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1.  Antibiotic Restriction Might Facilitate the Emergence of Multi-drug Resistance 
PLoS Computational Biology  2015;11(6):e1004340.
High antibiotic resistance frequencies have become a major public health issue. The decrease in new antibiotics' production, combined with increasing frequencies of multi-drug resistant (MDR) bacteria, cause substantial limitations in treatment options for some bacterial infections. To diminish overall resistance, and especially the occurrence of bacteria that are resistant to all antibiotics, certain drugs are deliberately scarcely used—mainly when other options are exhausted. We use a mathematical model to explore the efficiency of such antibiotic restrictions. We assume two commonly used drugs and one restricted drug. The model is examined for the mixing strategy of antibiotic prescription, in which one of the drugs is randomly assigned to each incoming patient. Data obtained from Rabin medical center, Israel, is used to estimate realistic single and double antibiotic resistance frequencies in incoming patients. We find that broad usage of the hitherto restricted drug can reduce the number of incorrectly treated patients, and reduce the spread of bacteria resistant to both common antibiotics. Such double resistant infections are often eventually treated with the restricted drug, and therefore are prone to become resistant to all three antibiotics. Thus, counterintuitively, a broader usage of a formerly restricted drug can sometimes lead to a decrease in the emergence of bacteria resistant to all drugs. We recommend re-examining restriction of specific drugs, when multiple resistance to the relevant alternative drugs already exists.
Author Summary
Methods for minimizing antibiotic resistance are becoming more important as antibiotic resistance frequencies are rising, coupled with low discovery rates of new antibiotics. In this work we examined the practice of restricting specific drugs to be used only as 'last resort'. The goal of such restrictions is to maintain low resistance levels to certain drugs, and prevent the creation of bacteria resistant to all available treatment options. We used a mathematical model to study the impact of such restrictions, when some resistance to the unrestricted drugs is already present. We estimated the resistance frequencies of common bacteria from hospital data. We find that restricting drugs leads to increased rates of incorrect treatment, and might simultaneously lead to increased emergence of multidrug resistant bacteria. We conclude that restricting specific antibiotics should be done with caution. In some cases lifting restrictions might even delay MDR emergence.
PMCID: PMC4481510  PMID: 26110266
2.  Food Selectivity and Diet Switch Can Explain the Slow Feeding of Herbivorous Coral-Reef Fishes during the Morning 
PLoS ONE  2013;8(12):e82391.
Most herbivorous coral-reef fishes feed slower in the morning than in the afternoon. Given the typical scarcity of algae in coral reefs, this behavior seems maladaptive. Here we suggest that the fishes' slow feeding during the morning is an outcome of highly selective feeding on scarcely found green algae. The rarity of the food requires longer search time and extended swimming tracks, resulting in lower bite rates. According to our findings by noon the fish seem to stop their search and switch to indiscriminative consumption of benthic algae, resulting in apparent higher feeding rates. The abundance of the rare preferable algae gradually declines from morning to noon and seems to reach its lowest levels around the switch time. Using in situ experiments we found that the feeding pattern is flexible, with the fish exhibiting fast feeding rates when presented with ample supply of preferable algae, regardless of the time of day. Analyses of the fish's esophagus content corroborated our conclusion that their feeding was highly selective in the morning and non-selective in the afternoon. Modeling of the fishes' behavior predicted that the fish should perform a diel diet shift when the preferred food is relatively rare, a situation common in most coral reefs found in a warm, oligotrophic ocean.
PMCID: PMC3866113  PMID: 24358178
3.  Dispersing away from bad genotypes: the evolution of Fitness-Associated Dispersal (FAD) in homogeneous environments 
Dispersal is a major factor in ecological and evolutionary dynamics. Although empirical evidence shows that the tendency to disperse varies among individuals in many organisms, the evolution of dispersal patterns is not fully understood. Previous theoretical studies have shown that condition-dependent dispersal may evolve as a means to move to a different environment when environments are heterogeneous in space or in time. However, dispersal is also a means to genetically diversify offspring, a genetic advantage that might be particularly important when the individual fitness is low. We suggest that plasticity in dispersal, in which fit individuals are less likely to disperse (Fitness-Associated Dispersal, or FAD), can evolve due to its evolutionary advantages even when the environment is homogeneous and stable, kin competition is weak, and the cost of dispersal is high.
Using stochastic simulations we show that throughout the parameter range, selection favors FAD over uniform dispersal (in which all individuals disperse with equal probability). FAD also has significant long-term effects on the mean fitness and genotypic variance of the population.
We show that FAD evolves under a very wide parameter range, regardless of its effects on the population mean fitness. We predict that individuals of low quality will have an increased tendency for dispersal, even when the environment is homogeneous, there is no direct competition with neighbors, and dispersal carries significant costs.
PMCID: PMC3704926  PMID: 23777293
Phenotypic plasticity; Genetic mixing; Outcrossing; Stress-induced variation; Fitness-dependent dispersal; Condition-dependent dispersal; Partial migration; Stochastic simulations
4.  Does stress induce (para)sex? Implications for Candida albicans evolution 
Trends in Genetics  2012;28(5):197-203.
Theory predicts that stress is a key factor in explaining the evolutionary role of sex in facultatively sexual organisms, including microorganisms. Organisms capable of reproducing both sexually and asexually are expected to mate more frequently when stressed, and such stress-induced mating is predicted to facilitate adaptation. Here, we propose that stress has an analogous effect on the parasexual cycle in Candida albicans, which involves alternation of generations between diploid and tetraploid cells. The parasexual cycle can generate high levels of diversity, including aneuploidy, yet it apparently occurs only rarely in nature. We review the evidence that stress facilitates four major steps in the parasexual cycle, and suggest that parasex ensues much more frequently under stress conditions. This may explain both the evolutionary significance of parasex and its apparent rarity.
PMCID: PMC3340477  PMID: 22364928
5.  Implications of stress-induced genetic variation for minimizing multidrug resistance in bacteria 
BMC Medicine  2012;10:89.
Antibiotic resistance in bacterial infections is a growing threat to public health. Recent evidence shows that when exposed to stressful conditions, some bacteria perform higher rates of horizontal gene transfer and mutation, and thus acquire antibiotic resistance more rapidly.
We incorporate this new notion into a mathematical model for the emergence of antibiotic multi-resistance in a hospital setting.
We show that when stress has a considerable effect on genetic variation, the emergence of antibiotic resistance is dramatically affected. A strategy in which patients receive a combination of antibiotics (combining) is expected to facilitate the emergence of multi-resistant bacteria when genetic variation is stress-induced. The preference between a strategy in which one of two effective drugs is assigned randomly to each patient (mixing), and a strategy where only one drug is administered for a specific period of time (cycling) is determined by the resistance acquisition mechanisms. We discuss several features of the mechanisms by which stress affects variation and predict the conditions for success of different antibiotic treatment strategies.
These findings should encourage research on the mechanisms of stress-induced genetic variation and establish the importance of incorporating data about these mechanisms when considering antibiotic treatment strategies.
PMCID: PMC3482572  PMID: 22889082
stress induced mutagenesis; HGT; antibiotic resistance; evolution; mathematical model
6.  Home and away- the evolutionary dynamics of homing endonucleases 
Homing endonucleases (HEases) are a large and diverse group of site-specific DNAases. They reside within self-splicing introns and inteins, and promote their horizontal dissemination. In recent years, HEases have been the focus of extensive research due to their promising potential use in gene targeting procedures for the treatment of genetic diseases and for the genetic engineering of crop, animal models and cell lines.
Using mathematical analysis and computational modeling, we present here a novel account for the evolution and population dynamics of HEase genes (HEGs). We describe HEGs as paradoxical selfish elements whose long-term persistence in a single population relies on low transmission rates and a positive correlation between transmission efficiency and toxicity.
Plausible conditions allow HEGs to sustain at high frequency through long evolutionary periods, with the endonuclease frequency being either at equilibrium or periodically oscillating. The predictions of our model may prove important not only for evolutionary theory but also for gene therapy and bio-engineering applications of HEases.
PMCID: PMC3229294  PMID: 22054298
7.  Mutability and Importance of a Hypermutable Cell Subpopulation that Produces Stress-Induced Mutants in Escherichia coli 
PLoS Genetics  2008;4(10):e1000208.
In bacterial, yeast, and human cells, stress-induced mutation mechanisms are induced in growth-limiting environments and produce non-adaptive and adaptive mutations. These mechanisms may accelerate evolution specifically when cells are maladapted to their environments, i.e., when they are are stressed. One mechanism of stress-induced mutagenesis in Escherichia coli occurs by error-prone DNA double-strand break (DSB) repair. This mechanism was linked previously to a differentiated subpopulation of cells with a transiently elevated mutation rate, a hypermutable cell subpopulation (HMS). The HMS could be important, producing essentially all stress-induced mutants. Alternatively, the HMS was proposed to produce only a minority of stress-induced mutants, i.e., it was proposed to be peripheral. We characterize three aspects of the HMS. First, using improved mutation-detection methods, we estimate the number of mutations per genome of HMS-derived cells and find that it is compatible with fitness after the HMS state. This implies that these mutants are not necessarily an evolutionary dead end, and could contribute to adaptive evolution. Second, we show that stress-induced Lac+ mutants, with and without evidence of descent from the HMS, have similar Lac+ mutation sequences. This provides evidence that HMS-descended and most stress-induced mutants form via a common mechanism. Third, mutation-stimulating DSBs introduced via I-SceI endonuclease in vivo do not promote Lac+ mutation independently of the HMS. This and the previous finding support the hypothesis that the HMS underlies most stress-induced mutants, not just a minority of them, i.e., it is important. We consider a model in which HMS differentiation is controlled by stress responses. Differentiation of an HMS potentially limits the risks of mutagenesis in cell clones.
Author Summary
Mutational processes are being discovered in which bacterial, yeast, and human cells under various stresses activate programs that increase mutagenesis, often under the control of cellular stress responses. These programs may potentially increase genetic variability in populations specifically when they are maladapted to their environments, i.e., when they are stressed. When mutation supply is limiting for evolution (for example, in small populations), these mechanisms might enhance the intrinsic ability of organisms/cells/populations to evolve, specifically during stress. Stress-induced mutagenesis mechanisms recast understanding of, and strategies for combating, problems such as host-pathogen interactions, generation of bacterial antibiotic resistance, cancer progression, and evolution of chemotherapy resistance, all problems of evolution of fitter variant clones fueled by genetic change under stress. A key problem in stress-induced mutagenesis concerns how cells survive the deleterious effects of enhanced mutagenesis. One proposed strategy is the differentiation of a subpopulation of transiently hypermutable cells. This study investigates a previously discovered hypermutable cell subpopulation (HMS) postulated either to underlie most stress-induced mutagenesis in E. coli or only a small fraction of it. First, improved methods allow estimation of mutations per genome accumulated during HMS-generated bursts of mutagenesis and show numbers compatible with fitness after the HMS state. Second, two lines of evidence presented support models in which the HMS is central to this stress-induced mutagenesis pathway. Third, a specific model, with general consequences, for HMS differentiation is discussed.
PMCID: PMC2543114  PMID: 18833303
8.  Sexual selection and the evolution of obligatory sex 
Among the long-standing conundrums of evolutionary theory, obligatory sex is one of the hardest. Current theory suggests multiple factors that might explain the benefits of sex when compared with complete asexuality, but no satisfactory explanation for the prevalence of obligatory sex in the face of facultative sexual reproduction.
Results and Conclusion
We show that when sexual selection is present obligatory sex can evolve and be maintained even against facultative sex, under common scenarios of deleterious mutations and environmental changes.
PMCID: PMC2248195  PMID: 18096075
9.  Why is stress so deadly? An evolutionary perspective 
The reaction of the body to prolonged stress has many harmful effects. Classical theory assumes that stress responses have evolved due to their short-term selective advantages (‘flight or fight’), and despite their adverse long-term effects. In contrast, we demonstrate that the adverse effects of stress responses may have a selective advantage. Using an analytical model we show that a gene that causes the early death of a relatively unfit individual can increase in frequency in a structured population even if it has no positive effect on that individual. This result offers a new perspective on the relations between stress factors, stress responses and stress-related diseases.
PMCID: PMC1560227  PMID: 16618683
stress; evolution; altruism; stress-related disease

Results 1-9 (9)