Biology subjects

Woods, R. J.

Publications and source records attributed to Woods, R. J..

7 recordsLinked to original sources

bioRxiv2018

A speed-fidelity trade-off determines the mutation rate and virulence of an RNA virus

Mutation rates can evolve through genetic drift, indirect selection due to genetic hitchhiking, or direct selection on the physicochemical cost of high fidelity. However, for many systems, it has been difficult to disentangle the relative impact of these forces empirically. In RNA viruses, an observed correlation between mutation rate and virulence has led many to argue that their extremely high mutation rates are advantageous, because they may allow for increased adaptability. This argument has profound implications, as it suggests that pathogenesis in many viral infections depends on rare or de novo mutations. Here we present data for an alternative model whereby RNA viruses evolve high mutation rates as a byproduct of selection for increased replicative speed. We find that a poliovirus antimutator, 3DG64S, has a significant replication defect and that wild type and 3DG64S populations have similar adaptability in two distinct cellular environments. Experimental evolution of 3DG64S under r-selection led to reversion and compensation of the fidelity phenotype. Mice infected with 3DG64S exhibited delayed morbidity at doses well above the LD50, consistent with attenuation by slower growth as opposed to reduced mutational supply. Furthermore, compensation of the 3DG64S growth defect restored virulence, while compensation of the fidelity phenotype did not. Our data are consistent with the kinetic proofreading model for biosynthetic reactions and suggest that speed is more important than accuracy. In contrast to what has been suggested for many RNA viruses, we find that within host spread is associated with viral replicative speed and not standing genetic diversity.\n\nAuthor SummaryMutation rate evolution has long been a fundamental problem in evolutionary biology. The polymerases of RNA viruses generally lack proofreading activity and exhibit extremely high mutation rates. Since most mutations are deleterious and mutation rates are tuned by natural selection, we asked why hasnt the virus evolved to have a lower mutation rate? We used experimental evolution and a murine infection model to show that RNA virus mutation rates may actually be too high and are not necessarily adaptive. Rather, our data indicate that viral mutation rates are driven higher as a result of selection for viruses with faster replication kinetics. We suggest that viruses have high mutation rates, not because they facilitate adaption, but because it is hard to be both fast and accurate.

microbiology↗

bioRxiv2017

Mapping of the Fondaparinux Binding Site of JR-FL gp120 by High Resolution Hydroxyl Radical Protein Footprinting and Computational Docking

The adhesion of HIV gp120 antigen to human cells is modulated in part by interactions with heparan sulfate. The HXB2 strain of gp120 has been shown to interact with heparin primarily through the V3 loop, although other domains including the C-terminal domain were also implicated. However, the JR-FL strain (representative of CCR5-interacting strains that make up newest infections) was shown to have a drastically lowered affinity to heparin due to the loss of several basic residues in the V3 loop, and deletion of the V3 loop in JR-FL gp120 was shown to abrogate some, but not all, heparin binding. Here, we use high resolution hydroxyl radical protein footprinting to measure the changes in protein surface oxidation levels that result from the binding of a model heparin fragment (fondaparinux). Protection in both the V3 loop and the N-terminus of JR-FP gp120 is observed. The well-defined composition of fondaparinux allowed us to perform docking simulations, which showed two clusters of fondaparinux binding: the V3 loop, and a domain consisting of the N- and C-termini. Together, the experimental and theoretical results indicate the heparin/heparan sulfate binding sites on JR-FL gp120 and the efficient interaction of fondaparinux, a widely exploited therapeutic carbohydrate, on gp120.

biochemistry↗

bioRxiv2017

Evolution-informed forecasting of seasonal influenza A (H3N2)

Inter-pandemic or seasonal influenza exacts an enormous annual burden both in terms of human health and economic impact. Incidence prediction ahead of season remains a challenge largely because of the virus antigenic evolution. We propose here a forecasting approach that incorporates evolutionary change into a mechanistic epidemiological model. The proposed models are simple enough that their parameters can be estimated from retrospective surveillance data. These models link amino-acid sequences of hemagglutinin epitopes with a transmission model for seasonal H3N2 influenza, also informed by H1N1 levels. With a monthly time series of H3N2 incidence in the United States over 10 years, we demonstrate the feasibility of prediction ahead of season and an accurate real-time forecast for the 2016/2017 influenza season.\n\nSUMMARYSkillful forecasting of seasonal (H3N2) influenza incidence ahead of the season is shown to be possible by means of a transmission model that explicitly tracks evolutionary change in the virus, integrating information from both epidemiological surveillance and readily available genetic sequences.

systems biology↗

bioRxiv2017

Enriched pathogen diversity under host-type heterogeneity and immune-mediated competition

Pathogen strains can stably coexist if they specialize on different hosts. Multiple strains can also coexist on a single host through negative frequency-dependent interactions mediated by partial cross-immunity. Understanding pathogen diversity remains a challenge however when both host specificity and cross-immunity are acting and may be functionally linked, as has been proposed for rotavirus, where a single protein is both antigenically important and determines host specificity by binding to the genetically encoded human blood group antigens. This situation is akin to the more general question in ecology of species coexistence when stabilizing and equalizing mechanisms interact. We examine this interaction with a theoretical model motivated by rotavirus and apply an adaptive dynamics framework to show how these two kinds of competition, typically considered separately, affect diversity. When cross-immunity depends on host-pathogen affinity, diversity is magnified as long-term evolution allows for the coexistence of multiple semi-specialized strains, similar to observations in rotavirus. In contrast, the simultaneous co-occurrence of several semi-specialized individuals is not observed when the degree of cross-immunity is independent from affinity distance among strains. The interplay of equalizing and stabilizing mechanisms fundamentally modifies diversity patterns and should be considered when addressing strain coexistence.

ecology↗

bioRxiv2017

The evolutionary dynamics of influenza A virus within and between human hosts

The global evolutionary dynamics of influenza virus ultimately derive from processes that take place within and between infected individuals. Here we define the dynamics of influenza A virus populations in human hosts through next generation sequencing of 249 specimens from 200 individuals collected over 6290 person-seasons of observation. Because these viruses were collected over 5 seasons from individuals in a prospective community-based cohort, they are broadly representative of natural human infections with seasonal viruses. We used viral sequence data from 35 serially sampled individuals to estimate a within host effective population size of 30-70 and an in vivo mutation rate of 4x10-5 per nucleotide per cellular infectious cycle. These estimates are consistent across several models and robust to the models' underlying assumptions. We also identified 43 epidemiologically linked and genetically validated transmission pairs. Maximum likelihood optimization of multiple transmission models estimates an effective transmission bottleneck of 1-2 distinct genomes. Our data suggest that positive selection of novel viral variants is inefficient at the level of the individual host and that genetic drift and other stochastic processes dominate the within and between host evolution of influenza A viruses.

microbiology↗

bioRxiv2017

Role Of Competition In The Strain Structure Of Rotavirus Under Invasion And Reassortment

The role of competitive interactions in the formation and coexistence of viral strains remains unresolved. Neglected aspects of existing strain theory are that viral pathogens are repeatedly introduced from animal sources and readily exchange their genes. The combined effect of introduction and reassortment opposes strain structure, in particular the predicted stable coexistence of antigenically differentiated strains under strong frequency-dependent selection mediated by cross-immunity. Here we use a stochastic model motivated by rotavirus, the most common cause of childhood diarrheal mortality, to investigate serotype structure under these conditions. We describe a regime in which the transient coexistence of distinct strains emerges despite only weak cross-immunity, but is disturbed by invasions of new antigenic segments that reassort into existing backgrounds. We find support for this behavior in global rotavirus sequence data and present evidence for the displacement of new strains towards open antigenic niches. Our work extends previous work to bacterial and viral pathogens that share these rotavirus-like characteristics, with important implications for the effects of interventions such as vaccination on strain composition, and for the understanding of the factors promoting emergence of new subtypes.

evolutionary biology↗

bioRxiv2017

Quantitative Protein Topography Measurements By High Resolution Hydroxyl Radical Protein Footprinting Enable Accurate Molecular Model Selection

We report an integrated workflow that allows mass spectrometry-based high-resolution hydroxyl radical protein footprinting (HR-HRPF) measurements to accurately measure the absolute average solvent accessible surface area ( ) of amino acid side chains. This approach is based on application of multi-point HR-HRPF, electron-transfer dissociation (ETD) tandem MS (MS/MS) acquisition, measurement of effective radical doses by radical dosimetry, and proper normalization of the inherent reactivity of the amino acids. The accuracy of the resulting measurements was tested by using well-characterized protein models. Moreover, we demonstrated the ability to use measurements from HR-HRPF to differentiate molecular models of high accuracy (< 3[A] backbone RMSD) from models of lower accuracy (> 4[A] backbone RMSD). The ability of data from HR-HRPF to differentiate molecular model quality was found to be comparable to that of data obtained from X-ray crystal structures, indicating the accuracy and utility of HR-HRPF for evaluating the accuracy of computational models.

biochemistry↗