A Bayesian approach to inferring chemical signal timing and amplitude in a temporal logic gate using the cell population distributional response

摘要

Stochastic gene expression poses an important challenge for engineering robust behaviors in a heterogeneous cell population. Cells address this challenge by operating on distributions of cellular responses generated by noisy processes. Similarly, a previously published temporal logic gate considers the distribution of responses across a cell population under chemical inducer pulsing events. The design uses a system of two integrases to engineer an E. coli strain with four DNA states that records the temporal order of two chemical signal events. The heterogeneous cell population response was used to infer the timing and duration of the two chemical signals for a small set of events. Here we use the temporal logic gate system to address the problem of extracting information about chemical signal events. We use the heterogeneous cell population response to infer whether any event has occurred or not and also to infer its properties such as timing and amplitude. Bayesian inference provides a natural framework to answer our questions about chemical signal occurrence, timing, and amplitude. We develop a probabilistic model that incorporates uncertainty in the how well our model captures the cell population and in how well a sample of measured cells represents the entire population. Using our probabilistic model and cell population measurements taken every five minutes on generated data, we ask how likely it was to observe the data for parameter values that describe square-shaped inducer pulses. We compare the likelihood functions associated with the probabilistic models for the event with the chemical signal pulses turned on versus turned off. Hence, we can determine whether an event of chemical induction of integrase expression has occurred or not. Using Markov Chain Monte Carlo, we sample the posterior distribution of chemical pulse parameters to identify likely pulses that produce the data measurements. We implement this method and obtain accurate results for detecting chemical inducer pulse timing, length, and amplitude. We can detect and identify chemical inducer pulses as short as half an hour, as well as all pulse amplitudes that fall under biologically relevant conditions.