TY - GEN AB - The spread of adaptive alleles is fundamental to evolution, and in theory, this process is well‐understood. However, only rarely can we follow this process—whether it originates from the spread of a new mutation, or by introgression from another population. In this issue of Molecular Ecology, Hanemaaijer et al. (2018) report on a 25‐year long study of the mosquitoes Anopheles gambiae (Figure 1) and Anopheles coluzzi in Mali, based on genotypes at 15 single‐nucleotide polymorphism (SNP). The species are usually reproductively isolated from each other, but in 2002 and 2006, bursts of hybridization were observed, when F1 hybrids became abundant. Alleles backcrossed from A. gambiae into A. coluzzi, but after the first event, these declined over the following years. In contrast, after 2006, an insecticide resistance allele that had established in A. gambiae spread into A. coluzzi, and rose to high frequency there, over 6 years (~75 generations). Whole genome sequences of 74 individuals showed that A. gambiae SNP from across the genome had become common in the A. coluzzi population, but that most of these were clustered in 34 genes around the resistance locus. A new set of SNP from 25 of these genes were assayed over time; over the 4 years since near‐fixation of the resistance allele; some remained common, whereas others declined. What do these patterns tell us about this introgression event? AU - Barton, Nicholas H ID - 9805 TI - Data from: The consequences of an introgression event ER - TY - THES AB - Transcription factors, by binding to specific sequences on the DNA, control the precise spatio-temporal expression of genes inside a cell. However, this specificity is limited, leading to frequent incorrect binding of transcription factors that might have deleterious consequences on the cell. By constructing a biophysical model of TF-DNA binding in the context of gene regulation, I will first explore how regulatory constraints can strongly shape the distribution of a population in sequence space. Then, by directly linking this to a picture of multiple types of transcription factors performing their functions simultaneously inside the cell, I will explore the extent of regulatory crosstalk -- incorrect binding interactions between transcription factors and binding sites that lead to erroneous regulatory states -- and understand the constraints this places on the design of regulatory systems. I will then develop a generic theoretical framework to investigate the coevolution of multiple transcription factors and multiple binding sites, in the context of a gene regulatory network that performs a certain function. As a particular tractable version of this problem, I will consider the evolution of two transcription factors when they transmit upstream signals to downstream target genes. Specifically, I will describe the evolutionary steady states and the evolutionary pathways involved, along with their timescales, of a system that initially undergoes a transcription factor duplication event. To connect this important theoretical model to the prominent biological event of transcription factor duplication giving rise to paralogous families, I will then describe a bioinformatics analysis of C2H2 Zn-finger transcription factors, a major family in humans, and focus on the patterns of evolution that paralogs have undergone in their various protein domains in the recent past. AU - Prizak, Roshan ID - 6071 SN - 2663-337X TI - Coevolution of transcription factors and their binding sites in sequence space ER - TY - JOUR AB - Plant mating systems play a key role in structuring genetic variation both within and between species. In hybrid zones, the outcomes and dynamics of hybridization are usually interpreted as the balance between gene flow and selection against hybrids. Yet, mating systems can introduce selective forces that alter these expectations; with diverse outcomes for the level and direction of gene flow depending on variation in outcrossing and whether the mating systems of the species pair are the same or divergent. We present a survey of hybridization in 133 species pairs from 41 plant families and examine how patterns of hybridization vary with mating system. We examine if hybrid zone mode, level of gene flow, asymmetries in gene flow and the frequency of reproductive isolating barriers vary in relation to mating system/s of the species pair. We combine these results with a simulation model and examples from the literature to address two general themes: (i) the two‐way interaction between introgression and the evolution of reproductive systems, and (ii) how mating system can facilitate or restrict interspecific gene flow. We conclude that examining mating system with hybridization provides unique opportunities to understand divergence and the processes underlying reproductive isolation. AU - Pickup, Melinda AU - Barton, Nicholas H AU - Brandvain, Yaniv AU - Fraisse, Christelle AU - Yakimowski, Sarah AU - Dixit, Tanmay AU - Lexer, Christian AU - Cereghetti, Eva AU - Field, David ID - 6856 IS - 3 JF - New Phytologist SN - 0028-646X TI - Mating system variation in hybrid zones: Facilitation, barriers and asymmetries to gene flow VL - 224 ER - TY - JOUR AB - Pleiotropy is the well-established idea that a single mutation affects multiple phenotypes. If a mutation has opposite effects on fitness when expressed in different contexts, then genetic conflict arises. Pleiotropic conflict is expected to reduce the efficacy of selection by limiting the fixation of beneficial mutations through adaptation, and the removal of deleterious mutations through purifying selection. Although this has been widely discussed, in particular in the context of a putative “gender load,” it has yet to be systematically quantified. In this work, we empirically estimate to which extent different pleiotropic regimes impede the efficacy of selection in Drosophila melanogaster. We use whole-genome polymorphism data from a single African population and divergence data from D. simulans to estimate the fraction of adaptive fixations (α), the rate of adaptation (ωA), and the direction of selection (DoS). After controlling for confounding covariates, we find that the different pleiotropic regimes have a relatively small, but significant, effect on selection efficacy. Specifically, our results suggest that pleiotropic sexual antagonism may restrict the efficacy of selection, but that this conflict can be resolved by limiting the expression of genes to the sex where they are beneficial. Intermediate levels of pleiotropy across tissues and life stages can also lead to maladaptation in D. melanogaster, due to inefficient purifying selection combined with low frequency of mutations that confer a selective advantage. Thus, our study highlights the need to consider the efficacy of selection in the context of antagonistic pleiotropy, and of genetic conflict in general. AU - Fraisse, Christelle AU - Puixeu Sala, Gemma AU - Vicoso, Beatriz ID - 6089 IS - 3 JF - Molecular biology and evolution SN - 0737-4038 TI - Pleiotropy modulates the efficacy of selection in drosophila melanogaster VL - 36 ER - TY - JOUR AB - Cells need to reliably sense external ligand concentrations to achieve various biological functions such as chemotaxis or signaling. The molecular recognition of ligands by surface receptors is degenerate in many systems, leading to crosstalk between ligand-receptor pairs. Crosstalk is often thought of as a deviation from optimal specific recognition, as the binding of noncognate ligands can interfere with the detection of the receptor's cognate ligand, possibly leading to a false triggering of a downstream signaling pathway. Here we quantify the optimal precision of sensing the concentrations of multiple ligands by a collection of promiscuous receptors. We demonstrate that crosstalk can improve precision in concentration sensing and discrimination tasks. To achieve superior precision, the additional information about ligand concentrations contained in short binding events of the noncognate ligand should be exploited. We present a proofreading scheme to realize an approximate estimation of multiple ligand concentrations that reaches a precision close to the derived optimal bounds. Our results help rationalize the observed ubiquity of receptor crosstalk in molecular sensing. AU - Carballo-Pacheco, Martín AU - Desponds, Jonathan AU - Gavrilchenko, Tatyana AU - Mayer, Andreas AU - Prizak, Roshan AU - Reddy, Gautam AU - Nemenman, Ilya AU - Mora, Thierry ID - 6090 IS - 2 JF - Physical Review E TI - Receptor crosstalk improves concentration sensing of multiple ligands VL - 99 ER - TY - JOUR AB - Evolutionary studies are often limited by missing data that are critical to understanding the history of selection. Selection experiments, which reproduce rapid evolution under controlled conditions, are excellent tools to study how genomes evolve under selection. Here we present a genomic dissection of the Longshanks selection experiment, in which mice were selectively bred over 20 generations for longer tibiae relative to body mass, resulting in 13% longer tibiae in two replicates. We synthesized evolutionary theory, genome sequences and molecular genetics to understand the selection response and found that it involved both polygenic adaptation and discrete loci of major effect, with the strongest loci tending to be selected in parallel between replicates. We show that selection may favor de-repression of bone growth through inactivating two limb enhancers of an inhibitor, Nkx3-2. Our integrative genomic analyses thus show that it is possible to connect individual base-pair changes to the overall selection response. AU - Castro, João Pl AU - Yancoskie, Michelle N. AU - Marchini, Marta AU - Belohlavy, Stefanie AU - Hiramatsu, Layla AU - Kučka, Marek AU - Beluch, William H. AU - Naumann, Ronald AU - Skuplik, Isabella AU - Cobb, John AU - Barton, Nicholas H AU - Rolian, Campbell AU - Chan, Yingguang Frank ID - 6713 JF - eLife TI - An integrative genomic analysis of the Longshanks selection experiment for longer limbs in mice VL - 8 ER - TY - JOUR AB - More than 100 years after Grigg’s influential analysis of species’ borders, the causes of limits to species’ ranges still represent a puzzle that has never been understood with clarity. The topic has become especially important recently as many scientists have become interested in the potential for species’ ranges to shift in response to climate change—and yet nearly all of those studies fail to recognise or incorporate evolutionary genetics in a way that relates to theoretical developments. I show that range margins can be understood based on just two measurable parameters: (i) the fitness cost of dispersal—a measure of environmental heterogeneity—and (ii) the strength of genetic drift, which reduces genetic diversity. Together, these two parameters define an ‘expansion threshold’: adaptation fails when genetic drift reduces genetic diversity below that required for adaptation to a heterogeneous environment. When the key parameters drop below this expansion threshold locally, a sharp range margin forms. When they drop below this threshold throughout the species’ range, adaptation collapses everywhere, resulting in either extinction or formation of a fragmented metapopulation. Because the effects of dispersal differ fundamentally with dimension, the second parameter—the strength of genetic drift—is qualitatively different compared to a linear habitat. In two-dimensional habitats, genetic drift becomes effectively independent of selection. It decreases with ‘neighbourhood size’—the number of individuals accessible by dispersal within one generation. Moreover, in contrast to earlier predictions, which neglected evolution of genetic variance and/or stochasticity in two dimensions, dispersal into small marginal populations aids adaptation. This is because the reduction of both genetic and demographic stochasticity has a stronger effect than the cost of dispersal through increased maladaptation. The expansion threshold thus provides a novel, theoretically justified, and testable prediction for formation of the range margin and collapse of the species’ range. AU - Polechova, Jitka ID - 315 IS - 6 JF - PLoS Biology SN - 15449173 TI - Is the sky the limit? On the expansion threshold of a species’ range VL - 16 ER - TY - GEN AB - Both classical and recent studies suggest that chromosomal inversion polymorphisms are important in adaptation and speciation. However, biases in discovery and reporting of inversions make it difficult to assess their prevalence and biological importance. Here, we use an approach based on linkage disequilibrium among markers genotyped for samples collected across a transect between contrasting habitats to detect chromosomal rearrangements de novo. We report 17 polymorphic rearrangements in a single locality for the coastal marine snail, Littorina saxatilis. Patterns of diversity in the field and of recombination in controlled crosses provide strong evidence that at least the majority of these rearrangements are inversions. Most show clinal changes in frequency between habitats, suggestive of divergent selection, but only one appears to be fixed for different arrangements in the two habitats. Consistent with widespread evidence for balancing selection on inversion polymorphisms, we argue that a combination of heterosis and divergent selection can explain the observed patterns and should be considered in other systems spanning environmental gradients. AU - Faria, Rui AU - Chaube, Pragya AU - Morales, Hernán E. AU - Larsson, Tomas AU - Lemmon, Alan R. AU - Lemmon, Emily M. AU - Rafajlović, Marina AU - Panova, Marina AU - Ravinet, Mark AU - Johannesson, Kerstin AU - Westram, Anja M AU - Butlin, Roger K. ID - 9837 TI - Data from: Multiple chromosomal rearrangements in a hybrid zone between Littorina saxatilis ecotypes ER - TY - JOUR AB - Herd immunity, a process in which resistant individuals limit the spread of a pathogen among susceptible hosts has been extensively studied in eukaryotes. Even though bacteria have evolved multiple immune systems against their phage pathogens, herd immunity in bacteria remains unexplored. Here we experimentally demonstrate that herd immunity arises during phage epidemics in structured and unstructured Escherichia coli populations consisting of differing frequencies of susceptible and resistant cells harboring CRISPR immunity. In addition, we develop a mathematical model that quantifies how herd immunity is affected by spatial population structure, bacterial growth rate, and phage replication rate. Using our model we infer a general epidemiological rule describing the relative speed of an epidemic in partially resistant spatially structured populations. Our experimental and theoretical findings indicate that herd immunity may be important in bacterial communities, allowing for stable coexistence of bacteria and their phages and the maintenance of polymorphism in bacterial immunity. AU - Payne, Pavel AU - Geyrhofer, Lukas AU - Barton, Nicholas H AU - Bollback, Jonathan P ID - 423 JF - eLife TI - CRISPR-based herd immunity can limit phage epidemics in bacterial populations VL - 7 ER - TY - GEN AB - Herd immunity, a process in which resistant individuals limit the spread of a pathogen among susceptible hosts has been extensively studied in eukaryotes. Even though bacteria have evolved multiple immune systems against their phage pathogens, herd immunity in bacteria remains unexplored. Here we experimentally demonstrate that herd immunity arises during phage epidemics in structured and unstructured Escherichia coli populations consisting of differing frequencies of susceptible and resistant cells harboring CRISPR immunity. In addition, we develop a mathematical model that quantifies how herd immunity is affected by spatial population structure, bacterial growth rate, and phage replication rate. Using our model we infer a general epidemiological rule describing the relative speed of an epidemic in partially resistant spatially structured populations. Our experimental and theoretical findings indicate that herd immunity may be important in bacterial communities, allowing for stable coexistence of bacteria and their phages and the maintenance of polymorphism in bacterial immunity. AU - Payne, Pavel AU - Geyrhofer, Lukas AU - Barton, Nicholas H AU - Bollback, Jonathan P ID - 9840 TI - Data from: CRISPR-based herd immunity limits phage epidemics in bacterial populations ER - TY - JOUR AB - Maladapted individuals can only colonise a new habitat if they can evolve a positive growth rate fast enough to avoid extinction, a process known as evolutionary rescue. We treat log fitness at low density in the new habitat as a single polygenic trait and thus use the infinitesimal model to follow the evolution of the growth rate; this assumes that the trait values of offspring of a sexual union are normally distributed around the mean of the parents’ trait values, with variance that depends only on the parents’ relatedness. The probability that a single migrant can establish depends on just two parameters: the mean and genetic variance of the trait in the source population. The chance of success becomes small if migrants come from a population with mean growth rate in the new habitat more than a few standard deviations below zero; this chance depends roughly equally on the probability that the initial founder is unusually fit, and on the subsequent increase in growth rate of its offspring as a result of selection. The loss of genetic variation during the founding event is substantial, but highly variable. With continued migration at rate M, establishment is inevitable; when migration is rare, the expected time to establishment decreases inversely with M. However, above a threshold migration rate, the population may be trapped in a ‘sink’ state, in which adaptation is held back by gene flow; above this threshold, the expected time to establishment increases exponentially with M. This threshold behaviour is captured by a deterministic approximation, which assumes a Gaussian distribution of the trait in the founder population with mean and variance evolving deterministically. By assuming a constant genetic variance, we also develop a diffusion approximation for the joint distribution of population size and trait mean, which extends to include stabilising selection and density regulation. Divergence of the population from its ancestors causes partial reproductive isolation, which we measure through the reproductive value of migrants into the newly established population. AU - Barton, Nicholas H AU - Etheridge, Alison ID - 564 IS - 7 JF - Theoretical Population Biology TI - Establishment in a new habitat by polygenic adaptation VL - 122 ER - TY - JOUR AB - In continuous populations with local migration, nearby pairs of individuals have on average more similar genotypes than geographically well separated pairs. A barrier to gene flow distorts this classical pattern of isolation by distance. Genetic similarity is decreased for sample pairs on different sides of the barrier and increased for pairs on the same side near the barrier. Here, we introduce an inference scheme that utilizes this signal to detect and estimate the strength of a linear barrier to gene flow in two-dimensions. We use a diffusion approximation to model the effects of a barrier on the geographical spread of ancestry backwards in time. This approach allows us to calculate the chance of recent coalescence and probability of identity by descent. We introduce an inference scheme that fits these theoretical results to the geographical covariance structure of bialleleic genetic markers. It can estimate the strength of the barrier as well as several demographic parameters. We investigate the power of our inference scheme to detect barriers by applying it to a wide range of simulated data. We also showcase an example application to a Antirrhinum majus (snapdragon) flower color hybrid zone, where we do not detect any signal of a strong genome wide barrier to gene flow. AU - Ringbauer, Harald AU - Kolesnikov, Alexander AU - Field, David AU - Barton, Nicholas H ID - 563 IS - 3 JF - Genetics TI - Estimating barriers to gene flow from distorted isolation-by-distance patterns VL - 208 ER - TY - JOUR AB - Self-incompatibility (SI) is a genetically based recognition system that functions to prevent self-fertilization and mating among related plants. An enduring puzzle in SI is how the high diversity observed in nature arises and is maintained. Based on the underlying recognition mechanism, SI can be classified into two main groups: self- and non-self recognition. Most work has focused on diversification within self-recognition systems despite expected differences between the two groups in the evolutionary pathways and outcomes of diversification. Here, we use a deterministic population genetic model and stochastic simulations to investigate how novel S-haplotypes evolve in a gametophytic non-self recognition (SRNase/S Locus F-box (SLF)) SI system. For this model the pathways for diversification involve either the maintenance or breakdown of SI and can vary in the order of mutations of the female (SRNase) and male (SLF) components. We show analytically that diversification can occur with high inbreeding depression and self-pollination, but this varies with evolutionary pathway and level of completeness (which determines the number of potential mating partners in the population), and in general is more likely for lower haplotype number. The conditions for diversification are broader in stochastic simulations of finite population size. However, the number of haplotypes observed under high inbreeding and moderate to high self-pollination is less than that commonly observed in nature. Diversification was observed through pathways that maintain SI as well as through self-compatible intermediates. Yet the lifespan of diversified haplotypes was sensitive to their level of completeness. By examining diversification in a non-self recognition SI system, this model extends our understanding of the evolution and maintenance of haplotype diversity observed in a self recognition system common in flowering plants. AU - Bodova, Katarina AU - Priklopil, Tadeas AU - Field, David AU - Barton, Nicholas H AU - Pickup, Melinda ID - 316 IS - 3 JF - Genetics TI - Evolutionary pathways for the generation of new self-incompatibility haplotypes in a non-self recognition system VL - 209 ER - TY - GEN AB - File S1 contains figures that clarify the following features: (i) effect of population size on the average number/frequency of SI classes, (ii) changes in the minimal completeness deficit in time for a single class, and (iii) diversification diagrams for all studied pathways, including the summary figure for k = 8. File S2 contains the code required for a stochastic simulation of the SLF system with an example. This file also includes the output in the form of figures and tables. AU - Bod'ová, Katarína AU - Priklopil, Tadeas AU - Field, David AU - Barton, Nicholas H AU - Pickup, Melinda ID - 9813 TI - Supplemental material for Bodova et al., 2018 ER - TY - JOUR AB - Escaping local optima is one of the major obstacles to function optimisation. Using the metaphor of a fitness landscape, local optima correspond to hills separated by fitness valleys that have to be overcome. We define a class of fitness valleys of tunable difficulty by considering their length, representing the Hamming path between the two optima and their depth, the drop in fitness. For this function class we present a runtime comparison between stochastic search algorithms using different search strategies. The (1+1) EA is a simple and well-studied evolutionary algorithm that has to jump across the valley to a point of higher fitness because it does not accept worsening moves (elitism). In contrast, the Metropolis algorithm and the Strong Selection Weak Mutation (SSWM) algorithm, a famous process in population genetics, are both able to cross the fitness valley by accepting worsening moves. We show that the runtime of the (1+1) EA depends critically on the length of the valley while the runtimes of the non-elitist algorithms depend crucially on the depth of the valley. Moreover, we show that both SSWM and Metropolis can also efficiently optimise a rugged function consisting of consecutive valleys. AU - Oliveto, Pietro AU - Paixao, Tiago AU - Pérez Heredia, Jorge AU - Sudholt, Dirk AU - Trubenova, Barbora ID - 723 IS - 5 JF - Algorithmica TI - How to escape local optima in black box optimisation when non elitism outperforms elitism VL - 80 ER - TY - JOUR AB - Adaptive introgression is common in nature and can be driven by selection acting on multiple, linked genes. We explore the effects of polygenic selection on introgression under the infinitesimal model with linkage. This model assumes that the introgressing block has an effectively infinite number of genes, each with an infinitesimal effect on the trait under selection. The block is assumed to introgress under directional selection within a native population that is genetically homogeneous. We use individual-based simulations and a branching process approximation to compute various statistics of the introgressing block, and explore how these depend on parameters such as the map length and initial trait value associated with the introgressing block, the genetic variability along the block, and the strength of selection. Our results show that the introgression dynamics of a block under infinitesimal selection is qualitatively different from the dynamics of neutral introgression. We also find that in the long run, surviving descendant blocks are likely to have intermediate lengths, and clarify how the length is shaped by the interplay between linkage and infinitesimal selection. Our results suggest that it may be difficult to distinguish introgression of single loci from that of genomic blocks with multiple, tightly linked and weakly selected loci. AU - Sachdeva, Himani AU - Barton, Nicholas H ID - 282 IS - 4 JF - Genetics TI - Introgression of a block of genome under infinitesimal selection VL - 209 ER - TY - JOUR AB - We study how a block of genome with a large number of weakly selected loci introgresses under directional selection into a genetically homogeneous population. We derive exact expressions for the expected rate of growth of any fragment of the introduced block during the initial phase of introgression, and show that the growth rate of a single-locus variant is largely insensitive to its own additive effect, but depends instead on the combined effect of all loci within a characteristic linkage scale. The expected growth rate of a fragment is highly correlated with its long-term introgression probability in populations of moderate size, and can hence identify variants that are likely to introgress across replicate populations. We clarify how the introgression probability of an individual variant is determined by the interplay between hitchhiking with relatively large fragments during the early phase of introgression and selection on fine-scale variation within these, which at longer times results in differential introgression probabilities for beneficial and deleterious loci within successful fragments. By simulating individuals, we also investigate how introgression probabilities at individual loci depend on the variance of fitness effects, the net fitness of the introduced block, and the size of the recipient population, and how this shapes the net advance under selection. Our work suggests that even highly replicable substitutions may be associated with a range of selective effects, which makes it challenging to fine map the causal loci that underlie polygenic adaptation. AU - Sachdeva, Himani AU - Barton, Nicholas H ID - 39 IS - 4 JF - Genetics SN - 00166731 TI - Replicability of introgression under linked, polygenic selection VL - 210 ER - TY - JOUR AB - Genomes of closely-related species or populations often display localized regions of enhanced relative sequence divergence, termed genomic islands. It has been proposed that these islands arise through selective sweeps and/or barriers to gene flow. Here, we genetically dissect a genomic island that controls flower color pattern differences between two subspecies of Antirrhinum majus, A.m.striatum and A.m.pseudomajus, and relate it to clinal variation across a natural hybrid zone. We show that selective sweeps likely raised relative divergence at two tightly-linked MYB-like transcription factors, leading to distinct flower patterns in the two subspecies. The two patterns provide alternate floral guides and create a strong barrier to gene flow where populations come into contact. This barrier affects the selected flower color genes and tightlylinked loci, but does not extend outside of this domain, allowing gene flow to lower relative divergence for the rest of the chromosome. Thus, both selective sweeps and barriers to gene flow play a role in shaping genomic islands: sweeps cause elevation in relative divergence, while heterogeneous gene flow flattens the surrounding "sea," making the island of divergence stand out. By showing how selective sweeps establish alternative adaptive phenotypes that lead to barriers to gene flow, our study sheds light on possible mechanisms leading to reproductive isolation and speciation. AU - Tavares, Hugo AU - Whitley, Annabel AU - Field, David AU - Bradley, Desmond AU - Couchman, Matthew AU - Copsey, Lucy AU - Elleouet, Joane AU - Burrus, Monique AU - Andalo, Christophe AU - Li, Miaomiao AU - Li, Qun AU - Xue, Yongbiao AU - Rebocho, Alexandra B AU - Barton, Nicholas H AU - Coen, Enrico ID - 38 IS - 43 JF - PNAS SN - 00278424 TI - Selection and gene flow shape genomic islands that control floral guides VL - 115 ER - TY - JOUR AB - Hanemaaijer et al. (Molecular Ecology, 27, 2018) describe the genetic consequences of the introgression of an insecticide resistance allele into a mosquito population. Linked alleles initially increased, but many of these later declined. It is hard to determine whether this decline was due to counter‐selection, rather than simply to chance. AU - Barton, Nicholas H ID - 40 IS - 24 JF - Molecular Ecology SN - 1365294X TI - The consequences of an introgression event VL - 27 ER - TY - JOUR AB - We re-examine the model of Kirkpatrick and Barton for the spread of an inversion into a local population. This model assumes that local selection maintains alleles at two or more loci, despite immigration of alternative alleles at these loci from another population. We show that an inversion is favored because it prevents the breakdown of linkage disequilibrium generated by migration; the selective advantage of an inversion is proportional to the amount of recombination between the loci involved, as in other cases where inversions are selected for. We derive expressions for the rate of spread of an inversion; when the loci covered by the inversion are tightly linked, these conditions deviate substantially from those proposed previously, and imply that an inversion can then have only a small advantage. AU - Charlesworth, Brian AU - Barton, Nicholas H ID - 565 IS - 1 JF - Genetics TI - The spread of an inversion with migration and selection VL - 208 ER - TY - JOUR AB - In this issue of GENETICS, a new method for detecting natural selection on polygenic traits is developed and applied to sev- eral human examples ( Racimo et al. 2018 ). By de fi nition, many loci contribute to variation in polygenic traits, and a challenge for evolutionary ge neticists has been that these traits can evolve by small, nearly undetectable shifts in allele frequencies across each of many, typically unknown, loci. Recently, a helpful remedy has arisen. Genome-wide associ- ation studies (GWAS) have been illuminating sets of loci that can be interrogated jointly for c hanges in allele frequencies. By aggregating small signal s of change across many such loci, directional natural selection is now in principle detect- able using genetic data, even for highly polygenic traits. This is an exciting arena of progress – with these methods, tests can be made for selection associated with traits, and we can now study selection in what may be its most prevalent mode. The continuing fast pace of GWAS publications suggest there will be many more polygenic tests of selection in the near future, as every new GWAS is an opportunity for an accom- panying test of polygenic selection. However, it is important to be aware of complications th at arise in interpretation, especially given that these studies may easily be misinter- preted both in and outside the evolutionary genetics commu- nity. Here, we provide context for understanding polygenic tests and urge caution regarding how these results are inter- preted and reported upon more broadly. AU - Novembre, John AU - Barton, Nicholas H ID - 430 IS - 4 JF - Genetics TI - Tread lightly interpreting polygenic tests of selection VL - 208 ER - TY - JOUR AB - We study the Fokker-Planck equation derived in the large system limit of the Markovian process describing the dynamics of quantitative traits. The Fokker-Planck equation is posed on a bounded domain and its transport and diffusion coefficients vanish on the domain's boundary. We first argue that, despite this degeneracy, the standard no-flux boundary condition is valid. We derive the weak formulation of the problem and prove the existence and uniqueness of its solutions by constructing the corresponding contraction semigroup on a suitable function space. Then, we prove that for the parameter regime with high enough mutation rate the problem exhibits a positive spectral gap, which implies exponential convergence to equilibrium.Next, we provide a simple derivation of the so-called Dynamic Maximum Entropy (DynMaxEnt) method for approximation of observables (moments) of the Fokker-Planck solution, which can be interpreted as a nonlinear Galerkin approximation. The limited applicability of the DynMaxEnt method inspires us to introduce its modified version that is valid for the whole range of admissible parameters. Finally, we present several numerical experiments to demonstrate the performance of both the original and modified DynMaxEnt methods. We observe that in the parameter regimes where both methods are valid, the modified one exhibits slightly better approximation properties compared to the original one. AU - Bodova, Katarina AU - Haskovec, Jan AU - Markowich, Peter ID - 607 JF - Physica D: Nonlinear Phenomena TI - Well posedness and maximum entropy approximation for the dynamics of quantitative traits VL - 376-377 ER - TY - THES AB - This thesis is concerned with the inference of current population structure based on geo-referenced genetic data. The underlying idea is that population structure affects its spatial genetic structure. Therefore, genotype information can be utilized to estimate important demographic parameters such as migration rates. These indirect estimates of population structure have become very attractive, as genotype data is now widely available. However, there also has been much concern about these approaches. Importantly, genetic structure can be influenced by many complex patterns, which often cannot be disentangled. Moreover, many methods merely fit heuristic patterns of genetic structure, and do not build upon population genetics theory. Here, I describe two novel inference methods that address these shortcomings. In Chapter 2, I introduce an inference scheme based on a new type of signal, identity by descent (IBD) blocks. Recently, it has become feasible to detect such long blocks of genome shared between pairs of samples. These blocks are direct traces of recent coalescence events. As such, they contain ample signal for inferring recent demography. I examine sharing of IBD blocks in two-dimensional populations with local migration. Using a diffusion approximation, I derive formulas for an isolation by distance pattern of long IBD blocks and show that sharing of long IBD blocks approaches rapid exponential decay for growing sample distance. I describe an inference scheme based on these results. It can robustly estimate the dispersal rate and population density, which is demonstrated on simulated data. I also show an application to estimate mean migration and the rate of recent population growth within Eastern Europe. Chapter 3 is about a novel method to estimate barriers to gene flow in a two dimensional population. This inference scheme utilizes geographically localized allele frequency fluctuations - a classical isolation by distance signal. The strength of these local fluctuations increases on average next to a barrier, and there is less correlation across it. I again use a framework of diffusion of ancestral lineages to model this effect, and provide an efficient numerical implementation to fit the results to geo-referenced biallelic SNP data. This inference scheme is able to robustly estimate strong barriers to gene flow, as tests on simulated data confirm. AU - Ringbauer, Harald ID - 200 SN - 2663-337X TI - Inferring recent demography from spatial genetic structure ER - TY - JOUR AB - Genome-scale diversity data are increasingly available in a variety of biological systems, and can be used to reconstruct the past evolutionary history of species divergence. However, extracting the full demographic information from these data is not trivial, and requires inferential methods that account for the diversity of coalescent histories throughout the genome. Here, we evaluate the potential and limitations of one such approach. We reexamine a well-known system of mussel sister species, using the joint site frequency spectrum (jSFS) of synonymousmutations computed either fromexome capture or RNA-seq, in an Approximate Bayesian Computation (ABC) framework. We first assess the best sampling strategy (number of: individuals, loci, and bins in the jSFS), and show that model selection is robust to variation in the number of individuals and loci. In contrast, different binning choices when summarizing the jSFS, strongly affect the results: including classes of low and high frequency shared polymorphisms can more effectively reveal recent migration events. We then take advantage of the flexibility of ABC to compare more realistic models of speciation, including variation in migration rates through time (i.e., periodic connectivity) and across genes (i.e., genome-wide heterogeneity in migration rates). We show that these models were consistently selected as the most probable, suggesting that mussels have experienced a complex history of gene flow during divergence and that the species boundary is semi-permeable. Our work provides a comprehensive evaluation of ABC demographic inference in mussels based on the coding jSFS, and supplies guidelines for employing different sequencing techniques and sampling strategies. We emphasize, perhaps surprisingly, that inferences are less limited by the volume of data, than by the way in which they are analyzed. AU - Fraisse, Christelle AU - Roux, Camille AU - Gagnaire, Pierre AU - Romiguier, Jonathan AU - Faivre, Nicolas AU - Welch, John AU - Bierne, Nicolas ID - 139 IS - 7 JF - PeerJ TI - The divergence history of European blue mussel species reconstructed from Approximate Bayesian Computation: The effects of sequencing techniques and sampling strategies VL - 2018 ER - TY - JOUR AB - Secondary contact is the reestablishment of gene flow between sister populations that have diverged. For instance, at the end of the Quaternary glaciations in Europe, secondary contact occurred during the northward expansion of the populations which had found refugia in the southern peninsulas. With the advent of multi-locus markers, secondary contact can be investigated using various molecular signatures including gradients of allele frequency, admixture clines, and local increase of genetic differentiation. We use coalescent simulations to investigate if molecular data provide enough information to distinguish between secondary contact following range expansion and an alternative evolutionary scenario consisting of a barrier to gene flow in an isolation-by-distance model. We find that an excess of linkage disequilibrium and of genetic diversity at the suture zone is a unique signature of secondary contact. We also find that the directionality index ψ, which was proposed to study range expansion, is informative to distinguish between the two hypotheses. However, although evidence for secondary contact is usually conveyed by statistics related to admixture coefficients, we find that they can be confounded by isolation-by-distance. We recommend to account for the spatial repartition of individuals when investigating secondary contact in order to better reflect the complex spatio-temporal evolution of populations and species. AU - Bertl, Johanna AU - Ringbauer, Harald AU - Blum, Michaël ID - 33 IS - 10 JF - PeerJ TI - Can secondary contact following range expansion be distinguished from barriers to gene flow? VL - 2018 ER - TY - JOUR AB - Pedigree and sibship reconstruction are important methods in quantifying relationships and fitness of individuals in natural populations. Current methods employ a Markov chain-based algorithm to explore plausible possible pedigrees iteratively. This provides accurate results, but is time-consuming. Here, we develop a method to infer sibship and paternity relationships from half-sibling arrays of known maternity using hierarchical clustering. Given 50 or more unlinked SNP markers and empirically derived error rates, the method performs as well as the widely used package Colony, but is faster by two orders of magnitude. Using simulations, we show that the method performs well across contrasting mating scenarios, even when samples are large. We then apply the method to open-pollinated arrays of the snapdragon Antirrhinum majus and find evidence for a high degree of multiple mating. Although we focus on diploid SNP data, the method does not depend on marker type and as such has broad applications in nonmodel systems. AU - Ellis, Thomas AU - Field, David AU - Barton, Nicholas H ID - 286 IS - 5 JF - Molecular Ecology Resources TI - Efficient inference of paternity and sibship inference given known maternity via hierarchical clustering VL - 18 ER - TY - CONF AB - There has been renewed interest in modelling the behaviour of evolutionary algorithms by more traditional mathematical objects, such as ordinary differential equations or Markov chains. The advantage is that the analysis becomes greatly facilitated due to the existence of well established methods. However, this typically comes at the cost of disregarding information about the process. Here, we introduce the use of stochastic differential equations (SDEs) for the study of EAs. SDEs can produce simple analytical results for the dynamics of stochastic processes, unlike Markov chains which can produce rigorous but unwieldy expressions about the dynamics. On the other hand, unlike ordinary differential equations (ODEs), they do not discard information about the stochasticity of the process. We show that these are especially suitable for the analysis of fixed budget scenarios and present analogs of the additive and multiplicative drift theorems for SDEs. We exemplify the use of these methods for two model algorithms ((1+1) EA and RLS) on two canonical problems(OneMax and LeadingOnes). AU - Paixao, Tiago AU - Pérez Heredia, Jorge ID - 1112 SN - 978-145034651-1 T2 - Proceedings of the 14th ACM/SIGEVO Conference on Foundations of Genetic Algorithms TI - An application of stochastic differential equations to evolutionary algorithms ER - TY - JOUR AB - Variation in genotypes may be responsible for differences in dispersal rates, directional biases, and growth rates of individuals. These traits may favor certain genotypes and enhance their spatiotemporal spreading into areas occupied by the less advantageous genotypes. We study how these factors influence the speed of spreading in the case of two competing genotypes under the assumption that spatial variation of the total population is small compared to the spatial variation of the frequencies of the genotypes in the population. In that case, the dynamics of the frequency of one of the genotypes is approximately described by a generalized Fisher–Kolmogorov–Petrovskii–Piskunov (F–KPP) equation. This generalized F–KPP equation with (nonlinear) frequency-dependent diffusion and advection terms admits traveling wave solutions that characterize the invasion of the dominant genotype. Our existence results generalize the classical theory for traveling waves for the F–KPP with constant coefficients. Moreover, in the particular case of the quadratic (monostable) nonlinear growth–decay rate in the generalized F–KPP we study in detail the influence of the variance in diffusion and mean displacement rates of the two genotypes on the minimal wave propagation speed. AU - Kollár, Richard AU - Novak, Sebastian ID - 1191 IS - 3 JF - Bulletin of Mathematical Biology TI - Existence of traveling waves for the generalized F–KPP equation VL - 79 ER - TY - JOUR AB - 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. AU - Lagator, Mato AU - Sarikas, Srdjan AU - Acar, Hande AU - Bollback, Jonathan P AU - Guet, Calin C ID - 570 JF - eLife SN - 2050084X TI - Regulatory network structure determines patterns of intermolecular epistasis VL - 6 ER - TY - JOUR AB - 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. AU - Bradley, Desmond AU - Xu, Ping AU - Mohorianu, Irina AU - Whibley, Annabel AU - Field, David AU - Tavares, Hugo AU - Couchman, Matthew AU - Copsey, Lucy AU - Carpenter, Rosemary AU - Li, Miaomiao AU - Li, Qun AU - Xue, Yongbiao AU - Dalmay, Tamas AU - Coen, Enrico ID - 611 IS - 6365 JF - Science SN - 00368075 TI - Evolution of flower color pattern through selection on regulatory small RNAs VL - 358 ER - TY - JOUR AB - 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. AU - Barton, Nicholas H AU - Etheridge, Alison AU - Véber, Amandine ID - 626 JF - Theoretical Population Biology SN - 00405809 TI - The infinitesimal model: Definition derivation and implications VL - 118 ER - TY - GEN AB - 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. AU - Lukacisinova, Marta AU - Novak, Sebastian AU - Paixao, Tiago ID - 9849 TI - Modelling and simulation details ER - TY - GEN AB - In this text, we discuss how a cost of resistance and the possibility of lethal mutations impact our model. AU - Lukacisinova, Marta AU - Novak, Sebastian AU - Paixao, Tiago ID - 9850 TI - Extensions of the model ER - TY - GEN AB - 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. AU - Lukacisinova, Marta AU - Novak, Sebastian AU - Paixao, Tiago ID - 9851 TI - Heuristic prediction for multiple stresses ER - TY - GEN AB - We show how different combination strategies affect the fraction of individuals that are multi-resistant. AU - Lukacisinova, Marta AU - Novak, Sebastian AU - Paixao, Tiago ID - 9852 TI - Resistance frequencies for different combination strategies ER - TY - THES AB - 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. AU - Payne, Pavel ID - 6291 SN - 2663-337X TI - Bacterial herd and social immunity to phages ER - TY - GEN AB - Mathematica notebooks used to generate figures. AU - Etheridge, Alison AU - Barton, Nicholas H ID - 9842 TI - Data for: Establishment in a new habitat by polygenic adaptation ER - TY - JOUR AB - 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 logic. 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. AU - Giacobbe, Mirco AU - Guet, Calin C AU - Gupta, Ashutosh AU - Henzinger, Thomas A AU - Paixao, Tiago AU - Petrov, Tatjana ID - 1351 IS - 8 JF - Acta Informatica SN - 00015903 TI - Model checking the evolution of gene regulatory networks VL - 54 ER - TY - JOUR AB - 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. AU - Paixao, Tiago AU - Pérez Heredia, Jorge AU - Sudholt, Dirk AU - Trubenova, Barbora ID - 1336 IS - 2 JF - Algorithmica SN - 01784617 TI - Towards a runtime comparison of natural and artificial evolution VL - 78 ER - TY - JOUR AB - Much of quantitative genetics is based on the ‘infinitesimal model’, under which selection has a negligible effect on the genetic variance. This is typically justified by assuming a very large number of loci with additive effects. However, it applies even when genes interact, provided that the number of loci is large enough that selection on each of them is weak relative to random drift. In the long term, directional selection will change allele frequencies, but even then, the effects of epistasis on the ultimate change in trait mean due to selection may be modest. Stabilising selection can maintain many traits close to their optima, even when the underlying alleles are weakly selected. However, the number of traits that can be optimised is apparently limited to ~4Ne by the ‘drift load’, and this is hard to reconcile with the apparent complexity of many organisms. Just as for the mutation load, this limit can be evaded by a particular form of negative epistasis. A more robust limit is set by the variance in reproductive success. This suggests that selection accumulates information most efficiently in the infinitesimal regime, when selection on individual alleles is weak, and comparable with random drift. A review of evidence on selection strength suggests that although most variance in fitness may be because of alleles with large Nes, substantial amounts of adaptation may be because of alleles in the infinitesimal regime, in which epistasis has modest effects. AU - Barton, Nicholas H ID - 1199 JF - Heredity TI - How does epistasis influence the response to selection? VL - 118 ER - TY - JOUR AB - Dispersal is a crucial factor in natural evolution, since it determines the habitat experienced by any population and defines the spatial scale of interactions between individuals. There is compelling evidence for systematic differences in dispersal characteristics within the same population, i.e., genotype-dependent dispersal. The consequences of genotype-dependent dispersal on other evolutionary phenomena, however, are poorly understood. In this article we investigate the effect of genotype-dependent dispersal on spatial gene frequency patterns, using a generalization of the classical diffusion model of selection and dispersal. Dispersal is characterized by the variance of dispersal (diffusion coefficient) and the mean displacement (directional advection term). We demonstrate that genotype-dependent dispersal may change the qualitative behavior of Fisher waves, which change from being “pulled” to being “pushed” wave fronts as the discrepancy in dispersal between genotypes increases. The speed of any wave is partitioned into components due to selection, genotype-dependent variance of dispersal, and genotype-dependent mean displacement. We apply our findings to wave fronts maintained by selection against heterozygotes. Furthermore, we identify a benefit of increased variance of dispersal, quantify its effect on the speed of the wave, and discuss the implications for the evolution of dispersal strategies. AU - Novak, Sebastian AU - Kollár, Richard ID - 1169 IS - 1 JF - Genetics SN - 00166731 TI - Spatial gene frequency waves under genotype dependent dispersal VL - 205 ER - TY - JOUR AB - Adaptation depends critically on the effects of new mutations and their dependency on the genetic background in which they occur. These two factors can be summarized by the fitness landscape. However, it would require testing all mutations in all backgrounds, making the definition and analysis of fitness landscapes mostly inaccessible. Instead of postulating a particular fitness landscape, we address this problem by considering general classes of landscapes and calculating an upper limit for the time it takes for a population to reach a fitness peak, circumventing the need to have full knowledge about the fitness landscape. We analyze populations in the weak-mutation regime and characterize the conditions that enable them to quickly reach the fitness peak as a function of the number of sites under selection. We show that for additive landscapes there is a critical selection strength enabling populations to reach high-fitness genotypes, regardless of the distribution of effects. This threshold scales with the number of sites under selection, effectively setting a limit to adaptation, and results from the inevitable increase in deleterious mutational pressure as the population adapts in a space of discrete genotypes. Furthermore, we show that for the class of all unimodal landscapes this condition is sufficient but not necessary for rapid adaptation, as in some highly epistatic landscapes the critical strength does not depend on the number of sites under selection; effectively removing this barrier to adaptation. AU - Heredia, Jorge AU - Trubenova, Barbora AU - Sudholt, Dirk AU - Paixao, Tiago ID - 1111 IS - 2 JF - Genetics SN - 00166731 TI - Selection limits to adaptive walks on correlated landscapes VL - 205 ER - TY - JOUR AB - Viral capsids are structurally constrained by interactions among the amino acids (AAs) of their constituent proteins. Therefore, epistasis is expected to evolve among physically interacting sites and to influence the rates of substitution. To study the evolution of epistasis, we focused on the major structural protein of the fX174 phage family by first reconstructing the ancestral protein sequences of 18 species using a Bayesian statistical framework. The inferred ancestral reconstruction differed at eight AAs, for a total of 256 possible ancestral haplotypes. For each ancestral haplotype and the extant species, we estimated, in silico, the distribution of free energies and epistasis of the capsid structure. We found that free energy has not significantly increased but epistasis has. We decomposed epistasis up to fifth order and found that higher-order epistasis sometimes compensates pairwise interactions making the free energy seem additive. The dN/dS ratio is low, suggesting strong purifying selection, and that structure is under stabilizing selection. We synthesized phages carrying ancestral haplotypes of the coat protein gene and measured their fitness experimentally. Our findings indicate that stabilizing mutations can have higher fitness, and that fitness optima do not necessarily coincide with energy minima. AU - Fernandes Redondo, Rodrigo A AU - Vladar, Harold AU - Włodarski, Tomasz AU - Bollback, Jonathan P ID - 1077 IS - 126 JF - Journal of the Royal Society Interface SN - 17425689 TI - Evolutionary interplay between structure, energy and epistasis in the coat protein of the ϕX174 phage family VL - 14 ER - TY - JOUR AB - 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. AU - Ringbauer, Harald AU - Coop, Graham AU - Barton, Nicholas H ID - 1074 IS - 3 JF - Genetics SN - 00166731 TI - Inferring recent demography from isolation by distance of long shared sequence blocks VL - 205 ER - TY - JOUR AB - Severe environmental change can drive a population extinct unless the population adapts in time to the new conditions (“evolutionary rescue”). How does biparental sexual reproduction influence the chances of population persistence compared to clonal reproduction or selfing? In this article, we set up a one‐locus two‐allele model for adaptation in diploid species, where rescue is contingent on the establishment of the mutant homozygote. Reproduction can occur by random mating, selfing, or clonally. Random mating generates and destroys the rescue mutant; selfing is efficient at generating it but at the same time depletes the heterozygote, which can lead to a low mutant frequency in the standing genetic variation. Due to these (and other) antagonistic effects, we find a nontrivial dependence of population survival on the rate of sex/selfing, which is strongly influenced by the dominance coefficient of the mutation before and after the environmental change. Importantly, since mating with the wild‐type breaks the mutant homozygote up, a slow decay of the wild‐type population size can impede rescue in randomly mating populations. AU - Uecker, Hildegard ID - 1063 IS - 4 JF - Evolution SN - 00143820 TI - Evolutionary rescue in randomly mating, selfing, and clonal populations VL - 71 ER - TY - JOUR AB - 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. AU - Sachdeva, Himani AU - Barton, Nicholas H ID - 990 IS - 6 JF - Evolution; International Journal of Organic Evolution SN - 00143820 TI - Divergence and evolution of assortative mating in a polygenic trait model of speciation with gene flow VL - 71 ER - TY - JOUR AB - 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. AU - Lagator, Mato AU - Paixao, Tiago AU - Barton, Nicholas H AU - Bollback, Jonathan P AU - Guet, Calin C ID - 954 JF - eLife SN - 2050084X TI - On the mechanistic nature of epistasis in a canonical cis-regulatory element VL - 6 ER - TY - JOUR AB - 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. AU - Friedlander, Tamar AU - Prizak, Roshan AU - Barton, Nicholas H AU - Tkacik, Gasper ID - 955 IS - 1 JF - Nature Communications SN - 20411723 TI - Evolution of new regulatory functions on biophysically realistic fitness landscapes VL - 8 ER - TY - JOUR AB - The role of natural selection in the evolution of adaptive phenotypes has undergone constant probing by evolutionary biologists, employing both theoretical and empirical approaches. As Darwin noted, natural selection can act together with other processes, including random changes in the frequencies of phenotypic differences that are not under strong selection, and changes in the environment, which may reflect evolutionary changes in the organisms themselves. As understanding of genetics developed after 1900, the new genetic discoveries were incorporated into evolutionary biology. The resulting general principles were summarized by Julian Huxley in his 1942 book Evolution: the modern synthesis. Here, we examine how recent advances in genetics, developmental biology and molecular biology, including epigenetics, relate to today's understanding of the evolution of adaptations. We illustrate how careful genetic studies have repeatedly shown that apparently puzzling results in a wide diversity of organisms involve processes that are consistent with neo-Darwinism. They do not support important roles in adaptation for processes such as directed mutation or the inheritance of acquired characters, and therefore no radical revision of our understanding of the mechanism of adaptive evolution is needed. AU - Charlesworth, Deborah AU - Barton, Nicholas H AU - Charlesworth, Brian ID - 953 IS - 1855 JF - Proceedings of the Royal Society of London Series B Biological Sciences TI - The sources of adaptive evolution VL - 284 ER - TY - JOUR AB - A novel strategy for controlling the spread of arboviral diseases such as dengue, Zika and chikungunya is to transform mosquito populations with virus-suppressing Wolbachia. In general, Wolbachia transinfected into mosquitoes induce fitness costs through lower viability or fecundity. These maternally inherited bacteria also produce a frequency-dependent advantage for infected females by inducing cytoplasmic incompatibility (CI), which kills the embryos produced by uninfected females mated to infected males. These competing effects, a frequency-dependent advantage and frequency-independent costs, produce bistable Wolbachia frequency dynamics. Above a threshold frequency, denoted pˆ, CI drives fitness-decreasing Wolbachia transinfections through local populations; but below pˆ, infection frequencies tend to decline to zero. If pˆ is not too high, CI also drives spatial spread once infections become established over sufficiently large areas. We illustrate how simple models provide testable predictions concerning the spatial and temporal dynamics of Wolbachia introductions, focusing on rate of spatial spread, the shape of spreading waves, and the conditions for initiating spread from local introductions. First, we consider the robustness of diffusion-based predictions to incorporating two important features of wMel-Aedes aegypti biology that may be inconsistent with the diffusion approximations, namely fast local dynamics induced by complete CI (i.e., all embryos produced from incompatible crosses die) and long-tailed, non-Gaussian dispersal. With complete CI, our numerical analyses show that long-tailed dispersal changes wave-width predictions only slightly; but it can significantly reduce wave speed relative to the diffusion prediction; it also allows smaller local introductions to initiate spatial spread. Second, we use approximations for pˆ and dispersal distances to predict the outcome of 2013 releases of wMel-infected Aedes aegypti in Cairns, Australia, Third, we describe new data from Ae. aegypti populations near Cairns, Australia that demonstrate long-distance dispersal and provide an approximate lower bound on pˆ for wMel in northeastern Australia. Finally, we apply our analyses to produce operational guidelines for efficient transformation of vector populations over large areas. We demonstrate that even very slow spatial spread, on the order of 10-20 m/month (as predicted), can produce area-wide population transformation within a few years following initial releases covering about 20-30% of the target area. AU - Turelli, Michael AU - Barton, Nicholas H ID - 952 JF - Theoretical Population Biology SN - 00405809 TI - Deploying dengue-suppressing Wolbachia: Robust models predict slow but effective spatial spread in Aedes aegypti VL - 115 ER -