly represented through the positive semidefiniteness of moment matrices. We find lower and upper bounds on a moment of interest via a semidefinite program that includes linear constraints obtained from moment dynamics, along with semidefinite constraints on moment matrices. We further show that these bounds improve as the size of the semidefinite program is increased by including dynamics of more moments as well as constraints involving them. We also extend the scope of this method for stochastic hybrid systems, which are a more general class of stochastic systems that integrate discrete and continuous dynamics. ☐ The second tool proposed in this thesis - a first-passage time framework to study event timing - is based on the premise that several cellular events in living cells occur upon attainment of critical levels by corresponding regulatory proteins. Two particular examples that we study here are the lysis of a bacterial cell infected by the virus bacteriophage lambda and the cell-division in exponentially growing bacterial cells. We provide analytical calculations for the first-passage time distribution and its moments for both these examples. We show that the first-passage time statistics can be used to explain several experimentally observed behaviors in both these systems. Finally, the thesis discusses potential directions for future research.University of Delaware, Department of Electrical and Computer EngineeringPh.D

Regulating gene expression to achieve temporal precision

Cellular response to an environmental change is often triggered by accumulation of an appropriate gene product up to a critical threshold. How do cells regulate gene expression to achieve precision in timing of such responses is a question of interest. Earlier work has shown that for a stable gene product, a constant rate of accumulation provides minimum noise in the time of response, provided that initial gene product distribution is degenerate. Here, we show that this strategy is no longer optimal if the initial gene product level is drawn from a non-degenerate distribution. Finally, we discuss biological relevance of these findings