@misc{5564, abstract = {Compressed Fastq files with whole-genome sequencing data of IS-wt strain D and clones from four evolved populations (A11, C08, C10, D08). Information on this data collection is available in the Methods Section of the primary publication.}, author = {Steinrück, Magdalena and Guet, Calin C}, publisher = {Institute of Science and Technology Austria}, title = {{Fastq files for "Complex chromosomal neighborhood effects determine the adaptive potential of a gene under selection"}}, doi = {10.15479/AT:ISTA:65}, year = {2017}, } @misc{5560, abstract = {This repository contains the data collected for the manuscript "Biased partitioning of the multi-drug efflux pump AcrAB-TolC underlies long-lived phenotypic heterogeneity". The data is compressed into a single archive. Within the archive, different folders correspond to figures of the main text and the SI of the related publication. Data is saved as plain text, with each folder containing a separate readme file describing the format. Typically, the data is from fluorescence microscopy measurements of single cells growing in a microfluidic "mother machine" device, and consists of relevant values (primarily arbitrary unit or normalized fluorescence measurements, and division times / growth rates) after raw microscopy images have been processed, segmented, and their features extracted, as described in the methods section of the related publication.}, author = {Bergmiller, Tobias and Andersson, Anna M and Tomasek, Kathrin and Balleza, Enrique and Kiviet, Daniel and Hauschild, Robert and Tkacik, Gasper and Guet, Calin C}, keywords = {single cell microscopy, mother machine microfluidic device, AcrAB-TolC pump, multi-drug efflux, Escherichia coli}, publisher = {Institute of Science and Technology Austria}, title = {{Biased partitioning of the multi-drug efflux pump AcrAB-TolC underlies long-lived phenotypic heterogeneity}}, doi = {10.15479/AT:ISTA:53}, year = {2017}, } @article{665, abstract = {The molecular mechanisms underlying phenotypic variation in isogenic bacterial populations remain poorly understood.We report that AcrAB-TolC, the main multidrug efflux pump of Escherichia coli, exhibits a strong partitioning bias for old cell poles by a segregation mechanism that is mediated by ternary AcrAB-TolC complex formation. Mother cells inheriting old poles are phenotypically distinct and display increased drug efflux activity relative to daughters. Consequently, we find systematic and long-lived growth differences between mother and daughter cells in the presence of subinhibitory drug concentrations. A simple model for biased partitioning predicts a population structure of long-lived and highly heterogeneous phenotypes. This straightforward mechanism of generating sustained growth rate differences at subinhibitory antibiotic concentrations has implications for understanding the emergence of multidrug resistance in bacteria.}, author = {Bergmiller, Tobias and Andersson, Anna M and Tomasek, Kathrin and Balleza, Enrique and Kiviet, Daniel and Hauschild, Robert and Tkacik, Gasper and Guet, Calin C}, issn = {00368075}, journal = {Science}, number = {6335}, pages = {311 -- 315}, publisher = {American Association for the Advancement of Science}, title = {{Biased partitioning of the multidrug efflux pump AcrAB TolC underlies long lived phenotypic heterogeneity}}, doi = {10.1126/science.aaf4762}, volume = {356}, year = {2017}, } @article{1028, abstract = {Optogenetics and photopharmacology provide spatiotemporally precise control over protein interactions and protein function in cells and animals. Optogenetic methods that are sensitive to green light and can be used to break protein complexes are not broadly available but would enable multichromatic experiments with previously inaccessible biological targets. Herein, we repurposed cobalamin (vitamin B12) binding domains of bacterial CarH transcription factors for green-light-induced receptor dissociation. In cultured cells, we observed oligomerization-induced cell signaling for the fibroblast growth factor receptor 1 fused to cobalamin-binding domains in the dark that was rapidly eliminated upon illumination. In zebrafish embryos expressing fusion receptors, green light endowed control over aberrant fibroblast growth factor signaling during development. Green-light-induced domain dissociation and light-inactivated receptors will critically expand the optogenetic toolbox for control of biological processes.}, author = {Kainrath, Stephanie and Stadler, Manuela and Gschaider-Reichhart, Eva and Distel, Martin and Janovjak, Harald L}, issn = {14337851}, journal = {Angewandte Chemie - International Edition}, number = {16}, pages = {4608--4611}, publisher = {Wiley-Blackwell}, title = {{Green-light-induced inactivation of receptor signaling using cobalamin-binding domains}}, doi = {10.1002/anie.201611998}, volume = {56}, year = {2017}, } @article{704, abstract = {How the organization of genes on a chromosome shapes adaptation is essential for understanding evolutionary paths. Here, we investigate how adaptation to rapidly increasing levels of antibiotic depends on the chromosomal neighborhood of a drug-resistance gene inserted at different positions of the Escherichia coli chromosome. Using a dual-fluorescence reporter that allows us to distinguish gene amplifications from other up-mutations, we track in real-time adaptive changes in expression of the drug-resistance gene. We find that the relative contribution of several mutation types differs systematically between loci due to properties of neighboring genes: essentiality, expression, orientation, termination, and presence of duplicates. These properties determine rate and fitness effects of gene amplification, deletions, and mutations compromising transcriptional termination. Thus, the adaptive potential of a gene under selection is a system-property with a complex genetic basis that is specific for each chromosomal locus, and it can be inferred from detailed functional and genomic data.}, author = {Steinrück, Magdalena and Guet, Calin C}, issn = {2050084X}, journal = {eLife}, publisher = {eLife Sciences Publications}, title = {{Complex chromosomal neighborhood effects determine the adaptive potential of a gene under selection}}, doi = {10.7554/eLife.25100}, volume = {6}, year = {2017}, } @article{696, abstract = {Mutator strains are expected to evolve when the availability and effect of beneficial mutations are high enough to counteract the disadvantage from deleterious mutations that will inevitably accumulate. As the population becomes more adapted to its environment, both availability and effect of beneficial mutations necessarily decrease and mutation rates are predicted to decrease. It has been shown that certain molecular mechanisms can lead to increased mutation rates when the organism finds itself in a stressful environment. While this may be a correlated response to other functions, it could also be an adaptive mechanism, raising mutation rates only when it is most advantageous. Here, we use a mathematical model to investigate the plausibility of the adaptive hypothesis. We show that such a mechanism can be mantained if the population is subjected to diverse stresses. By simulating various antibiotic treatment schemes, we find that combination treatments can reduce the effectiveness of second-order selection on stress-induced mutagenesis. We discuss the implications of our results to strategies of antibiotic therapy.}, author = {Lukacisinova, Marta and Novak, Sebastian and Paixao, Tiago}, issn = {1553734X}, journal = {PLoS Computational Biology}, number = {7}, publisher = {Public Library of Science}, title = {{Stress induced mutagenesis: Stress diversity facilitates the persistence of mutator genes}}, doi = {10.1371/journal.pcbi.1005609}, volume = {13}, year = {2017}, } @article{735, abstract = {Cell-cell contact formation constitutes an essential step in evolution, leading to the differentiation of specialized cell types. However, remarkably little is known about whether and how the interplay between contact formation and fate specification affects development. Here, we identify a positive feedback loop between cell-cell contact duration, morphogen signaling, and mesendoderm cell-fate specification during zebrafish gastrulation. We show that long-lasting cell-cell contacts enhance the competence of prechordal plate (ppl) progenitor cells to respond to Nodal signaling, required for ppl cell-fate specification. We further show that Nodal signaling promotes ppl cell-cell contact duration, generating a positive feedback loop between ppl cell-cell contact duration and cell-fate specification. Finally, by combining mathematical modeling and experimentation, we show that this feedback determines whether anterior axial mesendoderm cells become ppl or, instead, turn into endoderm. Thus, the interdependent activities of cell-cell signaling and contact formation control fate diversification within the developing embryo.}, author = {Barone, Vanessa and Lang, Moritz and Krens, Gabriel and Pradhan, Saurabh and Shamipour, Shayan and Sako, Keisuke and Sikora, Mateusz K and Guet, Calin C and Heisenberg, Carl-Philipp J}, issn = {15345807}, journal = {Developmental Cell}, number = {2}, pages = {198 -- 211}, publisher = {Cell Press}, title = {{An effective feedback loop between cell-cell contact duration and morphogen signaling determines cell fate}}, doi = {10.1016/j.devcel.2017.09.014}, volume = {43}, year = {2017}, } @article{1008, abstract = {Feedback loops in biological networks, among others, enable differentiation and cell cycle progression, and increase robustness in signal transduction. In natural networks, feedback loops are often complex and intertwined, making it challenging to identify which loops are mainly responsible for an observed behavior. However, minimal synthetic replicas could allow for such identification. Here, we engineered a synthetic permease-inducer-repressor system in Saccharomyces cerevisiae to analyze if a transport-mediated positive feedback loop could be a core mechanism for the switch-like behavior in the regulation of metabolic gene networks such as the S. cerevisiae GAL system or the Escherichia coli lac operon. We characterized the synthetic circuit using deterministic and stochastic mathematical models. Similar to its natural counterparts, our synthetic system shows bistable and hysteretic behavior, and the inducer concentration range for bistability as well as the switching rates between the two stable states depend on the repressor concentration. Our results indicate that a generic permease–inducer–repressor circuit with a single feedback loop is sufficient to explain the experimentally observed bistable behavior of the natural systems. We anticipate that the approach of reimplementing natural systems with orthogonal parts to identify crucial network components is applicable to other natural systems such as signaling pathways.}, author = {Gnügge, Robert and Dharmarajan, Lekshmi and Lang, Moritz and Stelling, Jörg}, journal = {ACS Synthetic Biology}, number = {10}, pages = {1098 -- 1107}, publisher = {American Chemical Society}, title = {{An orthogonal permease–inducer–repressor feedback loop shows bistability}}, doi = {10.1021/acssynbio.6b00013}, volume = {5}, year = {2016}, } @article{1170, abstract = {The increasing complexity of dynamic models in systems and synthetic biology poses computational challenges especially for the identification of model parameters. While modularization of the corresponding optimization problems could help reduce the “curse of dimensionality,” abundant feedback and crosstalk mechanisms prohibit a simple decomposition of most biomolecular networks into subnetworks, or modules. Drawing on ideas from network modularization and multiple-shooting optimization, we present here a modular parameter identification approach that explicitly allows for such interdependencies. Interfaces between our modules are given by the experimentally measured molecular species. This definition allows deriving good (initial) estimates for the inter-module communication directly from the experimental data. Given these estimates, the states and parameter sensitivities of different modules can be integrated independently. To achieve consistency between modules, we iteratively adjust the estimates for inter-module communication while optimizing the parameters. After convergence to an optimal parameter set---but not during earlier iterations---the intermodule communication as well as the individual modules\' state dynamics agree with the dynamics of the nonmodularized network. Our modular parameter identification approach allows for easy parallelization; it can reduce the computational complexity for larger networks and decrease the probability to converge to suboptimal local minima. We demonstrate the algorithm\'s performance in parameter estimation for two biomolecular networks, a synthetic genetic oscillator and a mammalian signaling pathway.}, author = {Lang, Moritz and Stelling, Jörg}, journal = {SIAM Journal on Scientific Computing}, number = {6}, pages = {B988 -- B1008}, publisher = {Society for Industrial and Applied Mathematics }, title = {{Modular parameter identification of biomolecular networks}}, doi = {10.1137/15M103306X}, volume = {38}, year = {2016}, } @inproceedings{1220, abstract = {Theoretical and numerical aspects of aerodynamic efficiency of propulsion systems coupled to the boundary layer of a fuselage are studied. We discuss the effects of local flow fields, which are affected both by conservative flow acceleration as well as total pressure losses, on the efficiency of boundary layer immersed propulsion devices. We introduce the concept of a boundary layer retardation turbine that helps reduce skin friction over the fuselage. We numerically investigate efficiency gains offered by boundary layer and wake interacting devices. We discuss the results in terms of a total energy consumption framework and show that efficiency gains of any device depend on all the other elements of the propulsion system.}, author = {Mikić, Gregor and Stoll, Alex and Bevirt, Joe and Grah, Rok and Moore, Mark}, location = {Washington, D.C., USA}, pages = {1 -- 19}, publisher = {AIAA}, title = {{Fuselage boundary layer ingestion propulsion applied to a thin haul commuter aircraft for optimal efficiency}}, doi = {10.2514/6.2016-3764}, year = {2016}, } @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}, } @article{5749, abstract = {Parasitism creates selection for resistance mechanisms in host populations and is hypothesized to promote increased host evolvability. However, the influence of these traits on host evolution when parasites are no longer present is unclear. We used experimental evolution and whole-genome sequencing of Escherichia coli to determine the effects of past and present exposure to parasitic viruses (phages) on the spread of mutator alleles, resistance, and bacterial competitive fitness. We found that mutator alleles spread rapidly during adaptation to any of four different phage species, and this pattern was even more pronounced with multiple phages present simultaneously. However, hypermutability did not detectably accelerate adaptation in the absence of phages and recovery of fitness costs associated with resistance. Several lineages evolved phage resistance through elevated mucoidy, and during subsequent evolution in phage-free conditions they rapidly reverted to nonmucoid, phage-susceptible phenotypes. Genome sequencing revealed that this phenotypic reversion was achieved by additional genetic changes rather than by genotypic reversion of the initial resistance mutations. Insertion sequence (IS) elements played a key role in both the acquisition of resistance and adaptation in the absence of parasites; unlike single nucleotide polymorphisms, IS insertions were not more frequent in mutator lineages. Our results provide a genetic explanation for rapid reversion of mucoidy, a phenotype observed in other bacterial species including human pathogens. Moreover, this demonstrates that the types of genetic change underlying adaptation to fitness costs, and consequently the impact of evolvability mechanisms such as increased point-mutation rates, depend critically on the mechanism of resistance.}, author = {Wielgoss, Sébastien and Bergmiller, Tobias and Bischofberger, Anna M. and Hall, Alex R.}, issn = {1537-1719}, journal = {Molecular Biology and Evolution}, number = {3}, pages = {770--782}, publisher = {Oxford University Press}, title = {{Adaptation to parasites and costs of parasite resistance in mutator and nonmutator bacteria}}, doi = {10.1093/molbev/msv270}, volume = {33}, year = {2016}, } @inproceedings{1093, abstract = {We introduce a general class of distances (metrics) between Markov chains, which are based on linear behaviour. This class encompasses distances given topologically (such as the total variation distance or trace distance) as well as by temporal logics or automata. We investigate which of the distances can be approximated by observing the systems, i.e. by black-box testing or simulation, and we provide both negative and positive results. }, author = {Daca, Przemyslaw and Henzinger, Thomas A and Kretinsky, Jan and Petrov, Tatjana}, location = {Quebec City; Canada}, publisher = {Schloss Dagstuhl - Leibniz-Zentrum für Informatik}, title = {{Linear distances between Markov chains}}, doi = {10.4230/LIPIcs.CONCUR.2016.20}, volume = {59}, year = {2016}, } @inproceedings{1234, abstract = {We present a new algorithm for the statistical model checking of Markov chains with respect to unbounded temporal properties, including full linear temporal logic. The main idea is that we monitor each simulation run on the fly, in order to detect quickly if a bottom strongly connected component is entered with high probability, in which case the simulation run can be terminated early. As a result, our simulation runs are often much shorter than required by termination bounds that are computed a priori for a desired level of confidence on a large state space. In comparison to previous algorithms for statistical model checking our method is not only faster in many cases but also requires less information about the system, namely, only the minimum transition probability that occurs in the Markov chain. In addition, our method can be generalised to unbounded quantitative properties such as mean-payoff bounds.}, author = {Daca, Przemyslaw and Henzinger, Thomas A and Kretinsky, Jan and Petrov, Tatjana}, location = {Eindhoven, The Netherlands}, pages = {112 -- 129}, publisher = {Springer}, title = {{Faster statistical model checking for unbounded temporal properties}}, doi = {10.1007/978-3-662-49674-9_7}, volume = {9636}, year = {2016}, } @article{1243, abstract = {Restriction-modification (RM) systems represent a minimal and ubiquitous biological system of self/non-self discrimination in prokaryotes [1], which protects hosts from exogenous DNA [2]. The mechanism is based on the balance between methyltransferase (M) and cognate restriction endonuclease (R). M tags endogenous DNA as self by methylating short specific DNA sequences called restriction sites, whereas R recognizes unmethylated restriction sites as non-self and introduces a double-stranded DNA break [3]. Restriction sites are significantly underrepresented in prokaryotic genomes [4-7], suggesting that the discrimination mechanism is imperfect and occasionally leads to autoimmunity due to self-DNA cleavage (self-restriction) [8]. Furthermore, RM systems can promote DNA recombination [9] and contribute to genetic variation in microbial populations, thus facilitating adaptive evolution [10]. However, cleavage of self-DNA by RM systems as elements shaping prokaryotic genomes has not been directly detected, and its cause, frequency, and outcome are unknown. We quantify self-restriction caused by two RM systems of Escherichia coli and find that, in agreement with levels of restriction site avoidance, EcoRI, but not EcoRV, cleaves self-DNA at a measurable rate. Self-restriction is a stochastic process, which temporarily induces the SOS response, and is followed by DNA repair, maintaining cell viability. We find that RM systems with higher restriction efficiency against bacteriophage infections exhibit a higher rate of self-restriction, and that this rate can be further increased by stochastic imbalance between R and M. Our results identify molecular noise in RM systems as a factor shaping prokaryotic genomes.}, author = {Pleska, Maros and Qian, Long and Okura, Reiko and Bergmiller, Tobias and Wakamoto, Yuichi and Kussell, Edo and Guet, Calin C}, journal = {Current Biology}, number = {3}, pages = {404 -- 409}, publisher = {Cell Press}, title = {{Bacterial autoimmunity due to a restriction-modification system}}, doi = {10.1016/j.cub.2015.12.041}, volume = {26}, year = {2016}, } @article{1358, abstract = {Gene regulation relies on the specificity of transcription factor (TF)–DNA interactions. Limited specificity may lead to crosstalk: a regulatory state in which a gene is either incorrectly activated due to noncognate TF–DNA interactions or remains erroneously inactive. As each TF can have numerous interactions with noncognate cis-regulatory elements, crosstalk is inherently a global problem, yet has previously not been studied as such. We construct a theoretical framework to analyse the effects of global crosstalk on gene regulation. We find that crosstalk presents a significant challenge for organisms with low-specificity TFs, such as metazoans. Crosstalk is not easily mitigated by known regulatory schemes acting at equilibrium, including variants of cooperativity and combinatorial regulation. Our results suggest that crosstalk imposes a previously unexplored global constraint on the functioning and evolution of regulatory networks, which is qualitatively distinct from the known constraints that act at the level of individual gene regulatory elements.}, author = {Friedlander, Tamar and Prizak, Roshan and Guet, Calin C and Barton, Nicholas H and Tkacik, Gasper}, journal = {Nature Communications}, publisher = {Nature Publishing Group}, title = {{Intrinsic limits to gene regulation by global crosstalk}}, doi = {10.1038/ncomms12307}, volume = {7}, year = {2016}, } @inproceedings{1430, abstract = {Evolutionary algorithms (EAs) form a popular optimisation paradigm inspired by natural evolution. In recent years the field of evolutionary computation has developed a rigorous analytical theory to analyse their runtime on many illustrative problems. Here we apply this theory to a simple model of natural evolution. In the Strong Selection Weak Mutation (SSWM) evolutionary regime the time between occurrence of new mutations is much longer than the time it takes for a new beneficial mutation to take over the population. In this situation, the population only contains copies of one genotype and evolution can be modelled as a (1+1)-type process where the probability of accepting a new genotype (improvements or worsenings) depends on the change in fitness. We present an initial runtime analysis of SSWM, quantifying its performance for various parameters and investigating differences to the (1+1) EA. We show that SSWM can have a moderate advantage over the (1+1) EA at crossing fitness valleys and study an example where SSWM outperforms the (1+1) EA by taking advantage of information on the fitness gradient.}, author = {Paixao, Tiago and Sudholt, Dirk and Heredia, Jorge and Trubenova, Barbora}, booktitle = {Proceedings of the 2015 Annual Conference on Genetic and Evolutionary Computation}, location = {Madrid, Spain}, pages = {1455 -- 1462}, publisher = {ACM}, title = {{First steps towards a runtime comparison of natural and artificial evolution}}, doi = {10.1145/2739480.2754758}, year = {2015}, } @article{1542, abstract = {The theory of population genetics and evolutionary computation have been evolving separately for nearly 30 years. Many results have been independently obtained in both fields and many others are unique to its respective field. We aim to bridge this gap by developing a unifying framework for evolutionary processes that allows both evolutionary algorithms and population genetics models to be cast in the same formal framework. The framework we present here decomposes the evolutionary process into its several components in order to facilitate the identification of similarities between different models. In particular, we propose a classification of evolutionary operators based on the defining properties of the different components. We cast several commonly used operators from both fields into this common framework. Using this, we map different evolutionary and genetic algorithms to different evolutionary regimes and identify candidates with the most potential for the translation of results between the fields. This provides a unified description of evolutionary processes and represents a stepping stone towards new tools and results to both fields. }, author = {Paixao, Tiago and Badkobeh, Golnaz and Barton, Nicholas H and Çörüş, Doğan and Dang, Duccuong and Friedrich, Tobias and Lehre, Per and Sudholt, Dirk and Sutton, Andrew and Trubenova, Barbora}, journal = { Journal of Theoretical Biology}, pages = {28 -- 43}, publisher = {Elsevier}, title = {{Toward a unifying framework for evolutionary processes}}, doi = {10.1016/j.jtbi.2015.07.011}, volume = {383}, year = {2015}, } @article{1840, abstract = {In this paper, we present a method for reducing a regular, discrete-time Markov chain (DTMC) to another DTMC with a given, typically much smaller number of states. The cost of reduction is defined as the Kullback-Leibler divergence rate between a projection of the original process through a partition function and a DTMC on the correspondingly partitioned state space. Finding the reduced model with minimal cost is computationally expensive, as it requires an exhaustive search among all state space partitions, and an exact evaluation of the reduction cost for each candidate partition. Our approach deals with the latter problem by minimizing an upper bound on the reduction cost instead of minimizing the exact cost. The proposed upper bound is easy to compute and it is tight if the original chain is lumpable with respect to the partition. Then, we express the problem in the form of information bottleneck optimization, and propose using the agglomerative information bottleneck algorithm for searching a suboptimal partition greedily, rather than exhaustively. The theory is illustrated with examples and one application scenario in the context of modeling bio-molecular interactions.}, author = {Geiger, Bernhard and Petrov, Tatjana and Kubin, Gernot and Koeppl, Heinz}, issn = {0018-9286}, journal = {IEEE Transactions on Automatic Control}, number = {4}, pages = {1010 -- 1022}, publisher = {IEEE}, title = {{Optimal Kullback-Leibler aggregation via information bottleneck}}, doi = {10.1109/TAC.2014.2364971}, volume = {60}, year = {2015}, } @misc{9712, author = {Tugrul, Murat and Paixao, Tiago and Barton, Nicholas H and Tkačik, Gašper}, publisher = {Public Library of Science}, title = {{Other fitness models for comparison & for interacting TFBSs}}, doi = {10.1371/journal.pgen.1005639.s001}, year = {2015}, } @misc{9719, abstract = {Parasitism creates selection for resistance mechanisms in host populations and is hypothesized to promote increased host evolvability. However, the influence of these traits on host evolution when parasites are no longer present is unclear. We used experimental evolution and whole-genome sequencing of Escherichia coli to determine the effects of past and present exposure to parasitic viruses (phages) on the spread of mutator alleles, resistance, and bacterial competitive fitness. We found that mutator alleles spread rapidly during adaptation to any of four different phage species, and this pattern was even more pronounced with multiple phages present simultaneously. However, hypermutability did not detectably accelerate adaptation in the absence of phages and recovery of fitness costs associated with resistance. Several lineages evolved phage resistance through elevated mucoidy, and during subsequent evolution in phage-free conditions they rapidly reverted to nonmucoid, phage-susceptible phenotypes. Genome sequencing revealed that this phenotypic reversion was achieved by additional genetic changes rather than by genotypic reversion of the initial resistance mutations. Insertion sequence (IS) elements played a key role in both the acquisition of resistance and adaptation in the absence of parasites; unlike single nucleotide polymorphisms, IS insertions were not more frequent in mutator lineages. Our results provide a genetic explanation for rapid reversion of mucoidy, a phenotype observed in other bacterial species including human pathogens. Moreover, this demonstrates that the types of genetic change underlying adaptation to fitness costs, and consequently the impact of evolvability mechanisms such as increased point-mutation rates, depend critically on the mechanism of resistance.}, author = {Wielgoss, Sébastien and Bergmiller, Tobias and Bischofberger, Anna M. and Hall, Alex R.}, publisher = {Dryad}, title = {{Data from: Adaptation to parasites and costs of parasite resistance in mutator and non-mutator bacteria}}, doi = {10.5061/dryad.cj910}, year = {2015}, } @article{1666, abstract = {Evolution of gene regulation is crucial for our understanding of the phenotypic differences between species, populations and individuals. Sequence-specific binding of transcription factors to the regulatory regions on the DNA is a key regulatory mechanism that determines gene expression and hence heritable phenotypic variation. We use a biophysical model for directional selection on gene expression to estimate the rates of gain and loss of transcription factor binding sites (TFBS) in finite populations under both point and insertion/deletion mutations. Our results show that these rates are typically slow for a single TFBS in an isolated DNA region, unless the selection is extremely strong. These rates decrease drastically with increasing TFBS length or increasingly specific protein-DNA interactions, making the evolution of sites longer than ∼ 10 bp unlikely on typical eukaryotic speciation timescales. Similarly, evolution converges to the stationary distribution of binding sequences very slowly, making the equilibrium assumption questionable. The availability of longer regulatory sequences in which multiple binding sites can evolve simultaneously, the presence of “pre-sites” or partially decayed old sites in the initial sequence, and biophysical cooperativity between transcription factors, can all facilitate gain of TFBS and reconcile theoretical calculations with timescales inferred from comparative genomics.}, author = {Tugrul, Murat and Paixao, Tiago and Barton, Nicholas H and Tkacik, Gasper}, journal = {PLoS Genetics}, number = {11}, publisher = {Public Library of Science}, title = {{Dynamics of transcription factor binding site evolution}}, doi = {10.1371/journal.pgen.1005639}, volume = {11}, year = {2015}, } @inproceedings{1835, abstract = {The behaviour of gene regulatory networks (GRNs) is typically analysed using simulation-based statistical testing-like methods. In this paper, we demonstrate that we can replace this approach by a formal verification-like method that gives higher assurance and scalability. We focus on Wagner’s weighted GRN model with varying weights, which is used in evolutionary biology. In the model, weight parameters represent the gene interaction strength that may change due to genetic mutations. For a property of interest, we synthesise the constraints over the parameter space that represent the set of GRNs satisfying the property. We experimentally show that our parameter synthesis procedure computes the mutational robustness of GRNs –an important problem of interest in evolutionary biology– more efficiently than the classical simulation method. We specify the property in linear temporal logics. We employ symbolic bounded model checking and SMT solving to compute the space of GRNs that satisfy the property, which amounts to synthesizing a set of linear constraints on the weights.}, author = {Giacobbe, Mirco and Guet, Calin C and Gupta, Ashutosh and Henzinger, Thomas A and Paixao, Tiago and Petrov, Tatjana}, location = {London, United Kingdom}, pages = {469 -- 483}, publisher = {Springer}, title = {{Model checking gene regulatory networks}}, doi = {10.1007/978-3-662-46681-0_47}, volume = {9035}, year = {2015}, } @article{1894, abstract = {Background: Bacterial Dsb enzymes are involved in the oxidative folding of many proteins, through the formation of disulfide bonds between their cysteine residues. The Dsb protein network has been well characterized in cells of the model microorganism Escherichia coli. To gain insight into the functioning of the Dsb system in epsilon-Proteobacteria, where it plays an important role in the colonization process, we studied two homologs of the main Escherichia coli Dsb oxidase (EcDsbA) that are present in the cells of the enteric pathogen Campylobacter jejuni, the most frequently reported bacterial cause of human enteritis in the world. Methods and Results: Phylogenetic analysis suggests the horizontal transfer of the epsilon-Proteobacterial DsbAs from a common ancestor to gamma-Proteobacteria, which then gave rise to the DsbL lineage. Phenotype and enzymatic assays suggest that the two C. jejuni DsbAs play different roles in bacterial cells and have divergent substrate spectra. CjDsbA1 is essential for the motility and autoagglutination phenotypes, while CjDsbA2 has no impact on those processes. CjDsbA1 plays a critical role in the oxidative folding that ensures the activity of alkaline phosphatase CjPhoX, whereas CjDsbA2 is crucial for the activity of arylsulfotransferase CjAstA, encoded within the dsbA2-dsbB-astA operon. Conclusions: Our results show that CjDsbA1 is the primary thiol-oxidoreductase affecting life processes associated with bacterial spread and host colonization, as well as ensuring the oxidative folding of particular protein substrates. In contrast, CjDsbA2 activity does not affect the same processes and so far its oxidative folding activity has been demonstrated for one substrate, arylsulfotransferase CjAstA. The results suggest the cooperation between CjDsbA2 and CjDsbB. In the case of the CjDsbA1, this cooperation is not exclusive and there is probably another protein to be identified in C. jejuni cells that acts to re-oxidize CjDsbA1. Altogether the data presented here constitute the considerable insight to the Epsilonproteobacterial Dsb systems, which have been poorly understood so far.}, author = {Grabowska, Anna and Wywiał, Ewa and Dunin Horkawicz, Stanislaw and Łasica, Anna and Wösten, Marc and Nagy-Staron, Anna A and Godlewska, Renata and Bocian Ostrzycka, Katarzyna and Pieńkowska, Katarzyna and Łaniewski, Paweł and Bujnicki, Janusz and Van Putten, Jos and Jagusztyn Krynicka, Elzbieta}, journal = {PLoS One}, number = {9}, publisher = {Public Library of Science}, title = {{Functional and bioinformatics analysis of two Campylobacter jejuni homologs of the thiol-disulfide oxidoreductase, DsbA}}, doi = {10.1371/journal.pone.0106247}, volume = {9}, year = {2014}, } @article{2056, abstract = {We consider a continuous-time Markov chain (CTMC) whose state space is partitioned into aggregates, and each aggregate is assigned a probability measure. A sufficient condition for defining a CTMC over the aggregates is presented as a variant of weak lumpability, which also characterizes that the measure over the original process can be recovered from that of the aggregated one. We show how the applicability of de-aggregation depends on the initial distribution. The application section is devoted to illustrate how the developed theory aids in reducing CTMC models of biochemical systems particularly in connection to protein-protein interactions. We assume that the model is written by a biologist in form of site-graph-rewrite rules. Site-graph-rewrite rules compactly express that, often, only a local context of a protein (instead of a full molecular species) needs to be in a certain configuration in order to trigger a reaction event. This observation leads to suitable aggregate Markov chains with smaller state spaces, thereby providing sufficient reduction in computational complexity. This is further exemplified in two case studies: simple unbounded polymerization and early EGFR/insulin crosstalk.}, author = {Ganguly, Arnab and Petrov, Tatjana and Koeppl, Heinz}, journal = {Journal of Mathematical Biology}, number = {3}, pages = {767 -- 797}, publisher = {Springer}, title = {{Markov chain aggregation and its applications to combinatorial reaction networks}}, doi = {10.1007/s00285-013-0738-7}, volume = {69}, year = {2014}, } @article{2083, abstract = {Understanding the effects of sex and migration on adaptation to novel environments remains a key problem in evolutionary biology. Using a single-cell alga Chlamydomonas reinhardtii, we investigated how sex and migration affected rates of evolutionary rescue in a sink environment, and subsequent changes in fitness following evolutionary rescue. We show that sex and migration affect both the rate of evolutionary rescue and subsequent adaptation. However, their combined effects change as the populations adapt to a sink habitat. Both sex and migration independently increased rates of evolutionary rescue, but the effect of sex on subsequent fitness improvements, following initial rescue, changed with migration, as sex was beneficial in the absence of migration but constraining adaptation when combined with migration. These results suggest that sex and migration are beneficial during the initial stages of adaptation, but can become detrimental as the population adapts to its environment.}, author = {Lagator, Mato and Morgan, Andrew and Neve, Paul and Colegrave, Nick}, journal = {Evolution}, number = {8}, pages = {2296 -- 2305}, publisher = {Wiley}, title = {{Role of sex and migration in adaptation to sink environments}}, doi = {10.1111/evo.12440}, volume = {68}, year = {2014}, } @misc{9747, abstract = {Understanding the effects of sex and migration on adaptation to novel environments remains a key problem in evolutionary biology. Using a single-cell alga Chlamydomonas reinhardtii, we investigated how sex and migration affected rates of evolutionary rescue in a sink environment, and subsequent changes in fitness following evolutionary rescue. We show that sex and migration affect both the rate of evolutionary rescue and subsequent adaptation. However, their combined effects change as the populations adapt to a sink habitat. Both sex and migration independently increased rates of evolutionary rescue, but the effect of sex on subsequent fitness improvements, following initial rescue, changed with migration, as sex was beneficial in the absence of migration but constraining adaptation when combined with migration. These results suggest that sex and migration are beneficial during the initial stages of adaptation, but can become detrimental as the population adapts to its environment.}, author = {Lagator, Mato and Morgan, Andrew and Neve, Paul and Colegrave, Nick}, publisher = {Dryad}, title = {{Data from: Role of sex and migration in adaptation to sink environments}}, doi = {10.5061/dryad.s42n1}, year = {2014}, } @article{2036, abstract = { In rapidly changing environments, selection history may impact the dynamics of adaptation. Mutations selected in one environment may result in pleiotropic fitness trade-offs in subsequent novel environments, slowing the rates of adaptation. Epistatic interactions between mutations selected in sequential stressful environments may slow or accelerate subsequent rates of adaptation, depending on the nature of that interaction. We explored the dynamics of adaptation during sequential exposure to herbicides with different modes of action in Chlamydomonas reinhardtii. Evolution of resistance to two of the herbicides was largely independent of selection history. For carbetamide, previous adaptation to other herbicide modes of action positively impacted the likelihood of adaptation to this herbicide. Furthermore, while adaptation to all individual herbicides was associated with pleiotropic fitness costs in stress-free environments, we observed that accumulation of resistance mechanisms was accompanied by a reduction in overall fitness costs. We suggest that antagonistic epistasis may be a driving mechanism that enables populations to more readily adapt in novel environments. These findings highlight the potential for sequences of xenobiotics to facilitate the rapid evolution of multiple-drug and -pesticide resistance, as well as the potential for epistatic interactions between adaptive mutations to facilitate evolutionary rescue in rapidly changing environments. }, author = {Lagator, Mato and Colegrave, Nick and Neve, Paul}, journal = {Proceedings of the Royal Society of London Series B Biological Sciences}, number = {1794}, publisher = {Royal Society, The}, title = {{Selection history and epistatic interactions impact dynamics of adaptation to novel environmental stresses}}, doi = {10.1098/rspb.2014.1679}, volume = {281}, year = {2014}, } @misc{9741, abstract = {In rapidly changing environments, selection history may impact the dynamics of adaptation. Mutations selected in one environment may result in pleiotropic fitness trade-offs in subsequent novel environments, slowing the rates of adaptation. Epistatic interactions between mutations selected in sequential stressful environments may slow or accelerate subsequent rates of adaptation, depending on the nature of that interaction. We explored the dynamics of adaptation during sequential exposure to herbicides with different modes of action in Chlamydomonas reinhardtii. Evolution of resistance to two of the herbicides was largely independent of selection history. For carbetamide, previous adaptation to other herbicide modes of action positively impacted the likelihood of adaptation to this herbicide. Furthermore, while adaptation to all individual herbicides was associated with pleiotropic fitness costs in stress-free environments, we observed that accumulation of resistance mechanisms was accompanied by a reduction in overall fitness costs. We suggest that antagonistic epistasis may be a driving mechanism that enables populations to more readily adapt in novel environments. These findings highlight the potential for sequences of xenobiotics to facilitate the rapid evolution of multiple-drug and -pesticide resistance, as well as the potential for epistatic interactions between adaptive mutations to facilitate evolutionary rescue in rapidly changing environments.}, author = {Lagator, Mato and Colegrave, Nick and Neve, Paul}, publisher = {Dryad}, title = {{Data from: Selection history and epistatic interactions impact dynamics of adaptation to novel environmental stresses}}, doi = {10.5061/dryad.85dn7}, year = {2014}, } @article{9931, abstract = {Gene duplication is important in evolution, because it provides new raw material for evolutionary adaptations. Several existing hypotheses about the causes of duplicate retention and diversification differ in their emphasis on gene dosage, subfunctionalization, and neofunctionalization. Little experimental data exist on the relative importance of gene expression changes and changes in coding regions for the evolution of duplicate genes. Furthermore, we do not know how strongly the environment could affect this importance. To address these questions, we performed evolution experiments with the TEM-1 beta lactamase gene in Escherichia coli to study the initial stages of duplicate gene evolution in the laboratory. We mimicked tandem duplication by inserting two copies of the TEM-1 gene on the same plasmid. We then subjected these copies to repeated cycles of mutagenesis and selection in various environments that contained antibiotics in different combinations and concentrations. Our experiments showed that gene dosage is the most important factor in the initial stages of duplicate gene evolution, and overshadows the importance of point mutations in the coding region.}, author = {Dhar, Riddhiman and Bergmiller, Tobias and Wagner, Andreas}, issn = {1558-5646}, journal = {Evolution}, number = {6}, pages = {1775--1791}, publisher = {Wiley}, title = {{Increased gene dosage plays a predominant role in the initial stages of evolution of duplicate TEM-1 beta lactamase genes}}, doi = {10.1111/evo.12373}, volume = {68}, year = {2014}, } @misc{9932, abstract = {Gene duplication is important in evolution, because it provides new raw material for evolutionary adaptations. Several existing hypotheses about the causes of duplicate retention and diversification differ in their emphasis on gene dosage, sub-functionalization, and neo-functionalization. Little experimental data exists on the relative importance of gene expression changes and changes in coding regions for the evolution of duplicate genes. Furthermore, we do not know how strongly the environment could affect this importance. To address these questions, we performed evolution experiments with the TEM-1 beta lactamase gene in E. coli to study the initial stages of duplicate gene evolution in the laboratory. We mimicked tandem duplication by inserting two copies of the TEM-1 gene on the same plasmid. We then subjected these copies to repeated cycles of mutagenesis and selection in various environments that contained antibiotics in different combinations and concentrations. Our experiments showed that gene dosage is the most important factor in the initial stages of duplicate gene evolution, and overshadows the importance of point mutations in the coding region.}, author = {Dhar, Riddhiman and Bergmiller, Tobias and Wagner, Andreas}, publisher = {Dryad}, title = {{Data from: Increased gene dosage plays a predominant role in the initial stages of evolution of duplicate TEM-1 beta lactamase genes}}, doi = {10.5061/dryad.jc402}, year = {2014}, } @article{1913, abstract = {Deposits of phosphorylated tau protein and convergence of pathology in the hippocampus are the hallmarks of neurodegenerative tauopathies. Thus we aimed to evaluate whether regional and cellular vulnerability patterns in the hippocampus distinguish tauopathies or are influenced by their concomitant presence. Methods: We created a heat map of phospho-tau (AT8) immunoreactivity patterns in 24 hippocampal subregions/layers in individuals with Alzheimer's disease (AD)-related neurofibrillary degeneration (n = 40), Pick's disease (n = 8), progressive supranuclear palsy (n = 7), corticobasal degeneration (n = 6), argyrophilic grain disease (AGD, n = 18), globular glial tauopathy (n = 5), and tau-astrogliopathy of the elderly (n = 10). AT8 immunoreactivity patterns were compared by mathematical analysis. Results: Our study reveals disease-specific hot spots and regional selective vulnerability for these disorders. The pattern of hippocampal AD-related tau pathology is strongly influenced by concomitant AGD. Mathematical analysis reveals that hippocampal involvement in primary tauopathies is distinguishable from early-stage AD-related neurofibrillary degeneration. Conclusion: Our data demonstrate disease-specific AT8 immunoreactivity patterns and hot spots in the hippocampus even in tauopathies, which primarily do not affect the hippocampus. These hot spots can be shifted to other regions by the co-occurrence of tauopathies like AGD. Our observations support the notion that globular glial tauopathies and tau-astrogliopathy of the elderly are distinct entities.}, author = {Milenković, Ivan and Petrov, Tatjana and Kovács, Gábor}, issn = {1420-8008}, journal = {Dementia and Geriatric Cognitive Disorders}, number = {5-6}, pages = {375 -- 388}, publisher = {Karger Publishers}, title = {{Patterns of hippocampal tau pathology differentiate neurodegenerative dementias}}, doi = {10.1159/000365548}, volume = {38}, year = {2014}, } @inproceedings{2718, abstract = {Even though both population and quantitative genetics, and evolutionary computation, deal with the same questions, they have developed largely independently of each other. I review key results from each field, emphasising those that apply independently of the (usually unknown) relation between genotype and phenotype. The infinitesimal model provides a simple framework for predicting the response of complex traits to selection, which in biology has proved remarkably successful. This allows one to choose the schedule of population sizes and selection intensities that will maximise the response to selection, given that the total number of individuals realised, C = ∑t Nt, is constrained. This argument shows that for an additive trait (i.e., determined by the sum of effects of the genes), the optimum population size and the maximum possible response (i.e., the total change in trait mean) are both proportional to √C.}, author = {Barton, Nicholas H and Paixao, Tiago}, booktitle = {Proceedings of the 15th annual conference on Genetic and evolutionary computation}, location = {Amsterdam, Netherlands}, pages = {1573 -- 1580}, publisher = {ACM}, title = {{Can quantitative and population genetics help us understand evolutionary computation?}}, doi = {10.1145/2463372.2463568}, year = {2013}, } @article{2720, abstract = {Knowledge of the rate and fitness effects of mutations is essential for understanding the process of evolution. Mutations are inherently difficult to study because they are rare and are frequently eliminated by natural selection. In the ciliate Tetrahymena thermophila, mutations can accumulate in the germline genome without being exposed to selection. We have conducted a mutation accumulation (MA) experiment in this species. Assuming that all mutations are deleterious and have the same effect, we estimate that the deleterious mutation rate per haploid germline genome per generation is U = 0.0047 (95% credible interval: 0.0015, 0.0125), and that germline mutations decrease fitness by s = 11% when expressed in a homozygous state (95% CI: 4.4%, 27%). We also estimate that deleterious mutations are partially recessive on average (h = 0.26; 95% CI: –0.022, 0.62) and that the rate of lethal mutations is <10% of the deleterious mutation rate. Comparisons between the observed evolutionary responses in the germline and somatic genomes and the results from individual-based simulations of MA suggest that the two genomes have similar mutational parameters. These are the first estimates of the deleterious mutation rate and fitness effects from the eukaryotic supergroup Chromalveolata and are within the range of those of other eukaryotes.}, author = {Long, Hongan and Paixao, Tiago and Azevedo, Ricardo and Zufall, Rebecca}, journal = {Genetics}, number = {2}, pages = {527--540}, publisher = {Genetics Society of America}, title = {{Accumulation of spontaneous mutations in the ciliate Tetrahymena thermophila}}, doi = {10.1534/genetics.113.153536}, volume = {195}, year = {2013}, } @inproceedings{2719, abstract = {Prediction of the evolutionary process is a long standing problem both in the theory of evolutionary biology and evolutionary computation (EC). It has long been realized that heritable variation is crucial to both the response to selection and the success of genetic algorithms. However, not all variation contributes in the same way to the response. Quantitative genetics has developed a large body of work trying to estimate and understand how different components of the variance in fitness in the population contribute to the response to selection. We illustrate how to apply some concepts of quantitative genetics to the analysis of genetic algorithms. In particular, we derive estimates for the short term prediction of the response to selection and we use variance decomposition to gain insight on local aspects of the landscape. Finally, we propose a new population based genetic algorithm that uses these methods to improve its operation.}, author = {Paixao, Tiago and Barton, Nicholas H}, booktitle = {Proceedings of the 15th annual conference on Genetic and evolutionary computation}, location = {Amsterdam, Netherlands}, pages = {845 -- 852}, publisher = {ACM}, title = {{A variance decomposition approach to the analysis of genetic algorithms}}, doi = {10.1145/2463372.2463470}, year = {2013}, } @article{499, abstract = {Exposure of an isogenic bacterial population to a cidal antibiotic typically fails to eliminate a small fraction of refractory cells. Historically, fractional killing has been attributed to infrequently dividing or nondividing "persisters." Using microfluidic cultures and time-lapse microscopy, we found that Mycobacterium smegmatis persists by dividing in the presence of the drug isoniazid (INH). Although persistence in these studies was characterized by stable numbers of cells, this apparent stability was actually a dynamic state of balanced division and death. Single cells expressed catalase-peroxidase (KatG), which activates INH, in stochastic pulses that were negatively correlated with cell survival. These behaviors may reflect epigenetic effects, because KatG pulsing and death were correlated between sibling cells. Selection of lineages characterized by infrequent KatG pulsing could allow nonresponsive adaptation during prolonged drug exposure.}, author = {Wakamoto, Yurichi and Dhar, Neraaj and Chait, Remy P and Schneider, Katrin and Signorino Gelo, François and Leibler, Stanislas and Mckinney, John}, journal = {Science}, number = {6115}, pages = {91 -- 95}, publisher = {American Association for the Advancement of Science}, title = {{Dynamic persistence of antibiotic-stressed mycobacteria}}, doi = {10.1126/science.1229858}, volume = {339}, year = {2013}, } @article{2853, abstract = {High relatedness among interacting individuals has generally been considered a precondition for the evolution of altruism. However, kin-selection theory also predicts the evolution of altruism when relatedness is low, as long as the cost of the altruistic act is minor compared with its benefit. Here, we demonstrate evidence for a low-cost altruistic act in bacteria. We investigated Escherichia coli responding to the attack of an obligately lytic phage by committing suicide in order to prevent parasite transmission to nearby relatives. We found that bacterial suicide provides large benefits to survivors at marginal costs to committers. The cost of suicide was low, because infected cells are moribund, rapidly dying upon phage infection, such that no more opportunity for reproduction remains. As a consequence of its marginal cost, host suicide was selectively favoured even when relatedness between committers and survivors approached zero. Altogether, our findings demonstrate that low-cost suicide can evolve with ease, represents an effective host-defence strategy, and seems to be widespread among microbes. Moreover, low-cost suicide might also occur in higher organisms as exemplified by infected social insect workers leaving the colony to die in isolation.}, author = {Refardt, Dominik and Bergmiller, Tobias and Kümmerli, Rolf}, issn = {1471-2954}, journal = {Proceedings of the Royal Society of London Series B Biological Sciences}, number = {1759}, publisher = {The Royal Society}, title = {{Altruism can evolve when relatedness is low: Evidence from bacteria committing suicide upon phage infection}}, doi = {10.1098/rspb.2012.3035}, volume = {280}, year = {2013}, } @misc{9751, abstract = {High relatedness among interacting individuals has generally been considered a precondition for the evolution of altruism. However, kin-selection theory also predicts the evolution of altruism when relatedness is low, as long as the cost of the altruistic act is minor compared to its benefit. Here, we demonstrate evidence for a low-cost altruistic act in bacteria. We investigated Escherichia coli responding to the attack of an obligately lytic phage by committing suicide in order to prevent parasite transmission to nearby relatives. We found that bacterial suicide provides large benefits to survivors at marginal costs to committers. The cost of suicide was low because infected cells are moribund, rapidly dying upon phage infection, such that no more opportunity for reproduction remains. As a consequence of its marginal cost, host suicide was selectively favoured even when relatedness between committers and survivors approached zero. Altogether, our findings demonstrate that low-cost suicide can evolve with ease, represents an effective host-defence strategy, and seems to be widespread among microbes. Moreover, low-cost suicide might also occur in higher organisms as exemplified by infected social insect workers leaving the colony to die in isolation.}, author = {Refardt, Dominik and Bergmiller, Tobias and Kümmerli, Rolf}, publisher = {Dryad}, title = {{Data from: Altruism can evolve when relatedness is low: evidence from bacteria committing suicide upon phage infection}}, doi = {10.5061/dryad.b1q2n}, year = {2013}, } @article{2302, abstract = {We introduce propagation models (PMs), a formalism able to express several kinds of equations that describe the behavior of biochemical reaction networks. Furthermore, we introduce the propagation abstract data type (PADT), which separates concerns regarding different numerical algorithms for the transient analysis of biochemical reaction networks from concerns regarding their implementation, thus allowing for portable and efficient solutions. The state of a propagation abstract data type is given by a vector that assigns mass values to a set of nodes, and its (next) operator propagates mass values through this set of nodes. We propose an approximate implementation of the (next) operator, based on threshold abstraction, which propagates only "significant" mass values and thus achieves a compromise between efficiency and accuracy. Finally, we give three use cases for propagation models: the chemical master equation (CME), the reaction rate equation (RRE), and a hybrid method that combines these two equations. These three applications use propagation models in order to propagate probabilities and/or expected values and variances of the model's variables.}, author = {Henzinger, Thomas A and Mateescu, Maria}, journal = {IEEE ACM Transactions on Computational Biology and Bioinformatics}, number = {2}, pages = {310 -- 322}, publisher = {IEEE}, title = {{The propagation approach for computing biochemical reaction networks}}, doi = {10.1109/TCBB.2012.91}, volume = {10}, year = {2012}, } @article{2943, abstract = {We examine whether the Escherichia coli chromosome is folded into a self-adherent nucleoprotein complex, or alternately is a confined but otherwise unconstrained self-avoiding polymer. We address this through in vivo visualization, using an inducible GFP fusion to the nucleoid-associated protein Fis to non-specifically decorate the entire chromosome. For a range of different growth conditions, the chromosome is a compact structure that does not fill the volume of the cell, and which moves from the new pole to the cell centre. During rapid growth, chromosome segregation occurs well before cell division, with daughter chromosomes coupled by a thin inter-daughter filament before complete segregation, whereas during slow growth chromosomes stay adjacent until cell division occurs. Image correlation analysis indicates that sub-nucleoid structure is stable on a 1min timescale, comparable to the timescale for redistribution time measured for GFP-Fis after photobleaching. Optical deconvolution and writhe calculation analysis indicate that the nucleoid has a large-scale coiled organization rather than being an amorphous mass. Our observations are consistent with the chromosome having a self-adherent filament organization.}, author = {Hadizadeh Yazdi, Nastaran and Guet, Calin C and Johnson, Reid and Marko, John}, journal = {Molecular Microbiology}, number = {6}, pages = {1318 -- 1333}, publisher = {Wiley-Blackwell}, title = {{Variation of the folding and dynamics of the Escherichia coli chromosome with growth conditions}}, doi = {10.1111/mmi.12071}, volume = {86}, year = {2012}, } @article{3130, abstract = {Essential genes code for fundamental cellular functions required for the viability of an organism. For this reason, essential genes are often highly conserved across organisms. However, this is not always the case: orthologues of genes that are essential in one organism are sometimes not essential in other organisms or are absent from their genomes. This suggests that, in the course of evolution, essential genes can be rendered nonessential. How can a gene become non-essential? Here we used genetic manipulation to deplete the products of 26 different essential genes in Escherichia coli. This depletion results in a lethal phenotype, which could often be rescued by the overexpression of a non-homologous, non-essential gene, most likely through replacement of the essential function. We also show that, in a smaller number of cases, the essential genes can be fully deleted from the genome, suggesting that complete functional replacement is possible. Finally, we show that essential genes whose function can be replaced in the laboratory are more likely to be non-essential or not present in other taxa. These results are consistent with the notion that patterns of evolutionary conservation of essential genes are influenced by their compensability-that is, by how easily they can be functionally replaced, for example through increased expression of other genes.}, author = {Bergmiller, Tobias and Ackermann, Martin and Silander, Olin}, journal = {PLoS Genetics}, number = {6}, publisher = {Public Library of Science}, title = {{Patterns of evolutionary conservation of essential genes correlate with their compensability}}, doi = {10.1371/journal.pgen.1002803}, volume = {8}, year = {2012}, } @inproceedings{3136, abstract = {Continuous-time Markov chains (CTMC) with their rich theory and efficient simulation algorithms have been successfully used in modeling stochastic processes in diverse areas such as computer science, physics, and biology. However, systems that comprise non-instantaneous events cannot be accurately and efficiently modeled with CTMCs. In this paper we define delayed CTMCs, an extension of CTMCs that allows for the specification of a lower bound on the time interval between an event's initiation and its completion, and we propose an algorithm for the computation of their behavior. Our algorithm effectively decomposes the computation into two stages: a pure CTMC governs event initiations while a deterministic process guarantees lower bounds on event completion times. Furthermore, from the nature of delayed CTMCs, we obtain a parallelized version of our algorithm. We use our formalism to model genetic regulatory circuits (biological systems where delayed events are common) and report on the results of our numerical algorithm as run on a cluster. We compare performance and accuracy of our results with results obtained by using pure CTMCs. © 2012 Springer-Verlag.}, author = {Guet, Calin C and Gupta, Ashutosh and Henzinger, Thomas A and Mateescu, Maria and Sezgin, Ali}, location = {Berkeley, CA, USA}, pages = {294 -- 309}, publisher = {Springer}, title = {{Delayed continuous time Markov chains for genetic regulatory circuits}}, doi = {10.1007/978-3-642-31424-7_24}, volume = {7358 }, year = {2012}, } @article{6496, abstract = {We report the switching behavior of the full bacterial flagellum system that includes the filament and the motor in wild-type Escherichia coli cells. In sorting the motor behavior by the clockwise bias, we find that the distributions of the clockwise (CW) and counterclockwise (CCW) intervals are either exponential or nonexponential with long tails. At low bias, CW intervals are exponentially distributed and CCW intervals exhibit long tails. At intermediate CW bias (0.5) both CW and CCW intervals are mainly exponentially distributed. A simple model suggests that these two distinct switching behaviors are governed by the presence of signaling noise within the chemotaxis network. Low noise yields exponentially distributed intervals, whereas large noise yields nonexponential behavior with long tails. These drastically different motor statistics may play a role in optimizing bacterial behavior for a wide range of environmental conditions.}, author = {Park, Heungwon and Oikonomou, Panos and Guet, Calin C and Cluzel, Philippe}, issn = {0006-3495}, journal = {Biophysical Journal}, number = {10}, pages = {2336--2340}, publisher = {Elsevier}, title = {{Noise underlies switching behavior of the bacterial flagellum}}, doi = {10.1016/j.bpj.2011.09.040}, volume = {101}, year = {2011}, } @inproceedings{3719, abstract = {The induction of a signaling pathway is characterized by transient complex formation and mutual posttranslational modification of proteins. To faithfully capture this combinatorial process in a math- ematical model is an important challenge in systems biology. Exploiting the limited context on which most binding and modification events are conditioned, attempts have been made to reduce the com- binatorial complexity by quotienting the reachable set of molecular species, into species aggregates while preserving the deterministic semantics of the thermodynamic limit. Recently we proposed a quotienting that also preserves the stochastic semantics and that is complete in the sense that the semantics of individual species can be recovered from the aggregate semantics. In this paper we prove that this quotienting yields a sufficient condition for weak lumpability and that it gives rise to a backward Markov bisimulation between the original and aggregated transition system. We illustrate the framework on a case study of the EGF/insulin receptor crosstalk.}, author = {Feret, Jérôme and Henzinger, Thomas A and Koeppl, Heinz and Petrov, Tatjana}, location = {Jena, Germany}, pages = {142--161}, publisher = {Open Publishing Association}, title = {{Lumpability abstractions of rule-based systems}}, volume = {40}, year = {2010}, } @inproceedings{3847, abstract = {The importance of stochasticity within biological systems has been shown repeatedly during the last years and has raised the need for efficient stochastic tools. We present SABRE, a tool for stochastic analysis of biochemical reaction networks. SABRE implements fast adaptive uniformization (FAU), a direct numerical approximation algorithm for computing transient solutions of biochemical reaction networks. Biochemical reactions networks represent biological systems studied at a molecular level and these reactions can be modeled as transitions of a Markov chain. SABRE accepts as input the formalism of guarded commands, which it interprets either as continuous-time or as discrete-time Markov chains. Besides operating in a stochastic mode, SABRE may also perform a deterministic analysis by directly computing a mean-field approximation of the system under study. We illustrate the different functionalities of SABRE by means of biological case studies.}, author = {Didier, Frédéric and Henzinger, Thomas A and Mateescu, Maria and Wolf, Verena}, location = {Williamsburg, USA}, pages = {193 -- 194}, publisher = {IEEE}, title = {{SABRE: A tool for the stochastic analysis of biochemical reaction networks}}, doi = {10.1109/QEST.2010.33}, year = {2010}, } @inproceedings{3843, abstract = {Within systems biology there is an increasing interest in the stochastic behavior of biochemical reaction networks. An appropriate stochastic description is provided by the chemical master equation, which represents a continuous- time Markov chain (CTMC). Standard Uniformization (SU) is an efficient method for the transient analysis of CTMCs. For systems with very different time scales, such as biochemical reaction networks, SU is computationally expensive. In these cases, a variant of SU, called adaptive uniformization (AU), is known to reduce the large number of iterations needed by SU. The additional difficulty of AU is that it requires the solution of a birth process. In this paper we present an on-the-fly variant of AU, where we improve the original algorithm for AU at the cost of a small approximation error. By means of several examples, we show that our approach is particularly well-suited for biochemical reaction networks.}, author = {Didier, Frédéric and Henzinger, Thomas A and Mateescu, Maria and Wolf, Verena}, location = {Trento, Italy}, number = {6}, pages = {118 -- 127}, publisher = {IEEE}, title = {{Fast adaptive uniformization of the chemical master equation}}, doi = {10.1109/HiBi.2009.23}, volume = {4}, year = {2009}, }