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Descrição:Reduced rates of genetic recombination are often associated with reduced genetic variability and levels of adaptation. Several different evolutionary processes, collectively known as Hill?Robertson (HR) effects, have been proposed as causes of these correlates of recombination. Here, we use DNA sequence polymorphism and divergence data from the noncrossing over dot chromosome of Drosophila to discriminate between two of the major forms of HR effects: selective sweeps and background selection. This chromosome shows reduced levels of silent variability and reduced effectiveness of selection. We show that neither model fits the data on variability. We propose that, in large genomic regions with restricted recombination, HR effects among nonsynonymous mutations undermine the effective strength of selection, so that their background selection effects are weakened. This modified model fits the data on variability and also explains why variability in very large nonrecombining genomes is not completely wiped out. We also show that HR effects of this type can produce an individual selection advantage to recombination, as well as greatly reduce the mean fitness of nonrecombining genomes and genomic regions

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Descrição:The evolution of multiple antibiotic resistance is an increasing global problem. Resistance mutations are known to impair fitness, and the evolution of resistance to multiple drugs depends both on their costs individually and on how they interact--epistasis. Information on the level of epistasis between antibiotic resistance mutations is of key importance to understanding epistasis amongst deleterious alleles, a key theoretical question, and to improving public health measures. Here we show that in an antibiotic-free environment the cost of multiple resistance is smaller than expected, a signature of pervasive positive epistasis among alleles that confer resistance to antibiotics. Competition assays reveal that the cost of resistance to a given antibiotic is dependent on the presence of resistance alleles for other antibiotics. Surprisingly we find that a significant fraction of resistant mutations can be beneficial in certain resistant genetic backgrounds, that some double resistances entail no measurable cost, and that some allelic combinations are hotspots for rapid compensation. These results provide additional insight as to why multi-resistant bacteria are so prevalent and reveal an extra layer of complexity on epistatic patterns previously unrecognized, since it is hidden in genome-wide studies of genetic interactions using gene knockouts

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Descrição:We introduce a model for assessing the levels and patterns of genetic diversity in pathogen populations, whose epidemiology follows a susceptible-infected-recovered model (SIR). We model the population of pathogens as a metapopulation composed of subpopulations (infected hosts), where pathogens replicate and mutate. Hosts transmit pathogens to uninfected hosts. We show that the level of pathogen variation is well predicted by analytical expressions, such that pathogen neutral molecular variation is bounded by the level of infection and increases with the duration of infection. We then introduce selection in the model and study the invasion probability of a new pathogenic strain whose fitness (R0(1+s)) is higher than the fitness of the resident strain (R0). We show that this invasion probability is given by the relative increment in R0 of the new pathogen (s). By analyzing the patterns of genetic diversity in this framework, we identify the molecular signatures during the replacement and compare these with those observed in sequences of influenza A.

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Descrição:BACKGROUND: Cellular functions are accomplished by the concerted actions of functional modules. The mechanisms driving the emergence and evolution of these modules are still unclear. Here we investigate the evolutionary origins of protein complexes, modules in physical protein-protein interaction networks. RESULTS: We studied protein complexes in Saccharomyces cerevisiae, complexes of known three-dimensional structure in the Protein Data Bank and clusters of pairwise protein interactions in the networks of several organisms. We found that duplication of homomeric interactions, a large class of protein interactions, frequently results in the formation of complexes of paralogous proteins. This route is a common mechanism for the evolution of complexes and clusters of protein interactions. Our conclusions are further confirmed by theoretical modelling of network evolution. We propose reasons for why this is favourable in terms of structure and function of protein complexes. CONCLUSION: Our study provides the first insight into the evolution of functional modularity in protein-protein interaction networks, and the origins of a large class of protein complexes.

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Descrição:The analysis of genetic variation in populations of infectious agents may help us understand their epidemiology and evolution. Here we study a model for assessing the levels and patterns of genetic diversity in populations of infectious agents. The population is structured into many small subpopulations, which correspond to their hosts, that are connected according to a specific type of contact network. We considered different types of networks, including fully connected networks and scale free networks, which have been considered as a model that captures some properties of real contact networks. Infectious agents transmit between hosts, through migration, where they grow and mutate until elimination by the host immune system

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Descrição:The all-time low incidence of measles in Portugal in the recent years, raises questions regarding whether the disease has been eliminated, the role of recent control measures, and the epidemiological consequences of the rise in the proportion of newborns to vaccinated mothers, as opposed to those born to mothers who acquired immunity by natural infection. We estimate the vaccination coverage against measles in Portugal. on a cohort-by-cohort basis, and incorporate this information into an age-structured seasonally-driven mathematical model aimed at reproducing measles dynamics in the past decades. The model reproduces documented trends in disease notifications and the serological profile of the Portuguese population, as estimated by a recent National Serological, Survey. We provide evidence that the effective reproduction number (R-e) of measles has been driven below 1 in Portugal, and that sustained measles elimination is crucially dependent upon the maintenance of a high (>95%) coverage with the MMR I vaccine in the future. If the vaccination coverage decreases to levels around 90% the anticipation of the first dose of the MMR I from 15 to 12 months of age, will. ensure that R-e remains below 1. (C) 2008 Elsevier Ltd. All. rights reserved

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Descrição:BACKGROUND: A characteristic of Plasmodium falciparum infections is the gradual acquisition of clinical immunity resulting from repeated exposures to the parasite. While the molecular basis of protection against clinical malaria remains unresolved, its effects on epidemiological patterns are well recognized. Accumulating epidemiological data constitute a valuable resource that must be intensively explored and interpreted as to effectively inform control planning. METHODOLOGY/PRINCIPAL FINDING: Here we apply a mathematical model to clinical data from eight endemic regions in sub-Saharan Africa. The model provides a quantitative framework within which differences in age distribution of clinical disease are assessed in terms of the parameters underlying transmission. The shorter infectious periods estimated for clinical infections induce a regime of bistability of endemic and malaria-free states in regions of mesoendemic transmission. The two epidemiological states are separated by a threshold that provides a convenient measure for intervention design. Scenarios of eradication and resurgence are simulated. CONCLUSIONS/SIGNIFICANCE: In regions that support mesoendemic transmission, intervention success depends critically on reducing prevalence below a threshold which separates endemic and malaria-free regimes

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Descrição:Physical systems often exhibit pattern-forming instabilities. Equivariant bifurcation theory is often used to investigate the existence and stability of spatially doubly periodic solutions with respect to the hexagonal lattice. Previous studies have focused on the six- and twelve-dimensional representation of the hexagonal lattice where the symmetry of the model is perfect. Here, perturbation of group orbits of translation-free axial planforms in the six- and twelve-dimensional representations is considered. This problem is studied via the abstract action of the symmetry group of the perturbation on the group orbit of the planform. A partial classification for the behaviour of the group orbits is obtained, showing the existence of homoclinic and heteroclinic cycles between equilibria

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Descrição:We study perturbations of cubic planforms, proving there exists perturbations with homoclinic cycles between persistent steady states. Our results do not depend on the representation of the symmetry group of the lattice, and are thus quite general. . The problem is studied using group theory rather than direct methods. We use the abstract action of the symmetry group of the perturbation on the group orbit to determine the existence of zero- and one-dimensional flow-invariant subspaces. The residual symmetry of the perturbation constrains the flows on these subspaces and, in certain cases, homoclinic cycles are guaranteed to exist. Cubic planforms are physically interesting due to their relevance to certain physical systems. Applications to reaction-diffusion systems, nonlinear optical systems and the polyacrylamide methylene blue oxygen reaction are discussed

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Descrição:One-third of the world population (approximately 2 billion individuals) is currently infected with Mycobacterium tuberculosis, the vast majority harboring a latent infection. As the risk of reactivation is around 10% in a lifetime, it follows that 200 million of these will eventually develop active pulmonary disease. Only therapeutic or post-exposure interventions can tame this vast reservoir of infection. Treatment of latent infections can reduce the risk of reactivation, and there is accumulating evidence that combination with post-exposure vaccines can reduce the risk of reinfection. Here we develop mathematical models to explore the potential of these post-exposure interventions to control tuberculosis on a global scale. Intensive programs targeting recent infections appear generally effective, but the benefit is potentially greater in intermediate prevalence scenarios. Extending these strategies to longer-term persistent infections appears more beneficial where prevalence is low. Finally, we consider that susceptibility to reinfection is altered by therapy, and explore its epidemiological consequences. When we assume that therapy reduces susceptibility to subsequent reinfection, catastrophic dynamics are observed. Thus, a bipolar outcome is obtained, where either small or large reductions in prevalence levels result, depending on the rate of detection and treatment of latent infections. By contrast, increased susceptibility after therapy may induce an increase in disease prevalence and does not lead to catastrophic dynamics. These potential outcomes are silent unless a widespread intervention is implemented

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Descrição:The awareness that pathogens can adapt and evolve over relatively short time-scales is changing our view of infectious disease epidemiology and control. Research on the transmission dynamics of antigenically diverse pathogens is progressing and there is increasing recognition for the need of new concepts and theories. Mathematical models have been developed considering the modelling unit in two extreme scales: either diversity is not explicitly represented or diversity is represented at the finest scale of single variants. Here, we use an intermediate approach and construct a model at the scale of clusters of variants. The model captures essential properties of more detailed systems and is much more amenable to mathematical treatment. Specificities of pathogen clusters and the overall potential for transmission determine the reinfection rates. These are, in turn, important regulators of cluster dynamics. Ultimately, we detect a reinfection threshold (RT) that separates different behaviours along the transmissibility axis: below RT, levels of infection are low and cluster substitutions are probable; while above RT, levels of infection are high and multiple cluster coexistence is the most probable outcome

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Descrição:There is increasing recognition that reinfection is an important component of TB transmission. Moreover, it has been shown that partial immunity has significant epidemiological consequences, particularly in what concerns disease prevalence and effectiveness of control measures. We address the problem of drug resistance as a competition between two types of strains of Mycobacterium tuberculosis: those that are sensitive to anti-tuberculosis drugs and those that are resistant. Our objective is to characterise the role of reinfection in the transmission of drug-resistant tuberculosis. The long-term behaviour of our model reflects how reinfection modifies the conditions for coexistence of sensitive and resistant strains. This sets the scene for discussing how strain prevalence is affected by different control strategies. It is shown that intervention effectiveness is highly sensitive to the baseline epidemiological setting.

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Descrição:Since the 1980s, the occurrence of pertussis cases in developed countries has increased and shifted towards older age groups. This resurgence follows 30 years of intense mass vaccination, and has been attributed primarily to three factors: (1) more effective diagnosis of the disease, (2) waning of vaccine-induced immunity, and (3) loss of vaccine efficacy due to the emergence of new Bordetella pertussis strains. Here we develop and analyse a mathematical model to assess the plausibility of these hypotheses. We consider that exposure to B pertussis through natural infection or vaccination induces an immune response that prevents severe disease but does not fully prevent mild infections. We also assume that these protective effects are temporary due to waning of immunity. These assumptions, describing the mode of action of adaptive immunity, are combined with a standard transmission model. Two distinct epidemiological scenarios are detected: under low transmission, most infections lead to severe disease; under high transmission, mild infections are frequent, boosting clinical immunity and maintaining low levels of severe disease. The two behaviours are separated by a reinfection threshold in transmission. As a result, the highest incidence of severe disease is expected to occur at intermediate transmission intensities--near the reinfection threshold--suggesting that pertussis resurgence may be induced by a reduction in transmission, independently of vaccination. The model is extended to interpret the outcomes of current control measures and explore scenarios for future interventions

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Descrição:We investigate the dynamics of a simple epidemiological model for the invasion by a pathogen strain of a population where another strain circulates. We assume that reinfection by the same strain is possible but occurs at a reduced rate due to acquired immunity. The rate of reinfection by a distinct strain is also reduced due to cross-immunity. Individual based simulations of this model on a 'small-world' network show that the proportion of local contacts in the host contact network structure significantly affects the outcome of such an invasion, and as a consequence will affect the patterns of pathogen evolution. In particular, hosts interacting through a 'small-world' network of contacts support lower prevalence of infection than well-mixed populations, and the region in parameter space for which an invading strain can become endemic and coexist with the circulating strain is smaller, reducing the potential to accommodate pathogen diversity. We discuss the underlying mechanisms for the reported effects, and we propose an effective mean-field model to account for the contact structure of the host population in 'small-world' networks

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Descrição:In this paper we analyze the dynamics of two families of epidemiological models which correspond to transitions from the SIR (susceptible-infectious-resistant) to the SIS (susceptible-infectious-susceptible) frameworks. In these models we assume that the force of infection is a nonlinear function of density of infectious individuals, I. Conditions for the existence of backwards bifurcations, oscillations and Bogdanov-Takens points are given

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Descrição:Thresholds in transmission are responsible for critical changes in infectious disease epidemiology. The epidemic threshold indicates whether infection invades a totally susceptible population. The reinfection threshold indicates whether self-sustained transmission occurs in a population that has developed a degree of partial immunity to the pathogen (by previous infection or vaccination). In models that combine susceptible and partially immune individuals, the reinfection threshold is technically not a bifurcation of equilibria as correctly pointed out by Breban and Blower. However, we show that a branch of equilibria to a reinfection submodel bifurcates from the disease-free equilibrium as transmission crosses this threshold. Consequently, the full model indicates that levels of infection increase by two orders of magnitude and the effect of mass vaccination becomes negligible as transmission increases across the reinfection threshold. (c) 2005 Elsevier Ltd. All rights reserved

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Descrição:The SIR (susceptible-infectious-resistant) and SIS (susceptible-infectious-susceptible) frameworks for infectious disease have been extensively studied and successfully applied. They implicitly assume the upper and lower limits of the range of possibilities for host immune response. However, the majority of infections do not fall into either of these extreme categories. We combine two general avenues that straddle this range: temporary immune protection (immunity wanes over time since infection), and partial immune protection (immunity is not fully protective but reduces the risk of reinfection). We present a systematic analysis of the dynamics and equilibrium properties of these models in comparison to SIR and SIS, and analyse the outcome of vaccination programmes. We describe how the waning of immunity shortens inter-epidemic periods, and poses major difficulties to disease eradication. We identify a "reinfection threshold" in transmission when partial immunity is included. Below the reinfection threshold primary infection dominates, levels of infection are low, and vaccination is highly effective (approximately an SIR model). Above the reinfection threshold reinfection dominates, levels of infection are high, and vaccination fails to protect (approximately an SIS situation). This association between high prevalence of infection and vaccine failure emphasizes the problems of controlling recurrent infections in high-burden regions. However, vaccines that induce a better protection than natural infection have the potential to increase the reinfection threshold, and therefore constitute interventions with a surprisingly high capacity to reduce infection where reduction is most needed

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Descrição:Population patterns of infection are determined largely by susceptibility to infection. Infection and vaccination induce an immune response that, typically, reduces susceptibility to subsequent infections. With a general epidemic model, we detect a 'reinfection threshold', above which reinfection is the principal type of transmission and, consequently, infection levels are much higher and vaccination fails. The model is further developed to address human tuberculosis (TB) and the impact of vaccination. The bacille Calmette-Guérin (BCG) is the only vaccine in current use against TB, and there is no consensus about its usefulness. Estimates of protection range from 0 to 80%, and this variability is aggravated by an association between low vaccine efficacy and high prevalence of the disease. We propose an explanation based on three postulates: (i) the potential for transmission varies between populations, owing to differences in socio-economic and environmental factors; (ii) exposure to mycobacteria induces an immune response that is partially protective against reinfection; and (iii) this protection is not significantly improved by BCG vaccination. These postulates combine to reproduce the observed trends, and this is attributed to a reinfection threshold intrinsic to the transmission dynamics. Finally, we demonstrate how reinfection thresholds can be manipulated by vaccination programmes, suggesting that they have a potentially powerful role in global control

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Descrição:Many pathogens exhibit antigenic diversity and elicit strain-specific immune responses. This potential for cross-immunity structure in the host resource motivates the development of mathematical models, stressing competition for susceptible hosts in driving pathogen population dynamics and genetics. Here we establish that certain model formulations exhibit characteristics of prototype pattern-forming systems, with pathogen population structure emerging as three possible patterns: (i) incidence is steady and homogeneous; (ii) incidence is steady but heterogeneous; and (iii) incidence shows oscillatory dynamics, with travelling waves in strain-space. Results are robust to strain number, but sensitive to the mechanism of cumulative immunity

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Descrição:Heterogeneity in susceptibility and infectivity is inherent to infectious disease transmission in nature. Here we are concerned with the formulation of mathematical models that capture the essence of heterogeneity while keeping a simple structure suitable of analytical treatment. We explore the consequences of host heterogeneity in the susceptibility to infection for epidemiological models for which immunity conferred by infection is partially protective, known as susceptible-infected-recovered-infected (SIRI) models. We analyze the impact of heterogeneity on disease prevalence and contrast the susceptibility profiles of the subpopulations at risk for primary infection and reinfection. We present a systematic study in the case of two frailty groups. We predict that the average rate of reinfection may be higher than the average rate of primary infection, which may seem paradoxical given that primary infection induces life-long partial protection. Infection generates a selection mechanism whereby fit individuals remain in S and frail individuals are transferred to R. If this effect is strong enough we have a scenario where, on average, the rate of reinfection is higher than the rate of primary infection even though each individual has a risk reduction following primary infection. This mechanism may explain high rates of tuberculosis reinfection recently reported. Finally, the enhanced benefits of vaccination strategies that target the high-risk groups are quantified.; http://dx.doi.org/10.1016/j.jtbi.2009.03.013