C. Brandon Ogbunugafor

Robustness promotes evolvability of thermotolerance in an RNA virus

BackgroundThe ability for an evolving population to adapt to a novel environment is achieved through a balance of robustness and evolvability. Robustness is the invariance of phenotype in the face of perturbation and evolvability is the capacity to adapt in response to selection. Genetic robustness has been posited, depending on the underlying mechanism, to either decrease the efficacy of selection, or increase the possibility of future adaptation. However, the true effect of genetic robustness on evolvability in biological systems remains uncertain.ResultsHere we demonstrate that genetic robustness increases evolvability of thermotolerance in laboratory populations of the RNA virus φ6. We observed that populations founded by robust clones evolved greater resistance to heat shock, relative to populations founded by brittle (less-robust) clones. Thus, we provide empirical evidence for the idea that robustness can promote evolvability in this environment, and further suggest that evolvability can arise indirectly via selection for robustness, rather than through direct selective action.ConclusionOur data imply that greater tolerance of mutational change is associated with virus adaptability in a new niche, a finding generally relevant to evolutionary biology, and informative for elucidating how viruses might evolve to emerge in new habitats and/or overcome novel therapies.

Regulation of oviposition in Anopheles gambiae s.s.: role of inter- and intra-specific signals.

Females of Anopheles gambiae Giles normally oviposit in a large number of fresh, small, sunlit, and spatially spread temporary pools. Such pools are associated with lower levels of predation compared to large, longer-lasting habitats. We compared oviposition levels on preferred (water collected from natural anopheline larval habitats) and non-preferred (distilled water) aqueous substrates by gravid females that contained different densities of conspecific eggs or early and late instar larvae. The presence of conspecific larvae, but not eggs, had a positive or negative effect on the ovipositional responses of gravid An. gambiae females, depending on the quality (preferred or non-preferred by the mosquito) of the oviposition water and the density of larvae. Presence of larvae, at all densities, in distilled water deterred oviposition. However, in natural anopheline pool water, a low density of larvae increased oviposition, whereas a higher density inhibited oviposition. Our results suggest that two signals produced by this mosquito may be involved in regulating oviposition: a volatile pheromone emitted by conspecific larvae, which augments the effect of a volatile signal emitted by preferred habitats, and a non-olfactory cue associated with high densities of larvae that deters oviposition.

Adaptive Landscape by Environment Interactions Dictate Evolutionary Dynamics in Models of Drug Resistance

The adaptive landscape analogy has found practical use in recent years, as many have explored how their understanding can inform therapeutic strategies that subvert the evolution of drug resistance. A major barrier to applications of these concepts is a lack of detail concerning how the environment affects adaptive landscape topography, and consequently, the outcome of drug treatment. Here we combine empirical data, evolutionary theory, and computer simulations towards dissecting adaptive landscape by environment interactions for the evolution of drug resistance in two dimensions—drug concentration and drug type. We do so by studying the resistance mediated by Plasmodium falciparum dihydrofolate reductase (DHFR) to two related inhibitors—pyrimethamine and cycloguanil—across a breadth of drug concentrations. We first examine whether the adaptive landscapes for the two drugs are consistent with common definitions of cross-resistance. We then reconstruct all accessible pathways across the landscape, observing how their structure changes with drug environment. We offer a mechanism for non-linearity in the topography of accessible pathways by calculating of the interaction between mutation effects and drug environment, which reveals rampant patterns of epistasis. We then simulate evolution in several different drug environments to observe how these individual mutation effects (and patterns of epistasis) influence paths taken at evolutionary “forks in the road” that dictate adaptive dynamics in silico. In doing so, we reveal how classic metrics like the IC50 and minimal inhibitory concentration (MIC) are dubious proxies for understanding how evolution will occur across drug environments. We also consider how the findings reveal ambiguities in the cross-resistance concept, as subtle differences in adaptive landscape topography between otherwise equivalent drugs can drive drastically different evolutionary outcomes. Summarizing, we discuss the results with regards to their basic contribution to the study of empirical adaptive landscapes, and in terms of how they inform new models for the evolution of drug resistance.

How evidence can be used to inform policy: A case study of early childhood evidence-based policy development

SummaryAlbeit science is clear in its support for early childhood, the developmental outcomes for young children, globally, are poor. It is hypothesized that evidence-based policies may be a potential mediator of the application of science to improve the lives and well-being of young children. However, the question arises — at what stage of policy formulation can evidence be infused into the process? The aim of the present study was to test the applicability of the infusion of evidence into the very initial stages of policy development by using a systematic analytical approach. A policy analysis and review protocol, generated from the early childhood and social policy science literatures, was applied to the early childhood (ECD) policy formulation for Lao PDR. The results of the analysis indicated, that while several certain aspects of ECD are addressed in the country, notable gaps need to be addressed. The analysis resulted in a set of recommendations to inform the subsequent stage of policy development. The application of this analytical methodology to use evidence to inform policy, the advantages, challenges and issues for further consideration are discussed in this paper.RésuméQuoique la science soit claire comme soutien aux jeunes enfants, les résultats sur le développement des petits enfants sont, globalement, pauvres. On a élaboré une hypothèse qui signale que les politiques basées sur des évidences peuvent être un médiateur potentiel de l’application de la science pour améliorer la vie et le bien-être des petits. Cependant, la question se pose: À quelle étape de la formulation des politiques, l’évidence peut-elle être infusée dans le processus? L’objectif de cette étude est d’examiner l’applicabilité de l’infusion de l’évidence dans les étapes très initiales du développement des politiques en employant une approche analytique systématique. Un protocole d’analyse et révision, généré de la littérature sur la petite enfance et la science politique sociale a été appliqué à la formulation de politiques d’éducation préscolaire (ECE) pour la République Démocratique Populaire (RDP) Lao. Les résultats du tel analyse ont indiqué que tandis que plusieurs certains aspects de l’ECE sont abordés dans le pays, des disparités notables doivent être adressées. L’analyse a eu comme conséquence un ensemble des recommandations d’informer l’étape suivante du développement de la politique. En ce document, l’application de cette méthodologie analytique pour utiliser lévidence pour informer des politiques, avantages, défis et issues pour un examen plus approfondi est discutée.ResumenAunque los cientificos apoyan de modo inequivoco el apoyo para el desarrollo temprano, en términos globales la mayoría de los niños no logran su máximo potencial. Proponemos como hipótesis que politicas basadas en evidencia pueden servir como un mediador efectivo para mejorar las vidas y el desarrollo de los niños. Sin embargo, surge la pregunta: ¿Cómo y en que momento debe aplicarse esta evidencia en el desarrollo de las políticas? El propósito de nuestro estudio es probar la aplicabilidad de esta inclisión de evidencia en el inicio de un proceso de desarrollo de políticas, usando un acercamiento sistemático y analítico. Un protocolo de análisis, fundamentado en la literatura de ciencias naturales y sociales orientadas al desarrollo temprano fue utilizado en el proceso de formulación de políticas de desarrollo infantil temprano de la Republica Popular Democrática de Lao PDR. El análisis de contenido puso en evidencia las fortalezas así como las lagunas relacionadas con el desarrollo temprano en este pais. El análisis genero recomendaciones que informaran las subsiguientes etapas en el desarrollo de las políticas. La utilización de esta metodologia, sus ventajas, los retos y las consideraciones para su futura aplicación en otros casos serán discutidas en este articulo.

On the possible role of robustness in the evolution of infectious diseases

Robustness describes the capacity for a biological system to remain canalized despite perturbation. Genetic robustness affords maintenance of phenotype despite mutational input, necessarily involving the role of epistasis. Environmental robustness is phenotypic constancy in the face of environmental variation, where epistasis may be uninvolved. Here we discuss genetic and environmental robustness, from the standpoint of infectious disease evolution, and suggest that robustness may be a unifying principle for understanding how different disease agents evolve. We focus especially on viruses with RNA genomes due to their importance in the evolution of emerging diseases and as model systems to test robustness theory. We present new data on adaptive constraints for a model RNA virus challenged to evolve in response to UV radiation. We also draw attention to other infectious disease systems where robustness theory may prove useful for bridging evolutionary biology and biomedicine, especially the evolution of antibiotic resistance in bacteria, immune evasion by influenza, and malaria parasite infections.

Delayed transmission selects for increased survival of vesicular stomatitis virus

Life‐history theory predicts that traits for survival and reproduction cannot be simultaneously maximized in evolving populations. For this reason, in obligate parasites such as infectious viruses, selection for improved between‐host survival during transmission may lead to evolution of decreased within‐host reproduction. We tested this idea using experimental evolution of RNA virus populations, passaged under differing transmission times in the laboratory. A single ancestral genotype of vesicular stomatitis virus (VSV), a negative‐sense RNA Rhabdovirus, was used to found multiple virus lineages evolved in either ordinary 24‐h cell‐culture passage, or in delayed passages of 48 h. After 30 passages (120 generations of viral evolution), we observed that delayed transmission selected for improved extracellular survival, which traded‐off with lowered viral fecundity (slower exponential population growth and smaller mean plaque size). To further examine the confirmed evolutionary trade‐off, we obtained consensus whole‐genome sequences of evolved virus populations, to infer phenotype–genotype associations. Results implied that increased virus survival did not occur via convergence; rather, improved virion stability was gained via independent mutations in various VSV structural proteins. Our study suggests that RNA viruses can evolve different molecular solutions for enhanced survival despite their limited genetic architecture, but suffer generalized reproductive trade‐offs that limit overall fitness gains.

Evolution of Increased Survival in RNA Viruses Specialized on Cancer-Derived Cells

Viruses and other pathogens can diverge in their evolved host-use strategies because of exposure to different host types and conflicts between within-host reproduction and between-host survival. Most host-pathogen studies have emphasized the role of intrahost reproduction in the evolution of pathogen virulence, whereas the role of extra-host survival has received less attention. Here, we examine the evolution of free-living virion survival in RNA virus populations differing in their histories of host use. To do so, we used lineages of vesicular stomatitis virus (VSV) that were experimentally evolved in laboratory tissue culture for 100 generations on cancer-derived cells, noncancerous cells, or alternating passages of the two host types. We observed that free-living survival improved when VSV populations specialized on human epithelial carcinoma (HeLa) cells, whereas this trait was not associated with selection on noncancer cells or combinations of the cell types. We attributed this finding to shorter-lived HeLa monolayers and/or rapid cell-to-cell spread of viruses on HeLa cells in tissue culture, both of which could select for enhanced virus stability between host-cell replenishment. We also showed evidence that increases in virion survival were associated with decreases in virulence, which suggests a trade-off between survival and virulence for the VSV populations on one cell type. Our results shed new light on the causes and consequences of “sit and wait” infection strategies in RNA viruses.

Combining mathematics and empirical data to predict emergence of RNA viruses that differ in reservoir use

RNA viruses may be particularly capable of contributing to the increasing biomedical problem of infectious disease emergence. Empirical studies and epidemiological models are informative for the understanding of evolutionary processes that promote pathogen emergence, but rarely are these approaches combined in the same study. Here, we used an epidemiology model containing observations of pathogen productivity in reservoirs, as a means to predict which pathogens should be most prone to emerge in a primary host such as humans. We employed as a model system a collection of vesicular stomatitis virus populations that had previously diverged in host-use strategy: specialists, directly selected generalists and indirectly selected (fortuitous) generalists. Using data from experiments where these viral strategists were challenged to grow on unencountered novel hosts in vitro, logistic growth models determined that the directly selected generalist viruses tended to grow best on model reservoirs. Furthermore, when we used the growth data to estimate average reproductive rate across secondary reservoirs, we showed that the combined approach could be used to estimate relative success of the differing virus strategists when encountering a primary host. Our study suggests that synergistic approaches combining epidemiological modelling with empirical data from experimental evolution may be useful for developing efforts to predict which types of pathogens pose the greatest probability of emerging in the future.

Behavioral evidence for the existence of a region-specific oviposition cue in Anopheles gambiae s.s.

Abstract Understanding oviposition behavior is important to behavioral and vector ecologists because of its potential use in developing vector control strategies for insect-borne infectious diseases. Our study compared the oviposition behaviors of Anopheles gambiae s.s mosquitoes from two different regions of East Africa, Mbita Point, Kenya and Ifakara, Tanzania. The work sought behavioral evidence for the presence of an olfactory cue that modulates oviposition behavior in these different regional strains of Anopheles gambiae s.s. Results demonstrated that the larval rearing water of the different mosquito strains produced a signal that yielded a positive oviposition response from Anopheles gambiae s.s. gravid females of the same region. This not only implies the presence of an olfactory determinant of oviposition but it also could be a model for how speciation could arise within related taxa of mosquitoes.

Competition along trajectories governs adaptation rates towards antimicrobial resistance

The increasing availability of genotype–phenotype maps for different combinations of mutations has empowered evolutionary biologists with the tools to interrogate the predictability of adaptive evolution, especially in the context of the evolution of antimicrobial resistance. Large microbial populations are known to generate competing beneficial mutations, but determining how these mutations contribute to the adaptive trajectories that are most likely to be followed remains a challenge. Despite a recognition that there may also be competition between successive alleles on the same trajectory, prior studies have not fully considered how this impacts adaptation rates along, or likelihood of following, individual trajectories. Here, we develop a metric that quantifies the competition between successive alleles along adaptive trajectories and show how this competition largely governs the rate of evolution in simulations on empirical fitness landscapes for proteins involved in drug resistance in two species of malaria (Plasmodium falciparum and P. vivax). Our findings reveal that a trajectory with a larger-than-average initial fitness increase may have smaller fitness increases in later steps, which slows adaptation. In some circumstances, these trajectories may be outcompeted by alleles on faster alternative trajectories that are being explored simultaneously. The ability to predict adaptation rates along accessible trajectories has implications for efforts to manage antimicrobial resistance in real-world settings and for the broader intellectual pursuit of predictive evolution in complex adaptive fitness landscapes for a variety of application domains.