@article {22088, title = {In silico Evolution of Lysis-Lysogeny Strategies Reproduces Observed Lysogeny Propensities in Temperate Bacteriophages.}, journal = {Front Microbiol}, volume = {8}, year = {2017}, month = {2017}, pages = {1386}, abstract = {

Bacteriophages are the most abundant organisms on the planet and both lytic and temperate phages play key roles as shapers of ecosystems and drivers of bacterial evolution. Temperate phages can choose between (i) lysis: exploiting their bacterial hosts by producing multiple phage particles and releasing them by lysing the host cell, and (ii) lysogeny: establishing a potentially mutually beneficial relationship with the host by integrating their chromosome into the host cell{\textquoteright}s genome. Temperate phages exhibit lysogeny propensities in the curiously narrow range of 5-15\%. For some temperate phages, the propensity is further regulated by the multiplicity of infection, such that single infections go predominantly lytic while multiple infections go predominantly lysogenic. We ask whether these observations can be explained by selection pressures in environments where multiple phage variants compete for the same host. Our models of pairwise competition, between phage variants that differ only in their propensity to lysogenize, predict the optimal lysogeny propensity to fall within the experimentally observed range. This prediction is robust to large variation in parameters such as the phage infection rate, burst size, decision rate, as well as bacterial growth rate, and initial phage to bacteria ratio. When we compete phage variants whose lysogeny strategies are allowed to depend upon multiplicity of infection, we find that the optimal strategy is one which switches from full lysis for single infections to full lysogeny for multiple infections. Previous attempts to explain lysogeny propensity have argued for bet-hedging that optimizes the response to fluctuating environmental conditions. Our results suggest that there is an additional selection pressure for lysogeny propensity within phage populations infecting a bacterial host, independent of environmental conditions.

}, issn = {1664-302X}, doi = {10.3389/fmicb.2017.01386}, author = {Sinha, Vaibhhav and Goyal, Akshit and Svenningsen, Sine L and Semsey, Szabolcs and Krishna, Sandeep} } @article {997, title = {Effects of Four Different Regulatory Mechanisms on the Dynamics of Gene Regulatory Cascades.}, journal = {Sci Rep}, volume = {5}, year = {2015}, month = {2015}, pages = {12186}, abstract = {

Gene regulatory cascades (GRCs) are common motifs in cellular molecular networks. A given logical function in these cascades, such as the repression of the activity of a transcription factor, can be implemented by a number of different regulatory mechanisms. The potential consequences for the dynamic performance of the GRC of choosing one mechanism over another have not been analysed systematically. Here, we report the construction of a synthetic GRC in Escherichia coli, which allows us for the first time to directly compare and contrast the dynamics of four different regulatory mechanisms, affecting the transcription, translation, stability, or activity of a transcriptional repressor. We developed a biologically motivated mathematical model which is sufficient to reproduce the response dynamics determined by experimental measurements. Using the model, we explored the potential response dynamics that the constructed GRC can perform. We conclude that dynamic differences between regulatory mechanisms at an individual step in a GRC are often concealed in the overall performance of the GRC, and suggest that the presence of a given regulatory mechanism in a certain network environment does not necessarily mean that it represents a single optimal evolutionary solution.

}, issn = {2045-2322}, doi = {10.1038/srep12186}, author = {Hansen, Sabine and Krishna, Sandeep and Semsey, Szabolcs and Svenningsen, Sine Lo} } @article {1006, title = {Restriction modification systems as engines of diversity.}, journal = {Front Microbiol}, volume = {6}, year = {2015}, month = {2015}, pages = {528}, abstract = {

Restriction modification (RM) systems provide protection against a broad spectrum of phages. However, the likelihood of a phage permanently bypassing this can be as high as 0.1 per infection (Korona et al., 1993) which makes for a relatively weak defense. Here we argue that, apart from providing such transient defenses, RM systems can facilitate long-term coexistence of many bacterial strains. We show that this diversity can be as large as the burst size of the phage but no larger-a curious correspondence between a number at the level of species and another number at the level of individuals. Such a highly diverse and stably coexisting ecosystem is robust to substantial variation in both bacterial growth rates and strength of their RM systems, which might be one reason why quite weak RM systems exist in the wild.

}, issn = {1664-302X}, doi = {10.3389/fmicb.2015.00528}, author = {Sneppen, Kim and Semsey, Szabolcs and Seshasayee, Aswin S N and Krishna, Sandeep} } @article {1034, title = {The role of mRNA and protein stability in the function of coupled positive and negative feedback systems in eukaryotic cells.}, journal = {Sci Rep}, volume = {5}, year = {2015}, month = {2015}, pages = {13910}, abstract = {

Oscillators and switches are important elements of regulation in biological systems. These are composed of coupling negative feedback loops, which cause oscillations when delayed, and positive feedback loops, which lead to memory formation. Here, we examine the behavior of a coupled feedback system, the Negative Autoregulated Frustrated bistability motif (NAF). This motif is a combination of two previously explored motifs, the frustrated bistability motif (FBM) and the negative auto regulation motif (NAR), which both can produce oscillations. The NAF motif was previously suggested to govern long term memory formation in animals, and was used as a synthetic oscillator in bacteria. We build a mathematical model to analyze the dynamics of the NAF motif. We show analytically that the NAF motif requires an asymmetry in the strengths of activation and repression links in order to produce oscillations. We show that the effect of time delays in eukaryotic cells, originating from mRNA export and protein import, are negligible in this system. Based on the reported protein and mRNA half-lives in eukaryotic cells, we find that even though the NAF motif possesses the ability for oscillations, it mostly promotes constant protein expression at the biologically relevant parameter regimes.

}, issn = {2045-2322}, doi = {10.1038/srep13910}, author = {Moss Bendtsen, Kristian and Jensen, Mogens H and Krishna, Sandeep and Semsey, Szabolcs} }