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1.  Genetic Architecture Promotes the Evolution and Maintenance of Cooperation 
PLoS Computational Biology  2013;9(11):e1003339.
When cooperation has a direct cost and an indirect benefit, a selfish behavior is more likely to be selected for than an altruistic one. Kin and group selection do provide evolutionary explanations for the stability of cooperation in nature, but we still lack the full understanding of the genomic mechanisms that can prevent cheater invasion. In our study we used Aevol, an agent-based, in silico genomic platform to evolve populations of digital organisms that compete, reproduce, and cooperate by secreting a public good for tens of thousands of generations. We found that cooperating individuals may share a phenotype, defined as the amount of public good produced, but have very different abilities to resist cheater invasion. To understand the underlying genetic differences between cooperator types, we performed bio-inspired genomics analyses of our digital organisms by recording and comparing the locations of metabolic and secretion genes, as well as the relevant promoters and terminators. Association between metabolic and secretion genes (promoter sharing, overlap via frame shift or sense-antisense encoding) was characteristic for populations with robust cooperation and was more likely to evolve when secretion was costly. In mutational analysis experiments, we demonstrated the potential evolutionary consequences of the genetic association by performing a large number of mutations and measuring their phenotypic and fitness effects. The non-cooperating mutants arising from the individuals with genetic association were more likely to have metabolic deleterious mutations that eventually lead to selection eliminating such mutants from the population due to the accompanying fitness decrease. Effectively, cooperation evolved to be protected and robust to mutations through entangled genetic architecture. Our results confirm the importance of second-order selection on evolutionary outcomes, uncover an important genetic mechanism for the evolution and maintenance of cooperation, and suggest promising methods for preventing gene loss in synthetically engineered organisms.
Author Summary
Cooperation is a much studied and debated phenomena in the microbial world marked by a key question: Given the survival of the fittest evolutionary paradigm, why do individuals act in seemingly altruistic ways, paying a cost to help others? Kin selection and group selection, together with mathematical tools from areas such as economics and game theory, have provided some answers. However, they largely ignored the underlying genetic and genomic mechanisms that drive the evolution of cooperation. In this study, we show that the architecture of the genomes has a major role in shaping the fate of cooperating populations. Specifically, we use an in silico evolution platform and discover that genes for cooperative traits are “hiding” behind metabolic ones by overlapping their sequences or sharing operons. In conditions where cheaters may outcompete the cooperators, this entangled architecture evolves spontaneously and effectively protects cooperation from invasion by cheater mutants. We describe a novel genetic mechanism for the evolution and maintenance of cooperation and, by taking into account the second order selection pressures on the genomes, highlight the need for going beyond simple game theory models in its study.
doi:10.1371/journal.pcbi.1003339
PMCID: PMC3836702  PMID: 24278000
2.  Expression of a Novel P22 ORFan Gene Reveals the Phage Carrier State in Salmonella Typhimurium 
PLoS Genetics  2013;9(2):e1003269.
We discovered a novel interaction between phage P22 and its host Salmonella Typhimurium LT2 that is characterized by a phage mediated and targeted derepression of the host dgo operon. Upon further investigation, this interaction was found to be instigated by an ORFan gene (designated pid for phage P22 encoded instigator of dgo expression) located on a previously unannotated moron locus in the late region of the P22 genome, and encoding an 86 amino acid protein of 9.3 kDa. Surprisingly, the Pid/dgo interaction was not observed during strict lytic or lysogenic proliferation of P22, and expression of pid was instead found to arise in cells that upon infection stably maintained an unintegrated phage chromosome that segregated asymmetrically upon subsequent cell divisions. Interestingly, among the emerging siblings, the feature of pid expression remained tightly linked to the cell inheriting this phage carrier state and became quenched in the other. As such, this study is the first to reveal molecular and genetic markers authenticating pseudolysogenic development, thereby exposing a novel mechanism, timing, and populational distribution in the realm of phage–host interactions.
Author Summary
Viruses of bacteria, also referred to as (bacterio)phages, are the most abundant biological entity on earth and have a tremendous impact on the ecology of their hosts. It has traditionally been recognized that upon infection by a temperate phage the host cell is forced either to produce and release new virions during lytic development or to replicate and segregate the phage chromosome together with its own genetic material during lysogenic development. These developmental paths are orchestrated by a dedicated set of phage–host interactions that are able to sense and redirect host cell physiology. In addition to this classical bifurcation of temperate phage development, many studies on phage biology in natural ecosystems hypothesize the existence and significance of stable phage carrier cells that are not engaged in either lytic or lysogenic proliferation. Using Salmonella Typhimurium and phage P22 as a model system, we provide substantial evidence authenticating the existence of the phage carrier state and demonstrate that this state (i) is asymmetrically inherited among carrier cell siblings and (ii) enables the execution of a novel phage–host interaction that is not encountered during lytic or lysogenic proliferation.
doi:10.1371/journal.pgen.1003269
PMCID: PMC3573128  PMID: 23483857
3.  Trade-Off between Bile Resistance and Nutritional Competence Drives Escherichia coli Diversification in the Mouse Gut 
PLoS Genetics  2011;7(6):e1002107.
Bacterial diversification is often observed, but underlying mechanisms are difficult to disentangle and remain generally unknown. Moreover, controlled diversification experiments in ecologically relevant environments are lacking. We studied bacterial diversification in the mammalian gut, one of the most complex bacterial environments, where usually hundreds of species and thousands of bacterial strains stably coexist. Herein we show rapid genetic diversification of an Escherichia coli strain upon colonisation of previously germ-free mice. In addition to the previously described mutations in the EnvZ/OmpR operon, we describe the rapid and systematic selection of mutations in the flagellar flhDC operon and in malT, the transcriptional activator of the maltose regulon. Moreover, within each mouse, the three mutant types coexisted at different levels after one month of colonisation. By combining in vivo studies and determination of the fitness advantages of the selected mutations in controlled in vitro experiments, we provide evidence that the selective forces that drive E. coli diversification in the mouse gut are the presence of bile salts and competition for nutrients. Altogether our results indicate that a trade-off between stress resistance and nutritional competence generates sympatric diversification of the gut microbiota. These results illustrate how experimental evolution in natural environments enables identification of both the selective pressures that organisms face in their natural environment and the diversification mechanisms.
Author Summary
The mechanisms generating the huge biodiversity on earth are not entirely understood. Bacterial populations are powerful models to explore the mechanisms of evolution, owing to their big population size, rapid growth, and high mutation rate. One of the more complex bacterial community is the mammalian gut microbiota, and Escherichia coli is one of the first colonizers of the newborn intestine. Herein we studied diversification of an Escherichia coli strain in germ-free mice, a simplified though ecologically relevant system. We show rapid genetic diversification upon colonization, characterized by the systematic selection of mutations in three different pathways: in the global regulator EnvZ/OmpR controlling outer membrane permeability, in the flagellar operon, and in the maltose regulon. By combining in vivo and in vitro experiments, we show that the selective forces that drive E. coli diversification are the presence of bile salts and the competition for nutrients. Altogether our results indicate that a trade-off between stress resistance and nutritional competence is sufficient to mediate diversification of bacteria. These results illustrate how experimental evolution in natural environments allows the identification of the selective pressures that organisms face in their natural environment, as well as the diversification mechanisms.
doi:10.1371/journal.pgen.1002107
PMCID: PMC3116916  PMID: 21698140
4.  Evidence for an evolutionary antagonism between Mrr and Type III modification systems 
Nucleic Acids Research  2011;39(14):5991-6001.
The Mrr protein of Escherichia coli is a laterally acquired Type IV restriction endonuclease with specificity for methylated DNA. While Mrr nuclease activity can be elicited by high-pressure stress in E. coli MG1655, its (over)expression per se does not confer any obvious toxicity. In this study, however, we discovered that Mrr of E. coli MG1655 causes distinct genotoxicity when expressed in Salmonella typhimurium LT2. Genetic screening enabled us to contribute this toxicity entirely to the presence of the endogenous Type III restriction modification system (StyLTI) of S. typhimurium LT2. The StyLTI system consists of the Mod DNA methyltransferase and the Res restriction endonuclease, and we revealed that expression of the LT2 mod gene was sufficient to trigger Mrr activity in E. coli MG1655. Moreover, we could demonstrate that horizontal acquisition of the MG1655 mrr locus can drive the loss of endogenous Mod functionality present in S. typhimurium LT2 and E. coli ED1a, and observed a strong anti-correlation between close homologues of MG1655 mrr and LT2 mod in the genome database. This apparent evolutionary antagonism is further discussed in the light of a possible role for Mrr as defense mechanism against the establishment of epigenetic regulation by foreign DNA methyltransferases.
doi:10.1093/nar/gkr219
PMCID: PMC3152355  PMID: 21504983
5.  Emergence of Variability in Isogenic Escherichia coli Populations Infected by a Filamentous Virus 
PLoS ONE  2010;5(7):e11823.
The spread of epidemics not only depends on the average number of parasites produced per host, but also on the existence of highly infectious individuals. It is widely accepted that infectiousness depends on genetic and environmental determinants. However, even in clonal populations of host and viruses growing in homogeneous conditions, high variability can exist. Here we show that Escherichia coli cells commonly display high differentials in viral burst size, and address the kinetics of emergence of such variability with the non-lytic filamentous virus M13. By single-cell imaging of a virally-encoded fluorescent reporter, we monitor the viral charge distribution in infected bacterial populations at different time following infection. A mathematical model assuming autocatalytic virus replication and inheritance of bacterial growth rates quantitatively reproduces the experimental distributions, demonstrating that deterministic amplification of small host inhomogeneities is a mechanism sufficient to explain large and highly skewed distributions. This mechanism of amplification is general and may occur whenever a parasite has an initial phase of exponential growth within its host. Moreover, it naturally reproduces the shift towards higher virulence when the host is experimenting poor conditions, as observed commonly in host-parasite systems.
doi:10.1371/journal.pone.0011823
PMCID: PMC2910729  PMID: 20676396
6.  Pre-dispositions and epigenetic inheritance in the Escherichia coli lactose operon bistable switch 
Under conditions of bistable induction of Escherichia coli lac operon, epigenetic patterns of sublineages of ‘on' and ‘off' cells originate from distinguishable ancestors up to two generations before induction.We found two switching pre-disposing factors, namely low repressor levels and slow growth, demonstrating that stochasticity in gene expression and global physiology synergistically determine the single-cell responses.A quantitative model where growth rate acts through simple dilution of intracellular content and repressor level controls the basal activity of the operon demonstrates that both growth rate and repressor concentration influence the cell switching ability.
The bacterium Escherichia coli, like many other microorganisms can use different sugars as a carbon source and uses some of these sugars in preference to others. For example, when grown in the presence of both lactose and glucose, the bacteria first consume glucose and use lactose only when glucose is exhausted. To this end, the enzymes necessary for lactose uptake and metabolism, grouped in one transcriptional unit called the lac operon (lacZ, Y, A encoding for the lactose degrading enzyme (β-galactosidase), permease and transacetylase, respectively) are produced only in the absence of glucose and in the presence of lactose or its analogs, such as the non-metabolizable analog thiomethyl-β-galactoside (TMG). In the absence of such inducers, the transcription of the operon is inhibited by the repressor molecule LacI. This inhibition is relieved by the inducers, which bind and inactivate LacI, initiating an amplifying feedback loop through the expression of the permease that ensures a high influx of inducer to maintain the operon's expression in the ‘on' state. This phenomenon of adaptive enzyme production has been widely studied since its discovery by Jacques Monod and François Jacob and is one of the most famous and best characterized examples of transcriptional gene regulation. E. coli lactose operon is also a paradigm of cellular differentiation. Indeed, in the presence of an intermediate concentration of TMG, an isogenic bacterial population is divided in two subpopulations of cells with the operon's genes either turned on or remaining off. The differentiation step is generally hypothesized to depend on fluctuations in expression of the operon's proteins. Nevertheless, it is still poorly characterized. On the basis of experimental and theoretical approaches, we explored the determinants of cell fate in this system.
We designed a microfluidic device allowing the observation of single cells growing within a microcolony under conditions that can be changed at will. We used this setup to study phenotypic variability in the lactose operon induction under conditions leading to a transient bimodality of lac expression in the population. We used an E. coli strain modified to express the yellow fluorescent protein (YFP) and the cyan fluorescent protein (CFP), both under the control of a promoter regulated by LacI (PLlacO1). Therefore, yellow and cyan fluorescence intensities both represent the concentration of active repressor molecules and indirectly, the expression state of the lactose operon. Microcolonies originating from a single cell were grown in the microfluidic device and followed by time-lapse microscopy. During the first generations of growth, cells were grown in the absence (or with a very low concentration) of inducer and after several generations, TMG was introduced at intermediate concenteration into the medium and maintained thereafter. In the absence of TMG, cells exhibit an overall weak fluorescence yet with significant variations between cells that were shown to correspond in part to the variability in the intracellular concentration of active LacI molecules. Upon induction, transient bimodality is observed, as the cells are divided between two subpopulations of bright and dim fluorescence.
We found a strong clustering of induced cells within their genealogical trees, indicating a substantial epigenetic inheritance. This epigenetic inheritance can be traced back up to two generations prior induction, suggesting that some molecular determinants of cell fate are epigenetically inherited with a short-range memory lasting around two divisions.
The promoter used to control fluorescence proteins expression is sensitive to small variations in active LacI concentration. Thus, in the absence of inducer, these variations result into correlated variations of YFP and CFP levels. We used the arithmetical mean of yellow and cyan fluorescence intensities to estimate the concentration of active LacI in the cells. We found that the cells exhibiting a low LacI concentration before induction are more likely to be induced upon TMG introduction. Likewise, the slowly growing cells were found to have a higher switching probability than the fast-growing ones. We used a multivariate analysis based on a generalized linear model to estimate the correlations of pre-induction LacI concentration and growth rate with the switching probability (Figure 5C). This analysis confirms that both LacI concentration and growth rate are correlated with the switching probability and demonstrates that even though LacI concentration and growth rate can be linked, their correlations with the switching probability represent independent effects. Together, these effects can account for 90% of the observed switching events.
To gain a better understanding of the possible influence of LacI expression fluctuations and growth rate on the switching probability of a cell, we used a model consisting in a system of differential equations and describing the dynamics of the lactose utilization network. In this model, LacI concentration controls the basal level of expression of the operon and the growth rate acts through the dilution of intracellular components. According to this model, depending on both LacI concentration and growth rate, a cell can be in a monostable or bistable regime. Therefore, monostable and bistable cells can coexist in the population due to parameters' variability. In addition, for cells in the bistable regime, the size of the minimal LacY burst necessary to trigger induction increases with LacI concentration and growth rate. Thus, in agreement with our experimental results, these two variables control the sensitivity of the cell to permease bursts and therefore influence its switching probability.
We thus found pre-disposing factors governing the lactose operon switching in a regime of transient bimodality. Some factors, such as LacI and LacY concentrations result from stochasticity at the local level of the network. On the contrary, growth rate variability represents variations in the cell global physiology. Therefore, the effects of local stochasticity are coupled with the influence of the global physiology, demonstrating the importance of considering the embedding of a particular genetic network in the whole cellular physiology to understand fully its dynamics.
The lactose operon regulation in Escherichia coli is a primary model of phenotypic switching, reminiscent of cell fate determination in higher organisms. Under conditions of bistability, an isogenic cell population partitions into two subpopulations, with the operon's genes turned on or remaining off. It is generally hypothesized that the final state of a cell depends solely on stochastic fluctuations of the network's protein concentrations, particularly on bursts of lactose permease expression. Nevertheless, the mechanisms underlying the cell switching decision are not fully understood. We designed a microfluidic system to follow the formation of a transiently bimodal population within growing microcolonies. The analysis of genealogy and cell history revealed the existence of pre-disposing factors for switching that are epigenetically inherited. Both the pre-induction expression stochasticity of the lactose operon repressor LacI and the cellular growth rate are predictive factors of the cell's response upon induction, with low LacI concentration and slow growth correlating with higher switching probability. Thus, stochasticity at the local level of the network and global physiology are synergistically involved in cell response determination.
doi:10.1038/msb.2010.12
PMCID: PMC2872608  PMID: 20393577
adaptation; bistability; differentiation; lac operon; stochastic gene expression
7.  Horizontal Gene Transfer of the Secretome Drives the Evolution of Bacterial Cooperation and Virulence 
Current Biology  2009;19(20):1683-1691.
Summary
Background
Microbes engage in a remarkable array of cooperative behaviors, secreting shared proteins that are essential for foraging, shelter, microbial warfare, and virulence. These proteins are costly, rendering populations of cooperators vulnerable to exploitation by nonproducing cheaters arising by gene loss or migration. In such conditions, how can cooperation persist?
Results
Our model predicts that differential gene mobility drives intragenomic variation in investment in cooperative traits. More mobile loci generate stronger among-individual genetic correlations at these loci (higher relatedness) and thereby allow the maintenance of more cooperative traits via kin selection. By analyzing 21 Escherichia genomes, we confirm that genes coding for secreted proteins—the secretome—are very frequently lost and gained and are associated with mobile elements. We show that homologs of the secretome are overrepresented among human gut metagenomics samples, consistent with increased relatedness at secretome loci across multiple species. The biosynthetic cost of secreted proteins is shown to be under intense selective pressure, even more than for highly expressed proteins, consistent with a cost of cooperation driving social dilemmas. Finally, we demonstrate that mobile elements are in conflict with their chromosomal hosts over the chimeric ensemble's social strategy, with mobile elements enforcing cooperation on their otherwise selfish hosts via the cotransfer of secretome genes with “mafia strategy” addictive systems (toxin-antitoxin and restriction-modification).
Conclusion
Our analysis matches the predictions of our model suggesting that horizontal transfer promotes cooperation, as transmission increases local genetic relatedness at mobile loci and enforces cooperation on the resident genes. As a consequence, horizontal transfer promoted by agents such as plasmids, phages, or integrons drives microbial cooperation.
doi:10.1016/j.cub.2009.08.056
PMCID: PMC2773837  PMID: 19800234
EVOL_ECOL
8.  Evolutionary ecology of microbial wars: within-host competition and (incidental) virulence 
Evolutionary Applications  2009;2(1):32-39.
Invading an occupied niche is a formidable ecological challenge, and one of particular human importance in the context of food-borne microbial pathogens. We discuss distinct categories of invader-triggered environmental change that facilitate invasion by emptying their niche of competitors. Evidence is reviewed that gut bacteria use such strategies to manipulate their environment (via bacteriocins, temperate phage viruses or immuno-manipulation) at the expense of their competitors are reviewed. The possible virulence implications of microbial warfare among multiple co-infecting strains are diverse. Killing competitors can reduce virulence by reducing overall microbial densities, or increase virulence if for example the allelopathic mechanism involves immuno-manipulation. Finally, we place microbial anti-competitor strategies in a social evolution framework, highlighting how costly anti-competitor strategies can be understood as examples of microbial spite. We conclude by discussing other invasive species that have also developed such proactive strategies of invasion.
doi:10.1111/j.1752-4571.2008.00059.x
PMCID: PMC3352407
disease biology; evolutionary theory; microbial biology; social evolution; virulence
9.  Evolution of virulence: triggering host inflammation allows invading pathogens to exclude competitors 
Ecology Letters  2008;11(1):44-51.
Virulence is generally considered to benefit parasites by enhancing resource-transfer from host to pathogen. Here, we offer an alternative framework where virulent immune-provoking behaviours and enhanced immune resistance are joint tactics of invading pathogens to eliminate resident competitors (transferring resources from resident to invading pathogen). The pathogen wins by creating a novel immunological challenge to which it is already adapted. We analyse a general ecological model of ‘proactive invasion’ where invaders not adapted to a local environment can succeed by changing it to one where they are better adapted than residents. However, the two-trait nature of the ‘proactive’ strategy (provocation of, and adaptation to environmental change) presents an evolutionary conundrum, as neither trait alone is favoured in a homogenous host population. We show that this conundrum can be resolved by allowing for host heterogeneity. We relate our model to emerging empirical findings on immunological mediation of parasite competition.
doi:10.1111/j.1461-0248.2007.01125.x
PMCID: PMC2228394  PMID: 18021245
Allelopathy; gut pathogens; host manipulation; multiple infection; niche construction; parasite epidemiology; rock paper scissors; virulence; within-host dynamics
10.  Mutations in two global regulators lower individual mortality in Escherichia coli 
Molecular Microbiology  2007;67(1):2-14.
There has been considerable investigation into the survival of bacterial cells under stress conditions, but little is known about the causes of mortality in the absence of exogenous stress. That there is a basal frequency of cell death in such populations may reflect that it is either impossible to avoid all lethal events, or alternatively, that it is too costly. Here, through a genetic screen in the model organism Escherichia coli, we identify two mutants with lower frequencies of mortality: rssB and fliA. Intriguingly, these two genes both affect the levels of different sigma factors within the cell. The rssB mutant displays enhanced resistance to multiple external stresses, possibly indicating that the cell gains its increased vitality through elevated resistance to spontaneous, endogenous stresses. The loss of fliA does not result in elevated stress resistance; rather, its survival is apparently due to a decreased physical stress linked to the insertion of the flagellum through the membrane and energy saved through the loss of the motor proteins. The identification of these two mutants implies that reducing mortality is not impossible; rather, due to its cost, it is subject to trade-offs with other traits that contribute to the competitive success of the organism.
doi:10.1111/j.1365-2958.2007.05988.x
PMCID: PMC2229837  PMID: 18036141
11.  Dissecting the Genetic Components of Adaptation of Escherichia coli to the Mouse Gut 
PLoS Genetics  2008;4(1):e2.
While pleiotropic adaptive mutations are thought to be central for evolution, little is known on the downstream molecular effects allowing adaptation to complex ecologically relevant environments. Here we show that Escherichia coli MG1655 adapts rapidly to the intestine of germ-free mice by single point mutations in EnvZ/OmpR two-component signal transduction system, which controls more than 100 genes. The selective advantage conferred by the mutations that modulate EnvZ/OmpR activities was the result of their independent and additive effects on flagellin expression and permeability. These results obtained in vivo thus suggest that global regulators may have evolved to coordinate activities that need to be fine-tuned simultaneously during adaptation to complex environments and that mutations in such regulators permit adjustment of the boundaries of physiological adaptation when switching between two very distinct environments.
Author Summary
The mammalian intestine is a privileged physiological site to study how coevolution between hosts and the trillions of bacteria present in the microbiota has shaped the genome of each partner and promoted the development of mutualistic interactions. Herein we have used germ-free mice, a simplified albeit ecologically relevant system, to analyse intestinal adaptation of a model bacterial strain, Escherichia coli MG1655. Our results show that single point mutations in the ompB master regulator confer a striking selective adaptive advantage. OmpB comprises EnvZ, a transmembrane sensor with a dual kinase/phosphatase activity, and OmpR, a transcription factor controlling more than 100 target genes. In response to environmental changes, EnvZ modulates the phosphorylation and thereby the transcriptional activity of OmpR. We further show that the selective advantage conferred by OmpB mutations is related to their additive and independent effects on genes regulating permeability and flagellin expression, two major set of genes controlled by OmpR. These results suggest that global regulators may have evolved to coordinate physiological activities necessary for adaptation to complex environments and that mutations offer a complementary genetic mechanism to adjust the scale of the physiological regulation controlled by these regulators in distinct environments.
doi:10.1371/journal.pgen.0040002
PMCID: PMC2174974  PMID: 18193944
12.  Dissecting the Genetic Components of Adaptation of Escherichia coli to the Mouse Gut 
PLoS Genetics  2008;4(1):e2.
While pleiotropic adaptive mutations are thought to be central for evolution, little is known on the downstream molecular effects allowing adaptation to complex ecologically relevant environments. Here we show that Escherichia coli MG1655 adapts rapidly to the intestine of germ-free mice by single point mutations in EnvZ/OmpR two-component signal transduction system, which controls more than 100 genes. The selective advantage conferred by the mutations that modulate EnvZ/OmpR activities was the result of their independent and additive effects on flagellin expression and permeability. These results obtained in vivo thus suggest that global regulators may have evolved to coordinate activities that need to be fine-tuned simultaneously during adaptation to complex environments and that mutations in such regulators permit adjustment of the boundaries of physiological adaptation when switching between two very distinct environments.
Author Summary
The mammalian intestine is a privileged physiological site to study how coevolution between hosts and the trillions of bacteria present in the microbiota has shaped the genome of each partner and promoted the development of mutualistic interactions. Herein we have used germ-free mice, a simplified albeit ecologically relevant system, to analyse intestinal adaptation of a model bacterial strain, Escherichia coli MG1655. Our results show that single point mutations in the ompB master regulator confer a striking selective adaptive advantage. OmpB comprises EnvZ, a transmembrane sensor with a dual kinase/phosphatase activity, and OmpR, a transcription factor controlling more than 100 target genes. In response to environmental changes, EnvZ modulates the phosphorylation and thereby the transcriptional activity of OmpR. We further show that the selective advantage conferred by OmpB mutations is related to their additive and independent effects on genes regulating permeability and flagellin expression, two major set of genes controlled by OmpR. These results suggest that global regulators may have evolved to coordinate physiological activities necessary for adaptation to complex environments and that mutations offer a complementary genetic mechanism to adjust the scale of the physiological regulation controlled by these regulators in distinct environments.
doi:10.1371/journal.pgen.0040002
PMCID: PMC2174974  PMID: 18193944
13.  The Durability of Public Goods Changes the Dynamics and Nature of Social Dilemmas 
PLoS ONE  2007;2(7):e593.
An implicit assumption underpins basic models of the evolution of cooperation, mutualism and altruism: The benefits (or pay-offs) of cooperation and defection are defined by the current frequency or distribution of cooperators. In social dilemmas involving durable public goods (group resources that can persist in the environment–ubiquitous from microbes to humans) this assumption is violated. Here, we examine the consequences of relaxing this assumption, allowing pay-offs to depend on both current and past numbers of cooperators. We explicitly trace the dynamic of a public good created by cooperators, and define pay-offs in terms of the current public good. By raising the importance of cooperative history in determining the current fate of cooperators, durable public goods cause novel dynamics (e.g., transient increases in cooperation in Prisoner's Dilemmas, oscillations in Snowdrift Games, or shifts in invasion thresholds in Stag-hunt Games), while changes in durability can transform one game into another, by moving invasion thresholds for cooperation or conditions for coexistence with defectors. This enlarged view challenges our understanding of social cheats. For instance, groups of cooperators can do worse than groups of defectors, if they inherit fewer public goods, while a rise in defectors no longer entails a loss of social benefits, at least not in the present moment (as highlighted by concerns over environmental lags). Wherever durable public goods have yet to reach a steady state (for instance due to external perturbations), the history of cooperation will define the ongoing dynamics of cooperators.
doi:10.1371/journal.pone.0000593
PMCID: PMC1899228  PMID: 17611625
14.  Correction: Viruses' Life History: Towards a Mechanistic Basis of a Trade-Off between Survival and Reproduction among Phages 
PLoS Biology  2006;4(8):e273.
A comparison of life-history traits of 16 phages infecting E. coli reveals that although these viruses don't age, there is a trade-off between mortality and growth rate, which parallels that observed in many other species.
doi:10.1371/journal.pbio.0040273
PMCID: PMC1543689
15.  Viruses' Life History: Towards a Mechanistic Basis of a Trade-Off between Survival and Reproduction among Phages 
PLoS Biology  2006;4(7):e193.
Life history theory accounts for variations in many traits involved in the reproduction and survival of living organisms, by determining the constraints leading to trade-offs among these different traits. The main life history traits of phages—viruses that infect bacteria—are the multiplication rate in the host, the survivorship of virions in the external environment, and their mode of transmission. By comparing life history traits of 16 phages infecting the bacteria Escherichia coli, we show that their mortality rate is constant with time and negatively correlated to their multiplication rate in the bacterial host. Even though these viruses do not age, this result is in line with the trade-off between survival and reproduction previously observed in numerous aging organisms. Furthermore, a multiple regression shows that the combined effects of two physical parameters, namely, the capsid thickness and the density of the packaged genome, account for 82% of the variation in the mortality rate. The correlations between life history traits and physical characteristics of virions may provide a mechanistic explanation of this trade-off. The fact that this trade-off is present in this very simple biological situation suggests that it might be a fundamental property of evolving entities produced under constraints. Moreover, such a positive correlation between mortality and multiplication reveals an underexplored trade-off in host–parasite interactions.
A comparison of life-history traits of 16 phages infecting E. coli reveals that although these viruses don't age, there is a trade-off between mortality and growth rate, which parallels that observed in many other species.
doi:10.1371/journal.pbio.0040193
PMCID: PMC1475768  PMID: 16756387
16.  Over-representation of repeats in stress response genes: a strategy to increase versatility under stressful conditions? 
Nucleic Acids Research  2002;30(9):1886-1894.
The survival of individual organisms facing stress is enhanced by the induction of a set of changes. As the intensity, duration and nature of stress is highly variable, the optimal response to stress may be unpredictable. To face such an uncertain future, it may be advantageous for a clonal population to increase its phenotypic heterogeneity (bet-hedging), ensuring that at least a subset of cells would survive the current stress. With current techniques, assessing the extent of this variability experimentally remains a challenge. Here, we use a bioinformatic approach to compare stress response genes with the rest of the genome for the presence of various kinds of repeated sequences, elements known to increase variability during the transfer of genetic information (i.e. during replication, but also during gene expression). We investigated the potential for illegitimate and homologous recombination of 296 Escherichia coli genes related to repair, recombination and physiological adaptations to different stresses. Although long repeats capable of engaging in homologous recombination are almost absent in stress response genes, we observed a significant high number of short close repeats capable of inducing phenotypic variability by slipped-mispair during DNA, RNA or protein synthesis.
PMCID: PMC113848  PMID: 11972324
17.  Mutator Bacteria as a Risk Factor in Treatment of Infectious Diseases† 
We show in a gnotobiotic mouse model that, in addition to direct selection of antibiotic-resistant bacteria, some antibiotic treatments also select for mutator alleles. Because of these mutator alleles' high mutation rates, the initial treatment failure increases the probability of failures in subsequent treatments with other drugs.
doi:10.1128/AAC.46.3.863-865.2002
PMCID: PMC127494  PMID: 11850274
18.  High Frequency of Mutator Strains among Human Uropathogenic Escherichia coli Isolates 
Journal of Bacteriology  2002;184(2):605-609.
By using a panel of 603 commensal and pathogenic Escherichia coli and Shigella isolates, we showed that mutation rates of strains vary considerably among different ecotypes. Uropathogenic strains had the highest frequency of mutators, while strains from patients with bacteremia had the lowest mutation rates. No correlation between the mutation rates and antibiotic resistance was observed among the studied strains.
doi:10.1128/JB.184.2.605-609.2002
PMCID: PMC139564  PMID: 11751844
19.  Mutator Natural Escherichia coli Isolates Have an Unusual Virulence Phenotype 
Infection and Immunity  2001;69(1):9-14.
A small percentage of natural Escherichia coli isolates (both commensal and pathogenic) have a mutator phenotype related to defects in methyl-directed mismatch repair (MR) genes. We investigated whether there was a direct link between the mutator phenotype and virulence by (i) studying the relationships between mutation rate and virulence in a mouse model of extraintestinal virulence for 88 commensal and extraintestinal pathogenic E. coli isolates and (ii) comparing the virulence in mice of MR-deficient and MR-proficient strains that were otherwise isogenic. The results provide no support for the hypothesis that the mutator phenotype has a direct role in virulence or is associated with increased virulence. Most of the natural mutator strains studied displayed an unusual virulence phenotype with (i) a lack of correspondence between the number of virulence determinants and pathogenicity in mice and (ii) an intermediate level of virulence. On a large evolutionary scale, the mutator phenotype may help parasites to achieve an intermediate rate of virulence which mathematical models predict to be selected for during long-term parasite-host interactions.
doi:10.1128/IAI.69.1.9-14.2001
PMCID: PMC97849  PMID: 11119483
20.  No Genetic Barriers between Salmonella enterica Serovar Typhimurium and Escherichia coli in SOS-Induced Mismatch Repair-Deficient Cells 
Journal of Bacteriology  2000;182(20):5922-5924.
Conjugational crosses trigger SOS induction in Escherichia coli F− cells mated with Salmonella enterica serovar Typhimurium Hfr donors. Using an epigenetic indicator of SOS induction, we showed that a strong SOS response occurring in a subpopulation of mated mismatch repair-deficient cells totally abolishes genetic barriers between these two genera.
PMCID: PMC94721  PMID: 11004198
21.  Aging and Death in an Organism That Reproduces by Morphologically Symmetric Division 
PLoS Biology  2005;3(2):e45.
In macroscopic organisms, aging is often obvious; in single-celled organisms, where there is the greatest potential to identify the molecular mechanisms involved, identifying and quantifying aging is harder. The primary results in this area have come from organisms that share the traits of a visibly asymmetric division and an identifiable juvenile phase. As reproductive aging must require a differential distribution of aged and young components between parent and offspring, it has been postulated that organisms without these traits do not age, thus exhibiting functional immortality. Through automated time-lapse microscopy, we followed repeated cycles of reproduction by individual cells of the model organism Escherichia coli, which reproduces without a juvenile phase and with an apparently symmetric division. We show that the cell that inherits the old pole exhibits a diminished growth rate, decreased offspring production, and an increased incidence of death. We conclude that the two supposedly identical cells produced during cell division are functionally asymmetric; the old pole cell should be considered an aging parent repeatedly producing rejuvenated offspring. These results suggest that no life strategy is immune to the effects of aging, and therefore immortality may be either too costly or mechanistically impossible in natural organisms.
Detailed time lapse photography reveals that organisms that divide symmetrically, such as the bacterium E. coli, can indeed age and consequently that no organism is immune to mortality
doi:10.1371/journal.pbio.0030045
PMCID: PMC546039  PMID: 15685293

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