Lauren Ancel Meyers

PERSPECTIVE:EVOLUTION AND DETECTION OF GENETIC ROBUSTNESS

Abstract Robustness is the invariance of phenotypes in the face of perturbation. The robustness of phenotypes appears at various levels of biological organization, including gene expression, protein folding, metabolic flux, physiological homeostasis, development, and even organismal fitness. The mechanisms underlying robustness are diverse, ranging from thermodynamic stability at the RNA and protein level to behavior at the organismal level. Phenotypes can be robust either against heritable perturbations (e.g., mutations) or nonheritable perturbations (e.g., the weather). Here we primarily focus on the first kind of robustness—genetic robustness—and survey three growing avenues of research: (1) measuring genetic robustness in nature and in the laboratory; (2) understanding the evolution of genetic robustness; and (3) exploring the implications of genetic robustness for future evolution.

Network theory and SARS: predicting outbreak diversity.

Abstract Many infectious diseases spread through populations via the networks formed by physical contacts among individuals. The patterns of these contacts tend to be highly heterogeneous. Traditional “compartmental” modeling in epidemiology, however, assumes that population groups are fully mixed, that is, every individual has an equal chance of spreading the disease to every other. Applications of compartmental models to Severe Acute Respiratory Syndrome (SARS) resulted in estimates of the fundamental quantity called the basic reproductive number R 0 —the number of new cases of SARS resulting from a single initial case—above one, implying that, without public health intervention, most outbreaks should spark large-scale epidemics. Here we compare these predictions to the early epidemiology of SARS. We apply the methods of contact network epidemiology to illustrate that for a single value of R 0 , any two outbreaks, even in the same setting, may have very different epidemiological outcomes. We offer quantitative insight into the heterogeneity of SARS outbreaks worldwide, and illustrate the utility of this approach for assessing public health strategies.

When individual behaviour matters: homogeneous and network models in epidemiology

Heterogeneity in host contact patterns profoundly shapes population-level disease dynamics. Many epidemiological models make simplifying assumptions about the patterns of disease-causing interactions among hosts. In particular, homogeneous-mixing models assume that all hosts have identical rates of disease-causing contacts. In recent years, several network-based approaches have been developed to explicitly model heterogeneity in host contact patterns. Here, we use a network perspective to quantify the extent to which real populations depart from the homogeneous-mixing assumption, in terms of both the underlying network structure and the resulting epidemiological dynamics. We find that human contact patterns are indeed more heterogeneous than assumed by homogeneous-mixing models, but are not as variable as some have speculated. We then evaluate a variety of methodologies for incorporating contact heterogeneity, including network-based models and several modifications to the simple SIR compartmental model. We conclude that the homogeneous-mixing compartmental model is appropriate when host populations are nearly homogeneous, and can be modified effectively for a few classes of non-homogeneous networks. In general, however, network models are more intuitive and accurate for predicting disease spread through heterogeneous host populations.

Fighting change with change: adaptive variation in an uncertain world

Organisms live in an ever-changing world. Most of evolutionary theory considers one solution to this problem: population-level adaptation. In fact, empirical studies have revealed an enormous variety of mechanisms to cope with environmental fluctuations. Some organisms use behavioral or physiological modifications that leave no permanent trace in the genes of future generations. Others withstand environmental change through the regular production of diverse offspring, in which the diversity can be either genetic or nongenetic. Evolutionary theorists now have the opportunity to catch up with the empirical evolutionary biology, and to integrate the diverse forms of ‘adaptive variation’ into a single conceptual framework. Here, we propose a classification according to the level at which the adaptive variation occurs and discuss some of the mechanisms underlying the variation. This perspective unites independent lines of research in molecular biology, microbiology, macroevolution, ecology, immunology and neurobiology, and suggests directions for a more comprehensive theory of adaptive variation.

Contact network epidemiology: Bond percolation applied to infectious disease prediction and control

Mathematics has long been an important tool in infectious disease epidemiology. I will provide a brief overview of compartmental models, the dominant framework for modeling disease transmission, and then contact network epidemiology, a more powerful approach that applies bond percolation on random graphs to model the spread of infectious disease through heterogeneous populations. I will derive important epidemiological quantities using this approach and provide examples of its application to issues of public health.

Susceptible-infected-recovered epidemics in dynamic contact networks

Contact patterns in populations fundamentally influence the spread of infectious diseases. Current mathematical methods for epidemiological forecasting on networks largely assume that contacts between individuals are fixed, at least for the duration of an outbreak. In reality, contact patterns may be quite fluid, with individuals frequently making and breaking social or sexual relationships. Here, we develop a mathematical approach to predicting disease transmission on dynamic networks in which each individual has a characteristic behaviour (typical contact number), but the identities of their contacts change in time. We show that dynamic contact patterns shape epidemiological dynamics in ways that cannot be adequately captured in static network models or mass-action models. Our new model interpolates smoothly between static network models and mass-action models using a mixing parameter, thereby providing a bridge between disparate classes of epidemiological models. Using epidemiological and sexual contact data from an Atlanta high school, we demonstrate the application of this method for forecasting and controlling sexually transmitted disease outbreaks.

Applying Network Theory to Epidemics: Control Measures for Mycoplasma pneumoniae Outbreaks

We introduce a novel mathematical approach to investigating the spread and control of communicable infections in closed communities. Mycoplasma pneumoniae is a major cause of bacterial pneumonia in the United States. Outbreaks of illness attributable to mycoplasma commonly occur in closed or semi-closed communities. These outbreaks are difficult to contain because of delays in outbreak detection, the long incubation period of the bacterium, and an incomplete understanding of the effectiveness of infection control strategies. Our model explicitly captures the patterns of interactions among patients and caregivers in an institution with multiple wards. Analysis of this contact network predicts that, despite the relatively low prevalence of mycoplasma pneumonia found among caregivers, the patterns of caregiver activity and the extent to which they are protected against infection may be fundamental to the control and prevention of mycoplasma outbreaks. In particular, the most effective interventions are those that reduce the diversity of interactions between caregivers and patients.

Initial human transmission dynamics of the pandemic (H1N1) 2009 virus in North America.

Background  Between 5 and 25 April 2009, pandemic (H1N1) 2009 caused a substantial, severe outbreak in Mexico, and subsequently developed into the first global pandemic in 41 years. We determined the reproduction number of pandemic (H1N1) 2009 by analyzing the dynamics of the complete case series in Mexico City during this early period.

Quasispecies Made Simple

Quasispecies are clouds of genotypes that appear in a population at mutation–selection balance. This concept has recently attracted the attention of virologists, because many RNA viruses appear to generate high levels of genetic variation that may enhance the evolution of drug resistance and immune escape. The literature on these important evolutionary processes is, however, quite challenging. Here we use simple models to link mutation–selection balance theory to the most novel property of quasispecies: the error threshold—a mutation rate below which populations equilibrate in a traditional mutation–selection balance and above which the population experiences an error catastrophe, that is, the loss of the favored genotype through frequent deleterious mutations. These models show that a single fitness landscape may contain multiple, hierarchically organized error thresholds and that an error threshold is affected by the extent of back mutation and redundancy in the genotype-to-phenotype map. Importantly, an error threshold is distinct from an extinction threshold, which is the complete loss of the population through lethal mutations. Based on this framework, we argue that the lethal mutagenesis of a viral infection by mutation-inducing drugs is not a true error catastophe, but is an extinction catastrophe.

Epidemic thresholds in dynamic contact networks

The reproductive ratio, R0, is a fundamental quantity in epidemiology, which determines the initial increase in an infectious disease in a susceptible host population. In most epidemic models, there is a specific value of R0, the epidemic threshold, above which epidemics are possible, but below which epidemics cannot occur. As the complexity of an epidemic model increases, so too does the difficulty of calculating epidemic thresholds. Here we derive the reproductive ratio and epidemic thresholds for susceptible–infected–recovered (SIR) epidemics in a simple class of dynamic random networks. As in most epidemiological models, R0 depends on two basic epidemic parameters, the transmission and recovery rates. We find that R0 also depends on social parameters, namely the degree distribution that describes heterogeneity in the numbers of concurrent contacts and the mixing parameter that gives the rate at which contacts are initiated and terminated. We show that social mixing fundamentally changes the epidemiological landscape and, consequently, that static network approximations of dynamic networks can be inadequate.