From Genotype to Phenotype: How Molecular Mechanisms and Environmental Stress Dictate Cell Fate

Abstract

In bacteria, stress can produce a variety of distinct phenotypes, including competence, sporulation, persistence, dormancy, and lysis. Yet despite a veritable mountain of genomic data and a growing understanding of the molecular mechanisms, characterizing the rules that dictate the expressed phenotype remains a challenge. This work bridges the gap for three systems at the heart of bacterial stress response: toxin-antitoxin regulation under stress-induced proteolysis, amino acid biosynthesis subject to starvation and the stringent response, and lysogen induction triggered by DNA damage. In each case, a model of the molecular mechanisms is analyzed using novel techniques, and the results quantitatively, rather than qualitatively, describe the kinetic or environmental changes that produce distinct phenotypic behaviors. The results agree with published experiments, answer several open questions, and offer new insights into the links between molecular mechanisms, stress, and cell fate. The core process—the construction and analysis of the system design space—is formalized and automated, offering a tantalizing glimpse of the future in which the full phenotypic repertoire of a system can be predicted and explored.