Red queen dynamics, competition and critical points in a model of RNA virus quasispecies.

RNA viruses offer a unique opportunity for the study of evolution at the molecular level. Recent experiments involving clonal populations of RNA viruses have shown that competition among virus strains of approximately equal relative fitness can result in the eventual competitive exclusion of one of the species. As competition proceeds in time, both the winners and the losers exhibited absolute gains in fitness, consistent with the "Red Queen" hypothesis of evolution. Further experiments involving closely related evolving quasispecies revealed a highly predictable nonlinear behavior suggesting a deterministic component in the underlying quasispecies dynamics. This is apparently in contradiction with the standard view of RNA virus evolution as a highly unpredictable process. In this paper we present a simple model which allows previous hypothesis to be tested and provides an interpretation for the observed experimental results.     

Hidden suppression of sex ratio distortion suggests Red queen dynamics between Wolbachia and its dwarf spider host

Genetic conflict theory predicts strong selection for host nuclear factors suppressing endosymbiont effects on reproduction; however, evidence of these suppressors is currently scarce. This can either be caused by a low suppressor evolution rate, or if suppressors originate frequently, by rapid spread and concurrent masking of their activity by silencing the endosymbiont effect. To explore this, we use two populations of a dwarf spider with a similar female bias, caused by a Wolbachia infection. Using inter‐ and intrapopulation crosses, we determine that one of these populations demonstrates a higher suppressing capability towards Wolbachia despite having a similar population sex ratio. This suggests that spider and endosymbiont are locked in so‐called red queen dynamics where, despite continuous coevolution, average fitness remains the same, hence hiding the presence of the suppressor. Finding different suppressor activity in populations that even lack phenotypic differentiation (i.e. similar sex ratio) further supports the hypothesis that suppressors originate often, but are often hidden by their own mode of action by countering endosymbiont effects.     

Molecular dynamics reveal a novel kinase-substrate interface that regulates protein translation

A key control point in gene expression is the initiation of protein translation, with a universal stress response being constituted by in- hibitory phosphoryiation of the eukaryotic initiation factor 2α （el F2oL）. In humans, four kinases sense diverse physiological stresses to regulate elF2α to control cell differentiation, adaptation, and survival. Here we develop a computational molecular model of elF2α and one of its kinases, the protein kinase R, to simulate the dynamics of their interaction. Predictions generated by coarse-grained dynamics simulations suggest a novel mode of action. Experimentation substantiates these predictions, identifying a previously unrecognized interface in the protein complex, which is constituted by dynamic residues in both elF2α and its kinases that are crucial to regulate protein translation. These findings call for a reinterpretation of the current mechanism of action of the el F2α kinases and demonstrate the value of conducting computational analysis to evaluate protein function.     

Red queen for a day: models of symmetry and selection in paleoecology

The Unified Theory of Biodiversity (UNTB), the Red Queen’s Hypothesis (RQH), and the Cascading Extinctions on Graphs hypothesis (CEG) are explored as members of a spectrum describing the ecological partitioning of species richness. All are models of historical biodiversity, but fare differently in explaining observed features of Phanerozoic biodiversity. The models treat species as symmetric, asymmetric, or partially symmetric respectively. Symmetry in the UNTB is broken by the generation and selection of variation of ecological performance, while the robustness and hence longevity of RQ communities are subject to selection. The CEG model reconciles some of the differences, demonstrating the importance of functional partitioning to both species evolution and selection at the community level. It is concluded that the UNTB explains communities partially on the shortest of evolutionary time scales, while RQ communities would be, at best, geologically ephemeral yet conditionally important.     

Three mechanisms of Red Queen dynamics

Models describing systems of coevolving populations often have asymptotically non-equilibrium dynamics (Red Queen dynamics (RQD)). We claim that if evolution is much slower than ecological changes, RQD arises due to either fast ecological processes, slow genetical processes, or to their interaction. The three corresponding generic types of RQD can be studied using singular perturbation theory and have very different properties and biological implications. We present simple examples of ecological, genetical, and ecogenetical RQD and describe how they may be recognized in natural populations. In particular, ecogenetical RQD often involve alternations of long epochs with radically different dynamics.     

Translating translation: Regulated protein translation as a biomedical intervention

Altering the cellular response to internal and external stressors is essential for survival, hence the process of translation is exquisitely regulated to rapidly change the proteomic profile upon physiological challenges. We recently reported that genetic and pharmacological manipulation of translation may be beneficial in the treatment of Parkinson disease (PD). Using two Drosophila models of PD, we showed that altering the regulation of protein translation is sufficient to ameliorate the phenotypes of these models, including neurodegeneration, mitochondrial defects and behavioral deficits. Previous studies implicating translation regulation in lifespan extension further implicates this as an important mechanism that can mediate cell protective pathways, not just for age-related diseases such as PD, but also of aging itself. As such, translation regulation represents a convergent target for therapeutic interventions. Here we highlight the therapeutic potential of translation regulation in disease and describe how determining profiles of protein synthesis may help in the fight for disease prevention and healthy aging.     

Anarchistic queen honey bees have normal queen mandibular pheromones

Summary. Anarchistic honey bees are a line developed by recurrent selection in which workers frequently lay eggs. In unselected colonies, workers refrain from reproduction in response to pheromonal signals that indicate the presence of brood and a queen. We show that queen type (anarchistic or wild type) has no effect on rates of ovary activation of anarchistic or wild type workers. In addition, we show that an important component of the queens signalling system, the queen mandibular gland pheromone, is similar in wild type and anarchistic queens. Anarchistic larvae do not inhibit worker ovary development to the same degree as wild type larvae, however all colonies in this experiment contained only wild type larvae. Anarchistic workers had greater rates of ovary activation than wild type workers in colonies headed by either queen type. We therefore conclude that there must be differences in the transmission or reception of queen pheromones, or worker sensitivity to these compounds. These results clearly demonstrate that anarchy is a complex syndrome, not simply the result of reduced pheromone production by anarchist queens and larvae.Received 23 December 2003; revised 14 May 2004; accepted 1 June 2004.     

Combinatorial analysis of translation dynamics reveals eIF2 dependence of translation initiation at near-cognate codons

Although ribosome-profiling and translation initiation sequencing (TI-seq) analyses have identified many noncanonical initiation codons, the precise detection of translation initiation sites (TISs) remains a challenge, mainly because of experimental artifacts of such analyses. Here, we describe a new method, TISCA (TIS detection by translation Complex Analysis), for the accurate identification of TISs. TISCA proved to be more reliable for TIS detection compared with existing tools, and it identified a substantial number of near-cognate codons in Kozak-like sequence contexts. Analysis of proteomics data revealed the presence of methionine at the NH₂-terminus of most proteins derived from near-cognate initiation codons. Although eukaryotic initiation factor 2 (eIF2), eIF2A and eIF2D have previously been shown to contribute to translation initiation at near-cognate codons, we found that most noncanonical initiation events are most probably dependent on eIF2, consistent with the initial amino acid being methionine. Comprehensive identification of TISs by TISCA should facilitate characterization of the mechanism of noncanonical initiation.     

The dynamics of supply and demand in mRNA translation

We study the elongation stage of mRNA translation in eukaryotes and find that, in contrast to the assumptions of previous models, both the supply and the demand for tRNA resources are important for determining elongation rates. We find that increasing the initiation rate of translation can lead to the depletion of some species of aa-tRNA, which in turn can lead to slow codons and queueing. Particularly striking "competition" effects are observed in simulations of multiple species of mRNA which are reliant on the same pool of tRNA resources. These simulations are based on a recent model of elongation which we use to study the translation of mRNA sequences from the Saccharomyces cerevisiae genome. This model includes the dynamics of the use and recharging of amino acid tRNA complexes, and we show via Monte Carlo simulation that this has a dramatic effect on the protein production behaviour of the system.     

Structural dynamics of bacterial translation initiation factor IF2

Bacterial translation initiation factor IF2 promotes ribosomal subunit association, recruitment, and binding of fMet-tRNA to the ribosomal P-site and initiation dipeptide formation. Here, we present the solution structures of GDP-bound and apo-IF2-G2 of Bacillus stearothermophilus and provide evidence that this isolated domain binds the 50 S ribosomal subunit and hydrolyzes GTP. Differences between the free and GDP-bound structures of IF2-G2 suggest that domain reorganization within the G2-G3-C1 regions underlies the different structural requirements of IF2 during the initiation process. However, these structural signals are unlikely forwarded from IF2-G2 to the C-terminal fMet-tRNA binding domain (IF2-C2) because the connected IF2-C1 and IF2-C2 modules show completely independent mobility, indicating that the bacterial interdomain connector lacks the rigidity that was found in the archaeal IF2 homolog aIF5B.     

Cell-free translation systems for protein engineering

Cell-free translation systems have developed significantly over the last two decades and improvements in yield have resulted in their use for protein production in the laboratory. These systems have protein engineering applications, such as the production of proteins containing unnatural amino acids and development of proteins exhibiting novel functions. Recently, it has been suggested that cell-free translation systems might be used as the fundamental basis for cell-like systems. We review recent progress in the field of cell-free translation systems and describe their use as tools for protein production and engineering.     

RNA-binding protein HuD controls insulin translation

Although expression of the mammalian RNA-binding protein HuD was considered to be restricted to neurons, we report that HuD is present in pancreatic β cells, where its levels are controlled by the insulin receptor pathway. We found that HuD associated with a 22-nucleotide segment of the 5' untranslated region (UTR) of preproinsulin (Ins2) mRNA. Modulating HuD abundance did not alter Ins2 mRNA levels, but HuD overexpression decreased Ins2 mRNA translation and insulin production, and conversely, HuD silencing enhanced Ins2 mRNA translation and insulin production. Following treatment with glucose, HuD rapidly dissociated from Ins2 mRNA and enabled insulin biosynthesis. Importantly, HuD-knockout mice displayed higher insulin levels in pancreatic islets, while HuD-overexpressing mice exhibited lower insulin levels in islets and in plasma. In sum, our results identify HuD as a pivotal regulator of insulin translation in pancreatic β cells.     

In-cell protein dynamics

The native intracellular environment of proteins is crowded with metabolites and macromolecules. However, most biophysical information concerning proteins is acquired in dilute solution. To determine whether there are differences in dynamics, nuclear magnetic resonance spectroscopy can be used to measure 15N relaxation in uniformly 15N-enriched apocytochrome b5 inside living Escherichia coli and in dilute solution. Such data can then be used to compare the fast backbone dynamics of the partially folded protein in cells to its dynamics in dilute solution by using Lipari-Szabo analysis. It appears that the intracellular environment does not alter the protein's structure, or significantly change its fast dynamics. Specifically, the cytosol does not change the amplitude of fast backbone motions, but does increase the average timescale of these motions, most likely due to the increase in viscosity of the cytosol.