@article{1290, abstract = {We developed a competition-based screening strategy to identify compounds that invert the selective advantage of antibiotic resistance. Using our assay, we screened over 19,000 compounds for the ability to select against the TetA tetracycline-resistance efflux pump in Escherichia coli and identified two hits, β-thujaplicin and disulfiram. Treating a tetracycline-resistant population with β-thujaplicin selects for loss of the resistance gene, enabling an effective second-phase treatment with doxycycline.}, author = {Stone, Laura and Baym, Michael and Lieberman, Tami and Chait, Remy P and Clardy, Jon and Kishony, Roy}, journal = {Nature Chemical Biology}, number = {11}, pages = {902 -- 904}, publisher = {Nature Publishing Group}, title = {{Compounds that select against the tetracycline-resistance efflux pump}}, doi = {10.1038/nchembio.2176}, volume = {12}, year = {2016}, } @inproceedings{1320, abstract = {In recent years, several biomolecular systems have been shown to be scale-invariant (SI), i.e. to show the same output dynamics when exposed to geometrically scaled input signals (u → pu, p > 0) after pre-adaptation to accordingly scaled constant inputs. In this article, we show that SI systems-as well as systems invariant with respect to other input transformations-can realize nonlinear differential operators: when excited by inputs obeying functional forms characteristic for a given class of invariant systems, the systems' outputs converge to constant values directly quantifying the speed of the input.}, author = {Lang, Moritz and Sontag, Eduardo}, location = {Boston, MA, USA}, publisher = {IEEE}, title = {{Scale-invariant systems realize nonlinear differential operators}}, doi = {10.1109/ACC.2016.7526722}, volume = {2016-July}, year = {2016}, } @article{1332, abstract = {Antibiotic-sensitive and -resistant bacteria coexist in natural environments with low, if detectable, antibiotic concentrations. Except possibly around localized antibiotic sources, where resistance can provide a strong advantage, bacterial fitness is dominated by stresses unaffected by resistance to the antibiotic. How do such mixed and heterogeneous conditions influence the selective advantage or disadvantage of antibiotic resistance? Here we find that sub-inhibitory levels of tetracyclines potentiate selection for or against tetracycline resistance around localized sources of almost any toxin or stress. Furthermore, certain stresses generate alternating rings of selection for and against resistance around a localized source of the antibiotic. In these conditions, localized antibiotic sources, even at high strengths, can actually produce a net selection against resistance to the antibiotic. Our results show that interactions between the effects of an antibiotic and other stresses in inhomogeneous environments can generate pervasive, complex patterns of selection both for and against antibiotic resistance.}, author = {Chait, Remy P and Palmer, Adam and Yelin, Idan and Kishony, Roy}, journal = {Nature Communications}, publisher = {Nature Publishing Group}, title = {{Pervasive selection for and against antibiotic resistance in inhomogeneous multistress environments}}, doi = {10.1038/ncomms10333}, volume = {7}, year = {2016}, } @article{1342, abstract = {A key aspect of bacterial survival is the ability to evolve while migrating across spatially varying environmental challenges. Laboratory experiments, however, often study evolution in well-mixed systems. Here, we introduce an experimental device, the microbial evolution and growth arena (MEGA)-plate, in which bacteria spread and evolved on a large antibiotic landscape (120 × 60 centimeters) that allowed visual observation of mutation and selection in a migrating bacterial front.While resistance increased consistently, multiple coexisting lineages diversified both phenotypically and genotypically. Analyzing mutants at and behind the propagating front,we found that evolution is not always led by the most resistant mutants; highly resistant mutants may be trapped behindmore sensitive lineages.TheMEGA-plate provides a versatile platformfor studying microbial adaption and directly visualizing evolutionary dynamics.}, author = {Baym, Michael and Lieberman, Tami and Kelsic, Eric and Chait, Remy P and Gross, Rotem and Yelin, Idan and Kishony, Roy}, journal = {Science}, number = {6304}, pages = {1147 -- 1151}, publisher = {American Association for the Advancement of Science}, title = {{Spatiotemporal microbial evolution on antibiotic landscapes}}, doi = {10.1126/science.aag0822}, volume = {353}, year = {2016}, } @inproceedings{1349, abstract = {Crossing fitness valleys is one of the major obstacles to function optimization. In this paper we investigate how the structure of the fitness valley, namely its depth d and length ℓ, influence the runtime of different strategies for crossing these valleys. We present a runtime comparison between the (1+1) EA and two non-elitist nature-inspired algorithms, Strong Selection Weak Mutation (SSWM) and the Metropolis algorithm. While the (1+1) EA has to jump across the valley to a point of higher fitness because it does not accept decreasing moves, the non-elitist algorithms may cross the valley by accepting worsening moves. We show that while the runtime of the (1+1) EA algorithm depends critically on the length of the valley, the runtimes of the non-elitist algorithms depend crucially only on the depth of the valley. In particular, the expected runtime of both SSWM and Metropolis is polynomial in ℓ and exponential in d while the (1+1) EA is efficient only for valleys of small length. Moreover, we show that both SSWM and Metropolis can also efficiently optimize a rugged function consisting of consecutive valleys.}, author = {Oliveto, Pietro and Paixao, Tiago and Heredia, Jorge and Sudholt, Dirk and Trubenova, Barbora}, booktitle = {Proceedings of the Genetic and Evolutionary Computation Conference 2016 }, location = {Denver, CO, USA}, pages = {1163 -- 1170}, publisher = {ACM}, title = {{When non-elitism outperforms elitism for crossing fitness valleys}}, doi = {10.1145/2908812.2908909}, year = {2016}, } @article{1359, abstract = {The role of gene interactions in the evolutionary process has long been controversial. Although some argue that they are not of importance, because most variation is additive, others claim that their effect in the long term can be substantial. Here, we focus on the long-term effects of genetic interactions under directional selection assuming no mutation or dominance, and that epistasis is symmetrical overall. We ask by how much the mean of a complex trait can be increased by selection and analyze two extreme regimes, in which either drift or selection dominate the dynamics of allele frequencies. In both scenarios, epistatic interactions affect the long-term response to selection by modulating the additive genetic variance. When drift dominates, we extend Robertson ’ s [Robertson A (1960) Proc R Soc Lond B Biol Sci 153(951):234 − 249] argument to show that, for any form of epistasis, the total response of a haploid population is proportional to the initial total genotypic variance. In contrast, the total response of a diploid population is increased by epistasis, for a given initial genotypic variance. When selection dominates, we show that the total selection response can only be increased by epistasis when s ome initially deleterious alleles become favored as the genetic background changes. We find a sim- ple approximation for this effect and show that, in this regime, it is the structure of the genotype - phenotype map that matters and not the variance components of the population.}, author = {Paixao, Tiago and Barton, Nicholas H}, journal = {PNAS}, number = {16}, pages = {4422 -- 4427}, publisher = {National Academy of Sciences}, title = {{The effect of gene interactions on the long-term response to selection}}, doi = {10.1073/pnas.1518830113}, volume = {113}, year = {2016}, } @article{1427, abstract = {Changes in gene expression are an important mode of evolution; however, the proximate mechanism of these changes is poorly understood. In particular, little is known about the effects of mutations within cis binding sites for transcription factors, or the nature of epistatic interactions between these mutations. Here, we tested the effects of single and double mutants in two cis binding sites involved in the transcriptional regulation of the Escherichia coli araBAD operon, a component of arabinose metabolism, using a synthetic system. This system decouples transcriptional control from any posttranslational effects on fitness, allowing a precise estimate of the effect of single and double mutations, and hence epistasis, on gene expression. We found that epistatic interactions between mutations in the araBAD cis-regulatory element are common, and that the predominant form of epistasis is negative. The magnitude of the interactions depended on whether the mutations are located in the same or in different operator sites. Importantly, these epistatic interactions were dependent on the presence of arabinose, a native inducer of the araBAD operon in vivo, with some interactions changing in sign (e.g., from negative to positive) in its presence. This study thus reveals that mutations in even relatively simple cis-regulatory elements interact in complex ways such that selection on the level of gene expression in one environment might perturb regulation in the other environment in an unpredictable and uncorrelated manner.}, author = {Lagator, Mato and Igler, Claudia and Moreno, Anaisa and Guet, Calin C and Bollback, Jonathan P}, journal = {Molecular Biology and Evolution}, number = {3}, pages = {761 -- 769}, publisher = {Oxford University Press}, title = {{Epistatic interactions in the arabinose cis-regulatory element}}, doi = {10.1093/molbev/msv269}, volume = {33}, year = {2016}, } @inproceedings{1524, abstract = {When designing genetic circuits, the typical primitives used in major existing modelling formalisms are gene interaction graphs, where edges between genes denote either an activation or inhibition relation. However, when designing experiments, it is important to be precise about the low-level mechanistic details as to how each such relation is implemented. The rule-based modelling language Kappa allows to unambiguously specify mechanistic details such as DNA binding sites, dimerisation of transcription factors, or co-operative interactions. Such a detailed description comes with complexity and computationally costly executions. We propose a general method for automatically transforming a rule-based program, by eliminating intermediate species and adjusting the rate constants accordingly. To the best of our knowledge, we show the first automated reduction of rule-based models based on equilibrium approximations. Our algorithm is an adaptation of an existing algorithm, which was designed for reducing reaction-based programs; our version of the algorithm scans the rule-based Kappa model in search for those interaction patterns known to be amenable to equilibrium approximations (e.g. Michaelis-Menten scheme). Additional checks are then performed in order to verify if the reduction is meaningful in the context of the full model. The reduced model is efficiently obtained by static inspection over the rule-set. The tool is tested on a detailed rule-based model of a λ-phage switch, which lists 92 rules and 13 agents. The reduced model has 11 rules and 5 agents, and provides a dramatic reduction in simulation time of several orders of magnitude.}, author = {Beica, Andreea and Guet, Calin C and Petrov, Tatjana}, location = {Madrid, Spain}, pages = {173 -- 191}, publisher = {Springer}, title = {{Efficient reduction of kappa models by static inspection of the rule-set}}, doi = {10.1007/978-3-319-26916-0_10}, volume = {9271}, year = {2016}, } @article{1250, abstract = {In bacteria, replicative aging manifests as a difference in growth or survival between the two cells emerging from division. One cell can be regarded as an aging mother with a decreased potential for future survival and division, the other as a rejuvenated daughter. Here, we aimed at investigating some of the processes involved in aging in the bacterium Escherichia coli, where the two types of cells can be distinguished by the age of their cell poles. We found that certain changes in the regulation of the carbohydrate metabolism can affect aging. A mutation in the carbon storage regulator gene, csrA, leads to a dramatically shorter replicative lifespan; csrA mutants stop dividing once their pole exceeds an age of about five divisions. These old-pole cells accumulate glycogen at their old cell poles; after their last division, they do not contain a chromosome, presumably because of spatial exclusion by the glycogen aggregates. The new-pole daughters produced by these aging mothers are born young; they only express the deleterious phenotype once their pole is old. These results demonstrate how manipulations of nutrient allocation can lead to the exclusion of the chromosome and limit replicative lifespan in E. coli, and illustrate how mutations can have phenotypic effects that are specific for cells with old poles. This raises the question how bacteria can avoid the accumulation of such mutations in their genomes over evolutionary times, and how they can achieve the long replicative lifespans that have recently been reported.}, author = {Boehm, Alex and Arnoldini, Markus and Bergmiller, Tobias and Röösli, Thomas and Bigosch, Colette and Ackermann, Martin}, journal = {PLoS Genetics}, number = {4}, publisher = {Public Library of Science}, title = {{Genetic manipulation of glycogen allocation affects replicative lifespan in E coli}}, doi = {10.1371/journal.pgen.1005974}, volume = {12}, year = {2016}, } @misc{9873, author = {Boehm, Alex and Arnoldini, Markus and Bergmiller, Tobias and Röösli, Thomas and Bigosch, Colette and Ackermann, Martin}, publisher = {Public Library of Science}, title = {{Quantification of the growth rate reduction as a consequence of age-specific mortality}}, doi = {10.1371/journal.pgen.1005974.s015}, year = {2016}, }