Specialization Can Drive the Evolution of Modularity

Organismal development and many cell biological processes are organized in a modular fashion, where regulatory molecules form groups with many interactions within a group and few interactions between groups. Thus, the activity of elements within a module depends little on elements outside of it. Modularity facilitates the production of heritable variation and of evolutionary innovations. There is no consensus on how modularity might evolve, especially for modules in development. We show that modularity can increase in gene regulatory networks as a byproduct of specialization in gene activity. Such specialization occurs after gene regulatory networks are selected to produce new gene activity patterns that appear in a specific body structure or under a specific environmental condition. Modules that arise after specialization in gene activity comprise genes that show concerted changes in gene activities. This and other observations suggest that modularity evolves because it decreases interference between different groups of genes. Our work can explain the appearance and maintenance of modularity through a mechanism that is not contingent on environmental change. We also show how modularity can facilitate co-option, the utilization of existing gene activity to build new gene activity patterns, a frequent feature of evolutionary innovations.     

Stable Heterogeneity for the Production of Diffusible Factors in Cell Populations

The production of diffusible molecules that promote survival and growth is common in bacterial and eukaryotic cell populations, and can be considered a form of cooperation between cells. While evolutionary game theory shows that producers and non-producers can coexist in well-mixed populations, there is no consensus on the possibility of a stable polymorphism in spatially structured populations where the effect of the diffusible molecule extends beyond one-step neighbours. I study the dynamics of biological public goods using an evolutionary game on a lattice, taking into account two assumptions that have not been considered simultaneously in existing models: that the benefit of the diffusible molecule is a non-linear function of its concentration, and that the molecule diffuses according to a decreasing gradient. Stable coexistence of producers and non-producers is observed when the benefit of the molecule is a sigmoid function of its concentration, while strictly diminishing returns lead to coexistence only for very specific parameters and linear benefits never lead to coexistence. The shape of the diffusion gradient is largely irrelevant and can be approximated by a step function. Since the effect of a biological molecule is generally a sigmoid function of its concentration (as described by the Hill equation), linear benefits or strictly diminishing returns are not an appropriate approximations for the study of biological public goods. A stable polymorphism of producers and non-producers is in line with the predictions of evolutionary game theory and likely to be common in cell populations.     

Influence of adenine nucleotides on oligomycin inhibition of energy-transducing reactions in intact rat-liver mitochondria.

The inhibitory effect of oligomycin was investigated in intact mitochondria through oxidative phosphorylation and uncoupler induced ATPase activity. Results show that oligomycin inhibition curves can be either sigmoidal or hyperbolic depending on experimental conditions and chiefly on the metabolic state of mitochondria with regard to the distribution of mitochondrial endogenous adenine-nucleotides. Active respiration and uncoupler-induced ATPse activity produce sigmoidal titration curves for a high initial ATP : ADP ratio and hyperbolic curves for a low ATP : ADP ratio. Time-dependent inhibitions are observed for the two reactions. The maximal inhibitory action for low concentrations of the inhibitor is delayed by the initial presence of ATP or the possibility of generating from inorganic phosphate before adding oligomycin. Results presented here show that the initial adenine-nucleotide distribution is important for oligomycin sensitivity of energy-linked reactions. Although a limited conformational change of the oligomycin-sensitivity to the inhibitor, it is more likely that a gross structural change of the inner membrane induced by adenine-nucleotides modifies membrane permeability to oligomycin.     

Multilevel selection analysis of a microbial social trait

The study of microbial communities often leads to arguments for the evolution of cooperation due to group benefits. However, multilevel selection models caution against the uncritical assumption that group benefits will lead to the evolution of cooperation. We analyze a microbial social trait to precisely define the conditions favoring cooperation. We combine the multilevel partition of the Price equation with a laboratory model system: swarming in Pseudomonas aeruginosa. We parameterize a population dynamics model using competition experiments where we manipulate expression, and therefore the cost‐to‐benefit ratio of swarming cooperation. Our analysis shows that multilevel selection can favor costly swarming cooperation because it causes population expansion. However, due to high costs and diminishing returns constitutive cooperation can only be favored by natural selection when relatedness is high. Regulated expression of cooperative genes is a more robust strategy because it provides the benefits of swarming expansion without the high cost or the diminishing returns. Our analysis supports the key prediction that strong group selection does not necessarily mean that microbial cooperation will always emerge.     

A reliable and safe T cell repertoire based on low-affinity T cell receptors

Antigens are presented to T cells as short peptides bound to MHC molecules on the surface of body cells. The binding between MHC/peptides and T cell receptors (TCRs) has a low affinity and is highly degenerate. Nevertheless, TCR-MHC/peptide recognition results in T cell activation of high specificity. Moreover, the immune system is able to mount a cellular response when only a small fraction of the MHC molecules on an antigen-presenting cell is occupied by foreign peptides, while autoimmunity remains relatively rare. We consider how to reconcile these seemingly contradictory facts using a quantitative model of TCR signalling and T cell activation. Taking into account the statistics of TCR recognition and antigen presentation, we show that thymic selection can produce a working T cell repertoire which will produce safe and effective responses, that is, recognizes foreign antigen presented at physiological levels while tolerating self. We introduce "activation curves" as a useful tool to study the repertoire's statistical activation properties.     

The influence of trade-off shape on evolutionary behaviour in classical ecological scenarios

Trade-off shapes are crucial to evolutionary outcomes. However, due to different ecological feedbacks their implications may depend not only on the trade-off being considered but also the ecological scenario. Here, we apply a novel geometric technique, trade-off and invasion plots (TIPs), to examine in detail how the shape of trade-off relationships affect evolutionary outcomes under a range of classic ecological scenarios including Lotka-Volterra type and host-parasite interactions. We choose models of increasing complexity in order to gain an insight into the features of ecological systems that determine the evolutionary outcomes. In particular we focus on when evolutionary attractors, repellors and branching points occur and how this depends on whether the costs are accelerating (benefits become ‘increasingly’ costly), decelerating (benefits become ‘decreasingly’ costly) or constant. In all cases strongly accelerating costs lead to attractors while strongly decelerating ones lead to repellors, but with weaker relationships, this no longer holds. For some systems weakly accelerating costs may lead to repellors and decelerating costs may lead to attractors. In many scenarios it is weakly decelerating costs that lead to branching points, but weakly accelerating and linear costs may also lead to disruptive selection in particular ecological scenarios. Using our models we suggest a classification of ecological interactions, based on three distinct criteria, that can produce one of four fundamental TIPs which allow for different evolutionary behaviour. This provides a baseline theory which may inform the prediction of evolutionary outcomes in similar yet unexplored ecological scenarios. In addition we discuss the implications of our results to a number of specific life-history trade-offs in the classic ecological scenarios represented by our models.     

Developmental causes of allometry: new models and implications for phenotypic plasticity and evolution

Shapes change during development because tissues, organs, and various anatomical features differ in onset, rate, and duration of growth. Allometry is the study of the consequences of differences in the growth of body parts on morphology, although the field of allometry has been surprisingly little concerned with understanding the causes of differential growth. The power-law equation y?=?ax(b), commonly used to describe allometries, is fundamentally an empirical equation whose biological foundation has been little studied. Huxley showed that the power-law equation can be derived if one assumes that body parts grow with exponential kinetics, for exactly the same amount of time. In life, however, the growth of body parts is almost always sigmoidal, and few, if any, grow for exactly the same amount of time during ontogeny. Here, we explore the shapes of allometries that result from real growth patterns and analyze them with new allometric equations derived from sigmoidal growth kinetics. We use an extensive ontogenetic dataset of the growth of internal organs in the rat from birth to adulthood, and show that they grow with Gompertz sigmoid kinetics. Gompertz growth parameters of body and internal organs accurately predict the shapes of their allometries, and that nonlinear regression on allometric data can accurately estimate the underlying kinetics of growth. We also use these data to discuss the developmental relationship between static and ontogenetic allometries. We show that small changes in growth kinetics can produce large and apparently qualitatively different allometries. Large evolutionary changes in allometry can be produced by small and simple changes in growth kinetics, and we show how understanding the development of traits can greatly simplify the interpretation of how they evolved.     

Microbial community development in the traps of aquatic Utricularia species

We examined trap fluid of three aquatic carnivorous species of Utricularia (Lentibulariaceae) to assess the role of microbial community within their traps in plant nutrient acquisition. In the context of increasing trap age, we characterized microbial community composition using phospholipid fatty acid (PLFA) analysis and microscopy. Nutrient content in various fractions of the trap fluid was analyzed and the abundance of free-suspended bacteria estimated. The activities of extracellular phosphatase in the trap fluid were determined using fluorometry and the contribution of the microbial community to phosphatase production assessed by epifluorescence microscopy. The trap microbial community seems to be largely derived from Utricularia associated periphyton. PLFA analysis revealed that trap fluid contained all components of a complex microbial food web with bacteria forming more than 58% of the viable microbial biomass in the trap. Trap age seems to be the key factor in determining the patterns of microbial community development as well as enzyme production. The amount of nutrients increases with increasing trap age, and the total amounts of C, N, and P accumulated within traps during their lifetime are relatively large—of the order of 100 mg L⁻¹ for C and N, and between 0.2 and 0.6 mg L⁻¹ for P. A significant part of the nutrient pool is present in the dissolved form. Trap fluid stoichiometry (molar N:P ratios about 100) as well as the presence of nutrient limited microbial cells (molar N:P ratios 25–61) indicates the importance of phosphorus rather than nitrogen for the nutrition of Utricularia. Our findings support the hypothesis that mutualism, apart from the predator–prey interaction, is an important association in aquatic Utricularia traps and that the trap-associated microbial community may be of benefit to the rootless aquatic Utricularia species facing problems with P acquisition due to the loss of roots in their evolution.     

Diminishing returns in social evolution: the not-so-tragic commons

A challenge for evolutionary theory is to understand how cooperation can occur in the presence of competition and cheating, a problem known as the tragedy of commons. Here I examine how varying the fitness returns from reproductive competition or cooperation affects the negative impact of competition on a social group. Varying linear returns does not affect the impact of competition. However, diminishing returns, where additional investments in either competition or cooperation give smaller and smaller rewards, reduce the effects of competition on the group. I show that diminishing returns are common in many systems, including social vertebrates, microbes, social insects and mutualisms among species. This suggests that the tragedy of the commons is not so tragic and that the disruptive effects of competition upon social life will often be minor.     

Resource supply and the evolution of public-goods cooperation in bacteria

Background  

Explaining public-goods cooperation is a challenge for evolutionary biology. However, cooperation is expected to more readily evolve if it imposes a smaller cost. Such costs of cooperation are expected to decline with increasing resource supply, an ecological parameter that varies widely in nature. We experimentally tested the effect of resource supply on the evolution of cooperation using two well-studied bacterial public-good traits: biofilm formation by Pseudomonas fluorescens and siderophore production by Pseudomonas aeruginosa.     

Selfishness driving reductive evolution shapes interdependent patterns in spatially structured microbial communities

Microbes release a wide variety of metabolites to the environment that benefit the whole population, called public goods. Public goods sharing drives adaptive function loss, and allows the rise of metabolic cross-feeding. However, how public goods sharing governs the succession of communities over evolutionary time scales remains unclear. To resolve this issue, we constructed an individual-based model, where an autonomous population that possessed functions to produce three essential public goods, was allowed to randomly lose functions. Simulations revealed that function loss genotypes could evolve from the autonomous ancestor, driven by the selfish public production trade-off at the individual level. These genotypes could then automatically develop to three possible types of interdependent patterns: complete functional division, one-way dependency, and asymmetric functional complementation, which were influenced by function cost and function redundancy. In addition, we found random evolutionary events, i.e., the priority and the relative spatial positioning of genotype emergence, are also important in governing community assembly. Moreover, communities occupied by interdependent patterns exhibited better resistance to environmental perturbation, suggesting such patterns are selectively favored. Our work integrates ecological interactions with evolution dynamics, providing a new perspective to explain how reductive evolution shapes microbial interdependencies and governs the succession of communities.Subject terms: Microbial ecology, Microbial ecology     

Molecular Adaptation Mechanisms Employed by Ethanologenic Bacteria in Response to Lignocellulose-derived Inhibitory Compounds

Current international interest in finding alternative sources of energy to the diminishing supplies of fossil fuels has encouraged research efforts in improving biofuel production technologies. In countries which lack sufficient food, the use of sustainable lignocellulosic feedstocks, for the production of bioethanol, is an attractive option. In the pre-treatment of lignocellulosic feedstocks for ethanol production, various chemicals and/or enzymatic processes are employed. These methods generally result in a range of fermentable sugars, which are subjected to microbial fermentation and distillation to produce bioethanol. However, these methods also produce compounds that are inhibitory to the microbial fermentation process. These compounds include products of sugar dehydration and lignin depolymerisation, such as organic acids, derivatised furaldehydes and phenolic acids. These compounds are known to have a severe negative impact on the ethanologenic microorganisms involved in the fermentation process by compromising the integrity of their cell membranes, inhibiting essential enzymes and negatively interact with their DNA/RNA. It is therefore important to understand the molecular mechanisms of these inhibitions, and the mechanisms by which these microorganisms show increased adaptation to such inhibitors. Presented here is a concise overview of the molecular adaptation mechanisms of ethanologenic bacteria in response to lignocellulose-derived inhibitory compounds. These include general stress response and tolerance mechanisms, which are typically those that maintain intracellular pH homeostasis and cell membrane integrity, activation/regulation of global stress responses and inhibitor substrate-specific degradation pathways. We anticipate that understanding these adaptation responses will be essential in the design of ''intelligent'' metabolic engineering strategies for the generation of hyper-tolerant fermentation bacteria strains.     

Ecological selection of siderophore‐producing microbial taxa in response to heavy metal contamination

Some microbial public goods can provide both individual and community‐wide benefits, and are open to exploitation by non‐producing species. One such example is the production of metal‐detoxifying siderophores. Here, we investigate whether conflicting selection pressures on siderophore production by heavy metals – a detoxifying effect of siderophores, and exploitation of this detoxifying effect – result in a net increase or decrease. We show that the proportion of siderophore‐producing taxa increases along a natural heavy metal gradient. A causal link between metal contamination and siderophore production was subsequently demonstrated in a microcosm experiment in compost, in which we observed changes in community composition towards taxa that produce relatively more siderophores following copper contamination. We confirmed the selective benefit of siderophores by showing that taxa producing large amounts of siderophore suffered less growth inhibition in toxic copper. Our results suggest that ecological selection will favour siderophore‐mediated decontamination, with important consequences for potential remediation strategies.     

Population genomics in natural microbial communities

Little is known about the evolutionary processes that structure and maintain microbial diversity because, until recently, it was difficult to explore individual-level patterns of variation at the microbial scale. Now, community-genomic sequence data enable such variation to be assessed across large segments of microbial genomes. Here, we discuss how population-genomic analysis of these data can be used to determine how selection and genetic exchange shape the evolution of new microbial lineages. We show that once independent lineages have been identified, such analyses enable the identification of genome changes that drive niche differentiation and promote the coexistence of closely related lineages within the same environment. We suggest that understanding the evolutionary ecology of natural microbial populations through population-genomic analyses will enhance our understanding of genome evolution across all domains of life.     

EXPLAINING THE SOCIOBIOLOGY OF PYOVERDIN PRODUCING PSEUDOMONAS: A COMMENT ON ZHANG AND RAINEY (2013)

Over the past decade, there has been enormous interest in understanding the great diversity of microbial cooperative behaviors, including communication, group‐based swarming, fruiting‐body formation, and the secretion of group‐beneficial enzymes and food‐scavenging molecules. Zhang and Rainey, henceforth Z&R, recently contended that sociomicrobiologists have been overzealous in their casting of microbes as inherently social organisms, and too hasty in interpreting microbial behaviors in a social evolutionary framework. This challenge accompanied a set of experiments in which they revisited one of the best‐studied social behaviors in bacteria—the production of diffusible, sharable iron‐scavenging siderophore molecules. Z&R posit that their findings challenge the view that siderophore production is a cooperative trait. Here, we demonstrate that their arguments are flawed, and stem from both technical mistakes and misunderstandings of social evolution theory.     

New physical interpretation of S-shaped curves: competition between various types of binding of ligands with DNA

In studies of interactions of ligands with nucleic acid molecules, S-shaped curves are often obtained. In this work we show that the sigmoidal shape of the curves is due to a competition of ligand molecules for DNA binding sites. If a ligand that binds to DNA can form two types of complexes with the binding constants K1 and K2 and binding site sizes L1 and L2, respectively, then in the event that K1 < K2 and L1 < L2, the dependence of the concentration of complexes of the first type on the concentration of the ligand added to solution can be S-shaped.     

Receptor-agonist interactions in service-theoretic perspective, effects of molecular timing on the shape of dose-response curves

Service-theoretic concepts and methods, widely used in other fields (e.g., telecommunication and operations research), are useful also in a biochemical setting because the treatment of biocatalysts (enzymes, receptors) as servers and their ligands as customers, based on the established formal methods of service or queuing theory, may lead to insights and results unobtainable by conventional, mass-action-law-based theories. In this article, we apply the service-theoretic approach to receptor-agonist systems and show how by changing the stochastic time pattern of "operationally relevant" point events (e.g., instants of agonist arrival, instants of post-climax agonist departure) a great variety of dose-response curves may be generated, even in very simple reaction schemes, which, according to mass action kinetics, invariably lead to hyperbolic r(A) curves (r and A stand for response and agonist concentration, respectively). The molecular timing inherent to a hyperbolic response system is not optimal: for instance, at the agonist concentration A(50), half of the agonist molecules are rejected ("lost") because of unfortunate timing of the arrival events. The fraction of lost arrivers can be diminished considerably if the arrivals are better timed: "sub-Poisson" arrivals improve the timing and, thus, convert hyperbolic r(A) curves into "lifted" nonhyperbolic ones. Conversely, "super-Poisson" arrivals make the non-optimal timing in hyperbolic response systems even worse and, thus, convert hyperbolic r(A) curves into "depressed" nonhyperbolic ones. Furthermore, under special timing conditions, nonhyperbolic r(A) curves can be generated, which are partly lifted, partly depressed relative to the reference hyperbola, and which resemble in shape well-known nonhyperbolic forms of enzyme and receptor kinetics (negatively cooperative, positively cooperative, and sigmoidal kinetics). In addition unusual (undulatory and sawtooth-like) r(A) curves can be generated solely by changing the temporal pattern of arrival and service completion instants. Virtually any shape of dose-response curves may be obtained by allowing for probability distributions whose characteristic shape varies with their mean; we call such distributions "variomorphic" and apply them to the arrival process of agonist molecules.     

Computational design and analysis of modular cells for large libraries of exchangeable product synthesis modules

Microbial metabolism can be harnessed to produce a large library of useful chemicals from renewable resources such as plant biomass. However, it is laborious and expensive to create microbial biocatalysts to produce each new product. To tackle this challenge, we have recently developed modular cell (ModCell) design principles that enable rapid generation of production strains by assembling a modular (chassis) cell with exchangeable production modules to achieve overproduction of target molecules. Previous computational ModCell design methods are limited to analyze small libraries of around 20 products. In this study, we developed a new computational method, named ModCell-HPC, that can design modular cells for large libraries with hundreds of products with a highly-parallel and multi-objective evolutionary algorithm and enable us to elucidate modular design properties. We demonstrated ModCell-HPC to design Escherichia coli modular cells towards a library of 161 endogenous production modules. From these simulations, we identified E. coli modular cells with few genetic manipulations that can produce dozens of molecules in a growth-coupled manner with different types of fermentable sugars. These designs revealed key genetic manipulations at the chassis and module levels to accomplish versatile modular cells, involving not only in the removal of major by-products but also modification of branch points in the central metabolism. We further found that the effect of various sugar degradation on redox metabolism results in lower compatibility between a modular cell and production modules for growth on pentoses than hexoses. To better characterize the degree of compatibility, we developed a method to calculate the minimal set cover, identifying that only three modular cells are all needed to couple with all compatible production modules. By determining the unknown compatibility contribution metric, we further elucidated the design features that allow an existing modular cell to be re-purposed towards production of new molecules. Overall, ModCell-HPC is a useful tool for understanding modularity of biological systems and guiding more efficient and generalizable design of modular cells that help reduce research and development cost in biocatalysis.     

Cysteine and iron accelerate the formation of ribose-5-phosphate,providing insights into the evolutionary origins of the metabolic network structure

The structure of the metabolic network is highly conserved, but we know little about its evolutionary origins. Key for explaining the early evolution of metabolism is solving a chicken–egg dilemma, which describes that enzymes are made from the very same molecules they produce. The recent discovery of several nonenzymatic reaction sequences that topologically resemble central metabolism has provided experimental support for a “metabolism first” theory, in which at least part of the extant metabolic network emerged on the basis of nonenzymatic reactions. But how could evolution kick-start on the basis of a metal catalyzed reaction sequence, and how could the structure of nonenzymatic reaction sequences be imprinted on the metabolic network to remain conserved for billions of years? We performed an in vitro screening where we add the simplest components of metabolic enzymes, proteinogenic amino acids, to a nonenzymatic, iron-driven reaction network that resembles glycolysis and the pentose phosphate pathway (PPP). We observe that the presence of the amino acids enhanced several of the nonenzymatic reactions. Particular attention was triggered by a reaction that resembles a rate-limiting step in the oxidative PPP. A prebiotically available, proteinogenic amino acid cysteine accelerated the formation of RNA nucleoside precursor ribose-5-phosphate from 6-phosphogluconate. We report that iron and cysteine interact and have additive effects on the reaction rate so that ribose-5-phosphate forms at high specificity under mild, metabolism typical temperature and environmental conditions. We speculate that accelerating effects of amino acids on rate-limiting nonenzymatic reactions could have facilitated a stepwise enzymatization of nonenzymatic reaction sequences, imprinting their structure on the evolving metabolic network.

The evolutionary origins of metabolism are largely unknown. This study shows that the prebiotically available proteinogenic amino acid cysteine can promote the metabolism-like rate-limiting formation of ribose-5-phosphate, suggesting that early metabolic pathways could have emerged thought the stepwise enzymatization of non-enzymatic reaction sequences.     

Can telomere shortening explain sigmoidal growth curves?

A general branching process model is proposed to describe the shortening of telomeres in eukaryotic chromosomes. The model is flexible and incorporates many special cases to be found in the literature. In particular, we show how telomere shortening can give rise to sigmoidal growth curves, an idea first expressed by Portugal et al. [A computational model for telomere-dependent cell-replicative aging, BioSystems 91 (2008), pp. 262-267]. We also demonstrate how other types of growth curves arise if telomere shortening is mitigated by other cellular processes. We compare our results with published data sets from the biological literature.