Pleiotropy drives evolutionary repair of the responsiveness of polarized cell growth to environmental cues.

The ability of cells to translate different extracellular cues into different intracellular responses is vital for their survival in unpredictable environments. In Saccharomyces cerevisiae, cell polarity is modulated in response to environmental signals which allows cells to adopt varying morphologies in different external conditions. The responsiveness of cell polarity to extracellular cues depends on the integration of the molecular network that regulates polarity establishment with networks that signal environmental changes. The coupling of molecular networks often leads to pleiotropic interactions that can make it difficult to determine whether the ability to respond to external signals emerges as an evolutionary response to environmental challenges or as a result of pleiotropic interactions between traits. Here, we study how the propensity of the polarity network of S. cerevisiae to evolve toward a state that is responsive to extracellular cues depends on the complexity of the environment. We show that the deletion of two genes, BEM3 and NRP1, disrupts the ability of the polarity network to respond to cues that signal the onset of the diauxic shift. By combining experimental evolution with whole-genome sequencing, we find that the restoration of the responsiveness to these cues correlates with mutations in genes involved in the sphingolipid synthesis pathway and that these mutations frequently settle in evolving populations irrespective of the complexity of the selective environment. We conclude that pleiotropic interactions make a significant contribution to the evolution of networks that are responsive to extracellular cues.

Predicting Evolution Using Regulatory Architecture.

The limits of evolution have long fascinated biologists. However, the causes of evolutionary constraint have remained elusive due to a poor mechanistic understanding of studied phenotypes. Recently, a range of innovative approaches have leveraged mechanistic information on regulatory networks and cellular biology. These methods combine systems biology models with population and single-cell quantification and with new genetic tools, and they have been applied to a range of complex cellular functions and engineered networks. In this article, we review these developments, which are revealing the mechanistic causes of epistasis at different levels of biological organization-in molecular recognition, within a single regulatory network, and between different networks-providing first indications of predictable features of evolutionary constraint.

Multistability and dynamic transitions of intracellular Min protein patterns.

Cells owe their internal organization to self-organized protein patterns, which originate and adapt to growth and external stimuli via a process that is as complex as it is little understood. Here, we study the emergence, stability, and state transitions of multistable Min protein oscillation patterns in live Escherichia coli bacteria during growth up to defined large dimensions. De novo formation of patterns from homogenous starting conditions is observed and studied both experimentally and in simulations. A new theoretical approach is developed for probing pattern stability under perturbations. Quantitative experiments and simulations show that, once established, Min oscillations tolerate a large degree of intracellular heterogeneity, allowing distinctly different patterns to persist in different cells with the same geometry. Min patterns maintain their axes for hours in experiments, despite imperfections, expansion, and changes in cell shape during continuous cell growth. Transitions between multistable Min patterns are found to be rare events induced by strong intracellular perturbations. The instances of multistability studied here are the combined outcome of boundary growth and strongly nonlinear kinetics, which are characteristic of the reaction-diffusion patterns that pervade biology at many scales.