BackgroundDengue is the most important mosquito-borne viral disease affecting humans. The only prevention measure currently available is the control of its vectors, primarily Aedes aegypti. Recent advances in genetic engineering have opened the possibility for a new range of control strategies based on genetically modified mosquitoes. Assessing the potential efficacy of genetic (and conventional) strategies requires the availability of modeling tools that accurately describe the dynamics and genetics of Ae. aegypti populations.Methodology/Principal findingsWe describe in this paper a new modeling tool of Ae. aegypti population dynamics and genetics named Skeeter Buster. This model operates at the scale of individual water-filled containers for immature stages and individual properties (houses) for adults. The biology of cohorts of mosquitoes is modeled based on the algorithms used in the non-spatial Container Inhabiting Mosquitoes Simulation Model (CIMSiM). Additional features incorporated into Skeeter Buster include stochasticity, spatial structure and detailed population genetics. We observe that the stochastic modeling of individual containers in Skeeter Buster is associated with a strongly reduced temporal variation in stage-specific population densities. We show that heterogeneity in container composition of individual properties has a major impact on spatial heterogeneity in population density between properties. We detail how adult dispersal reduces this spatial heterogeneity. Finally, we present the predicted genetic structure of the population by calculating FST values and isolation by distance patterns, and examine the effects of adult dispersal and container movement between properties.Conclusions/SignificanceWe demonstrate that the incorporated stochasticity and level of spatial detail have major impacts on the simulated population dynamics, which could potentially impact predictions in terms of control measures. The capacity to describe population genetics confers the ability to model the outcome of genetic control methods. Skeeter Buster is therefore an important tool to model Ae. aegypti populations and the outcome of vector control measures.

A number of genetic mechanisms have been suggested for driving anti-pathogen genes into natural populations. Each of these mechanisms requires complex genetic engineering, and most are theoretically expected to permanently spread throughout the target species' geographical range. In the near term, risk issues and technical limits of molecular methods could delay the development and use of these mechanisms. We propose a gene-drive mechanism that can be self-limiting over time and space, and is simpler to build. This mechanism involves one gene that codes for toxicity (killer) and a second that confers immunity to the toxic effects (rescue). We use population-genetic models to explore cases with one or two independent insertions of the killer gene and one insertion of the rescue gene. We vary the dominance and penetrance of gene action, as well as the magnitude of fitness costs. Even with the fitness costs of 10 per cent for each gene, the proportion of mosquitoes expected to transmit the pathogen decreases below 5 per cent for over 40 generations after one 2 : 1 release (engineered : wild) or after four 1 : 2 releases. Both the killer and rescue genes will be lost from the population over time, if the rescue construct has any associated fitness cost. Molecular approaches for constructing strains are discussed.

Density-dependent intraspecific competition has been considered an important determinant of the dynamics of larval stages of Aedes aegypti. A model was published in 1984 providing a mathematical description of this density dependence, based on field data, that has since been widely used. This description, however, is based on the strong assumption that all mortality is density-dependent. We re-examine the data without this premise and find a reduced importance of density dependence, as well as a different functional form. Based on these discrepancies, we emphasize that the characterization of density dependence in the larval stages of Ae. aegypti should be based on a more complete dataset, and we use artificially generated data to explore how such additional information could help developing a better description of this density dependence. We review other empirical studies on larval competition, discuss the need for further dedicated studies, and provide a few simple guidelines for the design of such studies. KeywordsAedes aegypti; density dependence; intraspecific competition; mathematical model; parameter estimation Aedes aegypti is the major vector of dengue and yellow fever viruses. Its close association with human populations makes it a particularly competent vector in urban environments and therefore an important target for population control.A key prerequisite to the design of any population control program is an understanding of the mechanisms underlying the dynamics of the pest population, and, in particular, whether the population is regulated by density-dependent processes. Three types of density dependence can be defined, based on the relationship between initial density at the stage at which density dependence occurs and the final number of individuals surviving to later stages. Density dependence is exactly compensatory when this final number is independent of the initial density. If the final number of survivors increases when initial density increases, density dependence is undercompensatory. Finally, if the final number of survivors decreases when initial density increases, density dependence is overcompensatory.

The potential benefits and risks of genetically engineered gene-drive systems for replacing wild pest strains with more benign strains must be assessed prior to any field releases. We develop a computer simulation model to assess the feasibility of using engineered underdominance constructs to drive transgenes into age- and spatially structured mosquito populations. Our practical criterion for success is the achievement of a transgene frequency of at least 0.80 within 3 years of release. The impacts of a number of parameters that may affect the success of gene-drive, such as the release area, release age, density-dependent larval survival, fitness cost of the engineered genes, and migration probability of adults, are examined. Results show that patchy release generally requires the release of fewer engineered insects to achieve success than central release. When the fitness cost is very low, central release covering 25% of the total area can be more effective than a completely uniform release over the whole area. This study demonstrates that to determine the best method of spatial release, and the total number of engineered insects that must be released, it is important to take into account the age and sex of the released insects and spatial structure of the population.

Suppression of dengue and malaria through releases of genetically engineered mosquitoes might soon become feasible. Aedes aegypti mosquitoes carrying a conditionally lethal transgene have recently been used to suppress local vector populations in small-scale field releases. Prior to releases of transgenic insects on a wider scale, however, most regulatory authorities will require additional evidence that suppression will be effective in natural heterogeneous habitats. We use a spatially explicit stochastic model of an Ae. aegypti population in Iquitos, Peru, along with an uncertainty analysis of its predictions, to quantitatively assess the outcome of varied operational approaches for releases of transgenic strains with conditional death of females. We show that population elimination might be an unrealistic objective in heterogeneous populations. We demonstrate that substantial suppression can nonetheless be achieved if releases are deployed in a uniform spatial pattern using strains combining multiple lethal elements, illustrating the importance of detailed spatial models for guiding genetic mosquito control strategies.