@article{954, abstract = {Understanding the relation between genotype and phenotype remains a major challenge. The difficulty of predicting individual mutation effects, and particularly the interactions between them, has prevented the development of a comprehensive theory that links genotypic changes to their phenotypic effects. We show that a general thermodynamic framework for gene regulation, based on a biophysical understanding of protein-DNA binding, accurately predicts the sign of epistasis in a canonical cis-regulatory element consisting of overlapping RNA polymerase and repressor binding sites. Sign and magnitude of individual mutation effects are sufficient to predict the sign of epistasis and its environmental dependence. Thus, the thermodynamic model offers the correct null prediction for epistasis between mutations across DNA-binding sites. Our results indicate that a predictive theory for the effects of cis-regulatory mutations is possible from first principles, as long as the essential molecular mechanisms and the constraints these impose on a biological system are accounted for.}, author = {Lagator, Mato and Paixao, Tiago and Barton, Nicholas H and Bollback, Jonathan P and Guet, Calin C}, issn = {2050-084X}, journal = {eLife}, publisher = {eLife Sciences Publications}, title = {{On the mechanistic nature of epistasis in a canonical cis-regulatory element}}, doi = {10.7554/eLife.25192}, volume = {6}, year = {2017}, } @article{570, abstract = {Most phenotypes are determined by molecular systems composed of specifically interacting molecules. However, unlike for individual components, little is known about the distributions of mutational effects of molecular systems as a whole. We ask how the distribution of mutational effects of a transcriptional regulatory system differs from the distributions of its components, by first independently, and then simultaneously, mutating a transcription factor and the associated promoter it represses. We find that the system distribution exhibits increased phenotypic variation compared to individual component distributions - an effect arising from intermolecular epistasis between the transcription factor and its DNA-binding site. In large part, this epistasis can be qualitatively attributed to the structure of the transcriptional regulatory system and could therefore be a common feature in prokaryotes. Counter-intuitively, intermolecular epistasis can alleviate the constraints of individual components, thereby increasing phenotypic variation that selection could act on and facilitating adaptive evolution. }, author = {Lagator, Mato and Sarikas, Srdjan and Acar, Hande and Bollback, Jonathan P and Guet, Calin C}, issn = {2050-084X}, journal = {eLife}, publisher = {eLife Sciences Publications}, title = {{Regulatory network structure determines patterns of intermolecular epistasis}}, doi = {10.7554/eLife.28921}, volume = {6}, year = {2017}, } @article{611, abstract = {Small RNAs (sRNAs) regulate genes in plants and animals. Here, we show that population-wide differences in color patterns in snapdragon flowers are caused by an inverted duplication that generates sRNAs. The complexity and size of the transcripts indicate that the duplication represents an intermediate on the pathway to microRNA evolution. The sRNAs repress a pigment biosynthesis gene, creating a yellow highlight at the site of pollinator entry. The inverted duplication exhibits steep clines in allele frequency in a natural hybrid zone, showing that the allele is under selection. Thus, regulatory interactions of evolutionarily recent sRNAs can be acted upon by selection and contribute to the evolution of phenotypic diversity.}, author = {Bradley, Desmond and Xu, Ping and Mohorianu, Irina and Whibley, Annabel and Field, David and Tavares, Hugo and Couchman, Matthew and Copsey, Lucy and Carpenter, Rosemary and Li, Miaomiao and Li, Qun and Xue, Yongbiao and Dalmay, Tamas and Coen, Enrico}, issn = {0036-8075}, journal = {Science}, number = {6365}, pages = {925 -- 928}, publisher = {American Association for the Advancement of Science}, title = {{Evolution of flower color pattern through selection on regulatory small RNAs}}, doi = {10.1126/science.aao3526}, volume = {358}, year = {2017}, } @article{614, abstract = {Moths and butterflies (Lepidoptera) usually have a pair of differentiated WZ sex chromosomes. However, in most lineages outside of the division Ditrysia, as well as in the sister order Trichoptera, females lack a W chromosome. The W is therefore thought to have been acquired secondarily. Here we compare the genomes of three Lepidoptera species (one Dytrisia and two non-Dytrisia) to test three models accounting for the origin of the W: (1) a Z-autosome fusion; (2) a sex chromosome turnover; and (3) a non-canonical mechanism (e.g., through the recruitment of a B chromosome). We show that the gene content of the Z is highly conserved across Lepidoptera (rejecting a sex chromosome turnover) and that very few genes moved onto the Z in the common ancestor of the Ditrysia (arguing against a Z-autosome fusion). Our comparative genomics analysis therefore supports the secondary acquisition of the Lepidoptera W by a non-canonical mechanism, and it confirms the extreme stability of well-differentiated sex chromosomes.}, author = {Fraisse, Christelle and Picard, Marion A and Vicoso, Beatriz}, issn = {2041-1723}, journal = {Nature Communications}, number = {1}, publisher = {Nature Publishing Group}, title = {{The deep conservation of the Lepidoptera Z chromosome suggests a non canonical origin of the W}}, doi = {10.1038/s41467-017-01663-5}, volume = {8}, year = {2017}, } @article{626, abstract = {Our focus here is on the infinitesimal model. In this model, one or several quantitative traits are described as the sum of a genetic and a non-genetic component, the first being distributed within families as a normal random variable centred at the average of the parental genetic components, and with a variance independent of the parental traits. Thus, the variance that segregates within families is not perturbed by selection, and can be predicted from the variance components. This does not necessarily imply that the trait distribution across the whole population should be Gaussian, and indeed selection or population structure may have a substantial effect on the overall trait distribution. One of our main aims is to identify some general conditions on the allelic effects for the infinitesimal model to be accurate. We first review the long history of the infinitesimal model in quantitative genetics. Then we formulate the model at the phenotypic level in terms of individual trait values and relationships between individuals, but including different evolutionary processes: genetic drift, recombination, selection, mutation, population structure, …. We give a range of examples of its application to evolutionary questions related to stabilising selection, assortative mating, effective population size and response to selection, habitat preference and speciation. We provide a mathematical justification of the model as the limit as the number M of underlying loci tends to infinity of a model with Mendelian inheritance, mutation and environmental noise, when the genetic component of the trait is purely additive. We also show how the model generalises to include epistatic effects. We prove in particular that, within each family, the genetic components of the individual trait values in the current generation are indeed normally distributed with a variance independent of ancestral traits, up to an error of order 1∕M. Simulations suggest that in some cases the convergence may be as fast as 1∕M.}, author = {Barton, Nicholas H and Etheridge, Alison and Véber, Amandine}, issn = {0040-5809}, journal = {Theoretical Population Biology}, pages = {50 -- 73}, publisher = {Academic Press}, title = {{The infinitesimal model: Definition derivation and implications}}, doi = {10.1016/j.tpb.2017.06.001}, volume = {118}, year = {2017}, } @misc{7163, abstract = {The de novo genome assemblies generated for this study, and the associated metadata.}, author = {Fraisse, Christelle}, publisher = {Institute of Science and Technology Austria}, title = {{Supplementary Files for "The deep conservation of the Lepidoptera Z chromosome suggests a non canonical origin of the W"}}, doi = {10.15479/AT:ISTA:7163}, year = {2017}, } @misc{9842, abstract = {Mathematica notebooks used to generate figures.}, author = {Etheridge, Alison and Barton, Nicholas H}, publisher = {Mendeley Data}, title = {{Data for: Establishment in a new habitat by polygenic adaptation}}, doi = {10.17632/nw68fxzjpm.1}, year = {2017}, } @misc{9849, abstract = {This text provides additional information about the model, a derivation of the analytic results in Eq (4), and details about simulations of an additional parameter set.}, author = {Lukacisinova, Marta and Novak, Sebastian and Paixao, Tiago}, publisher = {Public Library of Science}, title = {{Modelling and simulation details}}, doi = {10.1371/journal.pcbi.1005609.s001}, year = {2017}, } @misc{9850, abstract = {In this text, we discuss how a cost of resistance and the possibility of lethal mutations impact our model.}, author = {Lukacisinova, Marta and Novak, Sebastian and Paixao, Tiago}, publisher = {Public Library of Science}, title = {{Extensions of the model}}, doi = {10.1371/journal.pcbi.1005609.s002}, year = {2017}, } @misc{9851, abstract = {Based on the intuitive derivation of the dynamics of SIM allele frequency pM in the main text, we present a heuristic prediction for the long-term SIM allele frequencies with χ > 1 stresses and compare it to numerical simulations.}, author = {Lukacisinova, Marta and Novak, Sebastian and Paixao, Tiago}, publisher = {Public Library of Science}, title = {{Heuristic prediction for multiple stresses}}, doi = {10.1371/journal.pcbi.1005609.s003}, year = {2017}, } @misc{9852, abstract = {We show how different combination strategies affect the fraction of individuals that are multi-resistant.}, author = {Lukacisinova, Marta and Novak, Sebastian and Paixao, Tiago}, publisher = {Public Library of Science}, title = {{Resistance frequencies for different combination strategies}}, doi = {10.1371/journal.pcbi.1005609.s004}, year = {2017}, } @misc{9856, author = {Schmidt, Tom and Barton, Nicholas H and Rasic, Gordana and Turley, Andrew and Montgomery, Brian and Iturbe Ormaetxe, Inaki and Cook, Peter and Ryan, Peter and Ritchie, Scott and Hoffmann, Ary and O’Neill, Scott and Turelli, Michael}, publisher = {Public Library of Science}, title = {{Supporting Information concerning additional likelihood analyses and results}}, doi = {10.1371/journal.pbio.2001894.s014}, year = {2017}, } @misc{9857, author = {Schmidt, Tom and Barton, Nicholas H and Rasic, Gordana and Turley, Andrew and Montgomery, Brian and Iturbe Ormaetxe, Inaki and Cook, Peter and Ryan, Peter and Ritchie, Scott and Hoffmann, Ary and O’Neill, Scott and Turelli, Michael}, publisher = {Public Library of Science }, title = {{Supporting information concerning observed wMel frequencies and analyses of habitat variables}}, doi = {10.1371/journal.pbio.2001894.s015}, year = {2017}, } @misc{9858, author = {Schmidt, Tom and Barton, Nicholas H and Rasic, Gordana and Turley, Andrew and Montgomery, Brian and Iturbe Ormaetxe, Inaki and Cook, Peter and Ryan, Peter and Ritchie, Scott and Hoffmann, Ary and O’Neill, Scott and Turelli, Michael}, publisher = {Public Library of Science}, title = {{Excel file with data on mosquito densities, Wolbachia infection status and housing characteristics}}, doi = {10.1371/journal.pbio.2001894.s016}, year = {2017}, } @article{990, abstract = {Assortative mating is an important driver of speciation in populations with gene flow and is predicted to evolve under certain conditions in few-locus models. However, the evolution of assortment is less understood for mating based on quantitative traits, which are often characterized by high genetic variability and extensive linkage disequilibrium between trait loci. We explore this scenario for a two-deme model with migration, by considering a single polygenic trait subject to divergent viability selection across demes, as well as assortative mating and sexual selection within demes, and investigate how trait divergence is shaped by various evolutionary forces. Our analysis reveals the existence of sharp thresholds of assortment strength, at which divergence increases dramatically. We also study the evolution of assortment via invasion of modifiers of mate discrimination and show that the ES assortment strength has an intermediate value under a range of migration-selection parameters, even in diverged populations, due to subtle effects which depend sensitively on the extent of phenotypic variation within these populations. The evolutionary dynamics of the polygenic trait is studied using the hypergeometric and infinitesimal models. We further investigate the sensitivity of our results to the assumptions of the hypergeometric model, using individual-based simulations.}, author = {Sachdeva, Himani and Barton, Nicholas H}, issn = {0014-3820}, journal = {Evolution; International Journal of Organic Evolution}, number = {6}, pages = {1478 -- 1493 }, publisher = {Wiley-Blackwell}, title = {{Divergence and evolution of assortative mating in a polygenic trait model of speciation with gene flow}}, doi = {10.1111/evo.13252}, volume = {71}, year = {2017}, } @article{955, abstract = {Gene expression is controlled by networks of regulatory proteins that interact specifically with external signals and DNA regulatory sequences. These interactions force the network components to co-evolve so as to continually maintain function. Yet, existing models of evolution mostly focus on isolated genetic elements. In contrast, we study the essential process by which regulatory networks grow: the duplication and subsequent specialization of network components. We synthesize a biophysical model of molecular interactions with the evolutionary framework to find the conditions and pathways by which new regulatory functions emerge. We show that specialization of new network components is usually slow, but can be drastically accelerated in the presence of regulatory crosstalk and mutations that promote promiscuous interactions between network components.}, author = {Friedlander, Tamar and Prizak, Roshan and Barton, Nicholas H and Tkacik, Gasper}, issn = {2041-1723}, journal = {Nature Communications}, number = {1}, publisher = {Nature Publishing Group}, title = {{Evolution of new regulatory functions on biophysically realistic fitness landscapes}}, doi = {10.1038/s41467-017-00238-8}, volume = {8}, year = {2017}, } @article{1074, abstract = {Recently it has become feasible to detect long blocks of nearly identical sequence shared between pairs of genomes. These IBD blocks are direct traces of recent coalescence events and, as such, contain ample signal to infer recent demography. Here, we examine sharing of such blocks in two-dimensional populations with local migration. Using a diffusion approximation to trace genetic ancestry, we derive analytical formulae for patterns of isolation by distance of IBD blocks, which can also incorporate recent population density changes. We introduce an inference scheme that uses a composite likelihood approach to fit these formulae. We then extensively evaluate our theory and inference method on a range of scenarios using simulated data. We first validate the diffusion approximation by showing that the theoretical results closely match the simulated block sharing patterns. We then demonstrate that our inference scheme can accurately and robustly infer dispersal rate and effective density, as well as bounds on recent dynamics of population density. To demonstrate an application, we use our estimation scheme to explore the fit of a diffusion model to Eastern European samples in the POPRES data set. We show that ancestry diffusing with a rate of σ ≈ 50–100 km/√gen during the last centuries, combined with accelerating population growth, can explain the observed exponential decay of block sharing with increasing pairwise sample distance.}, author = {Ringbauer, Harald and Coop, Graham and Barton, Nicholas H}, issn = {0016-6731}, journal = {Genetics}, number = {3}, pages = {1335 -- 1351}, publisher = {Genetics Society of America}, title = {{Inferring recent demography from isolation by distance of long shared sequence blocks}}, doi = {10.1534/genetics.116.196220}, volume = {205}, year = {2017}, } @phdthesis{6291, abstract = {Bacteria and their pathogens – phages – are the most abundant living entities on Earth. Throughout their coevolution, bacteria have evolved multiple immune systems to overcome the ubiquitous threat from the phages. Although the molecu- lar details of these immune systems’ functions are relatively well understood, their epidemiological consequences for the phage-bacterial communities have been largely neglected. In this thesis we employed both experimental and theoretical methods to explore whether herd and social immunity may arise in bacterial popu- lations. Using our experimental system consisting of Escherichia coli strains with a CRISPR based immunity to the T7 phage we show that herd immunity arises in phage-bacterial communities and that it is accentuated when the populations are spatially structured. By fitting a mathematical model, we inferred expressions for the herd immunity threshold and the velocity of spread of a phage epidemic in partially resistant bacterial populations, which both depend on the bacterial growth rate, phage burst size and phage latent period. We also investigated the poten- tial for social immunity in Streptococcus thermophilus and its phage 2972 using a bioinformatic analysis of potentially coding short open reading frames with a signalling signature, encoded within the CRISPR associated genes. Subsequently, we tested one identified potentially signalling peptide and found that its addition to a phage-challenged culture increases probability of survival of bacteria two fold, although the results were only marginally significant. Together, these results demonstrate that the ubiquitous arms races between bacteria and phages have further consequences at the level of the population.}, author = {Payne, Pavel}, issn = {2663-337X}, pages = {83}, publisher = {Institute of Science and Technology Austria}, title = {{Bacterial herd and social immunity to phages}}, year = {2017}, } @article{1336, 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 the runtimes of EAs 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 occurrences of new mutations is much longer than the time it takes for a mutated genotype to take over the population. In this situation, the population only contains copies of one genotype and evolution can be modelled as a stochastic process evolving one genotype by means of mutation and selection between the resident and the mutated genotype. The probability of accepting the mutated genotype then depends on the change in fitness. We study this process, SSWM, from an algorithmic perspective, quantifying its expected optimisation time for various parameters and investigating differences to a similar evolutionary algorithm, the well-known (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 Pérez Heredia, Jorge and Sudholt, Dirk and Trubenova, Barbora}, issn = {0178-4617}, journal = {Algorithmica}, number = {2}, pages = {681 -- 713}, publisher = {Springer}, title = {{Towards a runtime comparison of natural and artificial evolution}}, doi = {10.1007/s00453-016-0212-1}, volume = {78}, 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 = {1553-734X}, 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}, }