ABSTRACT
Division of labor can evolve when social groups benefit from the functional specialization of its members. Recently, a novel means of coordinating the division of labor was found in the antibiotic-producing bacterium Streptomyces coelicolor, where specialized cells are generated through large-scale genomic re-organization. We investigate how the evolution of a genome architecture enables such mutation-driven division of labor, using a multiscale computational model of bacterial evolution. In this model, bacterial behavior-antibiotic production or replication-is determined by the structure and composition of their genome, which encodes antibiotics, growth-promoting genes, and fragile genomic loci that can induce chromosomal deletions. We find that a genomic organization evolves, which partitions growth-promoting genes and antibiotic-coding genes into distinct parts of the genome, separated by fragile genomic loci. Mutations caused by these fragile sites mostly delete growth-promoting genes, generating sterile, and antibiotic-producing mutants from weakly-producing progenitors, in agreement with experimental observations. This division of labor enhances the competition between colonies by promoting antibiotic diversity. These results show that genomic organization can co-evolve with genomic instabilities to enable reproductive division of labor.
Subject(s)
Genome , Genomics , Mutation , Anti-Bacterial AgentsABSTRACT
Here, we report an update of the VDJdb database with a substantial increase in the number of T-cell receptor (TCR) sequences and their cognate antigens. The update further provides a new database infrastructure featuring two additional analysis modes that facilitate database querying and real-world data analysis. The increased yield of TCR specificity identification methods and the overall increase in the number of studies in the field has allowed us to expand the database more than 5-fold. Furthermore, several new analysis methods are included. For example, batch annotation of TCR repertoire sequencing samples allows for annotating large datasets on-line. Using recently developed bioinformatic methods for TCR motif mining, we have built a reduced set of high-quality TCR motifs that can be used for both training TCR specificity predictors and matching against TCRs of interest. These additions enhance the versatility of the VDJdb in the task of exploring T-cell antigen specificities. The database is available at https://vdjdb.cdr3.net.
Subject(s)
Computational Biology/methods , Databases, Genetic , Nucleotide Motifs , Receptors, Antigen, T-Cell/genetics , V(D)J Recombination , Amino Acid Sequence , High-Throughput Nucleotide Sequencing , Humans , Position-Specific Scoring Matrices , Receptors, Antigen, T-Cell/chemistry , Sequence Analysis, DNA , Software , Web BrowserABSTRACT
Upon recognition of peptide-MHC complexes by T cell receptors (TCR), the cognate T cells expand and differentiate into effector T cells to generate protective immunity. Despite the fact that any immune response generates a diverse set of TCR clones against a particular epitope, only a few clones are highly expanded in any immune response. Previous studies observed that the highest frequency clones usually control viral infections better than subdominant clones, but the reasons for this dominance among T cell clones are still unclear. Here, we used publicly available TCR amino acid sequences to study which factors determine whether a response becomes immunodominance (ID) per donor; we classified the largest T cell clone as the epitope-specific dominant clone and all the other clones as subdominant responses (SD). We observed a distinctively hydrophobic CDR3 in ID responses against a dominant epitope from influenza A virus, compared to the SD responses. The common V-J combinations were shared between ID and SD responses, suggesting that the biased V-J recombination events are restricted by epitope specificity; thus, the immunodominance is not directly determined by a bias combination of V and J genetic segments. Our findings reveal a close similarity of global sequence properties between dominant and subdominant clones of epitope-specific responses but detectable distinctive amino acid enrichments in ID. Taken together, we believe this first comparative study of immunodominant and subdominant TCR sequences can guide further studies to resolve factors determining the immunodominance of antiviral as well as tumor-specific T cell responses.
Subject(s)
Complementarity Determining Regions/genetics , Immunodominant Epitopes/genetics , Receptors, Antigen, T-Cell/genetics , Amino Acid Sequence , CD8-Positive T-Lymphocytes/immunology , Complementarity Determining Regions/metabolism , Databases, Factual , Epitopes/genetics , Epitopes/immunology , Epitopes, T-Lymphocyte/immunology , Humans , Immunity, Cellular , Immunodominant Epitopes/immunology , Lymphocyte Activation , Molecular Sequence Data , Receptors, Antigen, T-Cell/immunology , V(D)J Recombination/geneticsABSTRACT
Somitogenesis is one of the major hallmarks of bilateral symmetry in vertebrates. This symmetry is lost when retinoic acid (RA) signalling is inhibited, allowing the left-right determination pathway to influence somitogenesis. In all three studied vertebrate model species, zebrafish, chicken and mouse, the frequency of somite formation becomes asymmetric, with slower gene expression oscillations driving somitogenesis on the right side. Still, intriguingly, the resulting left-right asymmetric phenotypes differ significantly between these model species. While somitogenesis is generally considered as functionally equivalent among different vertebrates, substantial differences exist in the subset of oscillating genes between different vertebrate species. Variation also appears to exist in the way oscillations cease and somite boundaries become patterned. In addition, in absence of RA, the FGF8 gradient thought to constitute the determination wavefront becomes asymmetric in zebrafish and mouse, extending more anteriorly to the right, while remaining symmetric in chicken. Here we use a computational modelling approach to decipher the causes underlying species differences in asymmetric somitogenesis. Specifically, we investigate to what extent differences can be explained from observed differences in FGF asymmetry and whether differences in somite determination dynamics may also be involved. We demonstrate that a simple clock-and-wavefront model incorporating the observed left-right differences in somitogenesis frequency readily reproduces asymmetric somitogenesis in chicken. However, incorporating asymmetry in FGF signalling was insufficient to robustly reproduce mouse or zebrafish asymmetry phenotypes. In order to explain these phenoptypes we needed to extend the basic model, incorporating species-specific details of the somitogenesis determination mechanism. Our results thus demonstrate that a combination of differences in FGF dynamics and somite determination cause species differences in asymmetric somitogenesis. In addition,they highlight the power of using computational models as well as studying left-right asymmetry to obtain more insight in somitogenesis.
Subject(s)
Algorithms , Body Patterning , Models, Biological , Somites/embryology , Animals , Chickens , Embryonic Development/drug effects , Embryonic Development/genetics , Fibroblast Growth Factor 8/metabolism , Gene Expression Regulation, Developmental , Mesoderm/drug effects , Mesoderm/embryology , Mesoderm/metabolism , Mice , Somites/metabolism , Species Specificity , Tretinoin/pharmacology , Vertebrates/classification , Vertebrates/embryology , Vertebrates/genetics , ZebrafishABSTRACT
Convergent extension, the simultaneous extension and narrowing of tissues, is a crucial event in the formation of the main body axis during embryonic development. It involves processes on multiple scales: the sub-cellular, cellular and tissue level, which interact via explicit or intrinsic feedback mechanisms. Computational modelling studies play an important role in unravelling the multiscale feedbacks underlying convergent extension. Convergent extension usually operates in tissue which has been patterned or is currently being patterned into distinct domains of gene expression. How such tissue patterns are maintained during the large scale tissue movements of convergent extension has thus far not been investigated. Intriguingly, experimental data indicate that in certain cases these tissue patterns may drive convergent extension rather than requiring safeguarding against convergent extension. Here we use a 2D Cellular Potts Model (CPM) of a tissue prepatterned into segments, to show that convergent extension tends to disrupt this pre-existing segmental pattern. However, when cells preferentially adhere to cells of the same segment type, segment integrity is maintained without any reduction in tissue extension. Strikingly, we demonstrate that this segment-specific adhesion is by itself sufficient to drive convergent extension. Convergent extension is enhanced when we endow our in silico cells with persistence of motion, which in vivo would naturally follow from cytoskeletal dynamics. Finally, we extend our model to confirm the generality of our results. We demonstrate a similar effect of differential adhesion on convergent extension in tissues that can only extend in a single direction (as often occurs due to the inertia of the head region of the embryo), and in tissues prepatterned into a sequence of domains resulting in two opposing adhesive gradients, rather than alternating segments.
Subject(s)
Body Patterning/physiology , Cell Adhesion/physiology , Computer Simulation , Models, Biological , Animals , Computational BiologyABSTRACT
In many immunological processes chemoattraction is thought to play a role in guiding cells to their sites of action. However, based on in vivo two-photon microscopy experiments in the absence of cognate antigen, T cell migration in lymph nodes (LNs) has been roughly described as a random walk. Although it has been shown that dendritic cells (DCs) carrying cognate antigen in some circumstances attract T cells chemotactically, it is currently still unclear whether chemoattraction of T cells towards DCs helps or hampers scanning. Chemoattraction towards DCs could on the one hand help T cells to rapidly find DCs. On the other hand, it could be deleterious if DCs become shielded by a multitude of attracted yet non-specific T cells. Results from a recent simulation study suggested that the deleterious effect dominates. We re-addressed the question whether T cell chemoattraction towards DCs is expected to promote or hamper the detection of rare antigens using the Cellular Potts Model, a formalism that allows for dynamic, flexible cellular shapes and cell migration. Our simulations show that chemoattraction of T cells enhances the DC scanning efficiency, leading to an increased probability that rare antigen-specific T cells find DCs carrying cognate antigen. Desensitization of T cells after contact with a DC further improves the scanning efficiency, yielding an almost threefold enhancement compared to random migration. Moreover, the chemotaxis-driven migration still roughly appears as a random walk, hence fine-tuned analysis of cell tracks will be required to detect chemotaxis within microscopy data.
Subject(s)
Antigens/immunology , Cell Movement/immunology , Chemotaxis/immunology , Dendritic Cells/immunology , Models, Immunological , T-Lymphocytes/immunology , Computer Simulation , Cytokines/immunologyABSTRACT
BACKGROUND: The unicellular ancestors of modern-day multicellular organisms were remarkably complex. They had an extensive set of regulatory and signalling genes, an intricate life cycle and could change their behaviour in response to environmental changes. At the transition to multicellularity, some of these behaviours were co-opted to organise the development of the nascent multicellular organism. Here, we focus on the transition to multicellularity before the evolution of stable cell differentiation, to reveal how the emergence of clusters affects the evolution of cell behaviour. RESULTS: We construct a computational model of a population of cells that can evolve the regulation of their behavioural state - either division or migration - and study both a unicellular and a multicellular context. Cells compete for reproduction and for resources to survive in a seasonally changing environment. We find that the evolution of multicellularity strongly determines the co-evolution of cell behaviour, by altering the competition dynamics between cells. When adhesion cannot evolve, cells compete for survival by rapidly migrating towards resources before dividing. When adhesion evolves, emergent collective migration alleviates the pressure on individual cells to reach resources. This allows individual cells to maximise their own replication. Migrating adhesive clusters display striking patterns of spatio-temporal cell state changes that visually resemble animal development. CONCLUSIONS: Our model demonstrates how emergent selection pressures at the onset of multicellularity can drive the evolution of cellular behaviour to give rise to developmental patterns.
Subject(s)
Biological Evolution , Reproduction , Animals , Cell DifferentiationABSTRACT
Evolution has traditionally been a historical and descriptive science, and predicting future evolutionary processes has long been considered impossible. However, evolutionary predictions are increasingly being developed and used in medicine, agriculture, biotechnology and conservation biology. Evolutionary predictions may be used for different purposes, such as to prepare for the future, to try and change the course of evolution or to determine how well we understand evolutionary processes. Similarly, the exact aspect of the evolved population that we want to predict may also differ. For example, we could try to predict which genotype will dominate, the fitness of the population or the extinction probability of a population. In addition, there are many uses of evolutionary predictions that may not always be recognized as such. The main goal of this review is to increase awareness of methods and data in different research fields by showing the breadth of situations in which evolutionary predictions are made. We describe how diverse evolutionary predictions share a common structure described by the predictive scope, time scale and precision. Then, by using examples ranging from SARS-CoV2 and influenza to CRISPR-based gene drives and sustainable product formation in biotechnology, we discuss the methods for predicting evolution, the factors that affect predictability and how predictions can be used to prevent evolution in undesirable directions or to promote beneficial evolution (i.e. evolutionary control). We hope that this review will stimulate collaboration between fields by establishing a common language for evolutionary predictions.
ABSTRACT
Evolution has been an inventive process since its inception, about 4 billion years ago. It has generated an astounding diversity of novel mechanisms and structures for adaptation to the environment, for competition and cooperation, and for organisation of the internal and external dynamics of the organism. How does this novelty come about? Evolution builds with the tools available, and on top of what it has already built - therefore, much novelty consists in repurposing old functions in a different context. In the process, the tools themselves evolve, allowing yet more novelty to arise. Despite evolutionary novelty being the most striking observable of evolution, it is not accounted for in classical evolutionary theory. Nevertheless, mathematical and computational models that illustrate mechanisms of evolutionary innovation have been developed. In the present review, we present and compare several examples of computational evo-devo models that capture two aspects of novelty: 'between-level novelty' and 'constructive novelty.' Novelty can evolve between predefined levels of organisation to dynamically transcode biological information across these levels - as occurs during development. Constructive novelty instead generates a level of biological organisation by exploiting the lower level as an informational scaffold to open a new space of possibilities - an example being the evolution of multicellularity. We propose that the field of computational evo-devo is well-poised to reveal many more exciting mechanisms for the evolution of novelty. A broader theory of evolutionary novelty may well be attainable in the near future.
ABSTRACT
Evolutionary developmental biology (or evo devo) is a broad field that aims to understand how developmental processes evolve and how this underpins phenotypic change and organismal diversification. This encompasses a need to understand theoretical concepts in evolutionary biology and how tissues, cells, genes, proteins and regulatory elements function and evolve. The articles in this special issue review key topics in the field of evo devo including advances in theory and methodology as well as our latest knowledge about molecular, cellular and organismal functionality and diversification.
Subject(s)
Developmental BiologyABSTRACT
The phytohormone auxin is implied in steering various developmental decisions during plant morphogenesis in a concentration-dependent manner. Auxin maxima have been shown to maintain meristematic activity, for example, of the root apical meristem, and position new sites of outgrowth, such as during lateral root initiation and phyllotaxis. More recently, it has been demonstrated that sites of auxin minima also provide positional information. In the developing Arabidopsis fruit, auxin minima are required for correct differentiation of the valve margin. It remains unclear, however, how this auxin minimum is generated and maintained. Here, we employ a systems biology approach to model auxin transport based on experimental observations. This allows us to determine the minimal requirements for its establishment. Our simulations reveal that two alternative processes-which we coin "flux-barrier" and "flux-passage"-are both able to generate an auxin minimum, but under different parameter settings. Both models are in principle able to yield similar auxin profiles but present qualitatively distinct patterns of auxin flux. The models were tested by tissue-specific inducible ablation, revealing that the auxin minimum in the fruit is most likely generated by a flux-passage process. Model predictions were further supported through 3D PIN localization imaging and implementing experimentally observed transporter localization. Through such an experimental-modeling cycle, we predict how the auxin minimum gradually matures during fruit development to ensure timely fruit opening and seed dispersal.
Subject(s)
Fruit/metabolism , Indoleacetic Acids/metabolism , Systems Biology/methods , Arabidopsis/metabolism , Arabidopsis/physiology , Arabidopsis Proteins/genetics , Arabidopsis Proteins/metabolism , Gene Expression Regulation, Plant/genetics , Gene Expression Regulation, Plant/physiology , Models, TheoreticalABSTRACT
BACKGROUND: Segmentation, the subdivision of the major body axis into repeated elements, is considered one of the major evolutionary innovations in bilaterian animals. In all three segmented animal clades, the predominant segmentation mechanism is sequential segmentation, where segments are generated one by one in anterior-posterior order from a posterior undifferentiated zone. In vertebrates and arthropods, sequential segmentation is thought to arise from a clock-and-wavefront-type mechanism, where oscillations in the posterior growth zone are transformed into a segmental prepattern in the anterior by a receding wavefront. Previous evo-devo simulation studies have demonstrated that this segmentation type repeatedly arises, supporting the idea of parallel evolutionary origins in these animal clades. Sequential segmentation has been studied most extensively in vertebrates, where travelling waves have been observed that reflect the slowing down of oscillations prior to their cessation and where these oscillations involve a highly complex regulatory network. It is currently unclear under which conditions this oscillator complexity and slowing should be expected to evolve, how they are related and to what extent similar properties should be expected for sequential segmentation in other animal species. RESULTS: To investigate these questions, we extend a previously developed computational model for the evolution of segmentation. We vary the slope of the posterior morphogen gradient and the strength of gene expression noise. We find that compared to a shallow gradient, a steep morphogen gradient allows for faster evolution and evolved oscillator networks are simpler. Furthermore, under steep gradients, damped oscillators often evolve, whereas shallow gradients appear to require persistent oscillators which are regularly accompanied by travelling waves, indicative of a frequency gradient. We show that gene expression noise increases the likelihood of evolving persistent oscillators under steep gradients and of evolving frequency gradients under shallow gradients. Surprisingly, we find that the evolutions of oscillator complexity and travelling waves are not correlated, suggesting that these properties may have evolved separately. CONCLUSIONS: Based on our findings, we suggest that travelling waves may have evolved in response to shallow morphogen gradients and gene expression noise. These two factors may thus also be responsible for the observed differences between different species within both the arthropod and chordate phyla.
ABSTRACT
BACKGROUND: The evolution of animal segmentation is a major research focus within the field of evolutionary-developmental biology. Most studied segmented animals generate their segments in a repetitive, anterior-to-posterior fashion coordinated with the extension of the body axis from a posterior growth zone. In the current study we ask which selection pressures and ordering of evolutionary events may have contributed to the evolution of this specific segmentation mode. RESULTS: To answer this question we extend a previous in silico simulation model of the evolution of segmentation by allowing the tissue growth pattern to freely evolve. We then determine the likelihood of evolving oscillatory sequential segmentation combined with posterior growth under various conditions, such as the presence or absence of a posterior morphogen gradient or selection for determinate growth. We find that posterior growth with sequential segmentation is the predominant outcome of our simulations only if a posterior morphogen gradient is assumed to have already evolved and selection for determinate growth occurs secondarily. Otherwise, an alternative segmentation mechanism dominates, in which divisions occur in large bursts through the entire tissue and all segments are created simultaneously. CONCLUSIONS: Our study suggests that the ancestry of a posterior signalling centre has played an important role in the evolution of sequential segmentation. In addition, it suggests that determinate growth evolved secondarily, after the evolution of posterior growth. More generally, we demonstrate the potential of evo-devo simulation models that allow us to vary conditions as well as the onset of selection pressures to infer a likely order of evolutionary innovations.