Project

MGDrivE: Mosquito Gene-Drive Explorer

Goal: Creating a flexible and comprehensive framework in which gene-drive releases can be simulated and assessed.

Date: 30 June 2017

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Project log

Héctor Manuel Sánchez Castellanos
added a research item
MGDrivE (Mosquito Gene Drive Explorer) is an open-source modeling framework to simulate and evaluate novel genetic control tools in spatial mosquito populations. The software has four modules: A) a genetic inheritance module accommodates the dynamics of gene drive systems, B) a population dynamic module accounts for mosquito life history, D) a landscape module generates the metapopulation by which insect populations are connected via migration, and C) an epidemiology module (in MGDrivE 2) models reciprocal pathogen transmission between mosquitoes and humans. We intend the package to provide a flexible tool to model a range of genetic control systems both in the lab, and as they move closer to field application.
Héctor Manuel Sánchez Castellanos
added a research item
MGDrivE (Mosquito Gene Drive Explorer) is an open-source modeling framework to simulate and evaluate novel genetic control tools in spatial mosquito populations. The software has four modules (right): i) a genetic inheritance module accommodates the dynamics of gene drive systems, ii) a population dynamic module accounts for mosquito life history, iii) a landscape module generates the metapopulation by which insect populations are connected via migration, and iv) an epidemiology module (in MGDrivE 2) models reciprocal pathogen transmission between mosquitoes and humans. We intend the package to provide a flexible tool to model a range of genetic control systems both in the lab, and as they move closer to field application.
Héctor Manuel Sánchez Castellanos
added a research item
CRISPR/Cas9-based technologies have revitalized interest in gene-editing technologies as means to control mosquito-borne diseases. Amongst candidate disease-control mechanisms, gene- replacement strategies are considered some of the most promising due to their resilience to generation of resistant alleles (caused by errors in homology-directed repair). These approaches focus on releasing and introgressing genes that prevent mosquitoes from transmitting pathogens to humans, thus disrupting the transmission chain.Genetically isolated populations provide perfect testing grounds to assess the viability of genetic-modification constructs, as they limit the probability of the drive escaping the area of study whilst also restricting the impact of heterogeneity in variables such as migration and spatial structure. The islands of São Tomé and Príncipe, in the equatorial region west of the African mainland are a couple of such settings that are being considered as potential testing grounds for gene drive studies.In this work, we explore release strategies to introgress a transgenic construct in a mosquito population using our published gene-drive model: MGDrivE. In doing so, we find that even though there is a benefit in increasing the ratio of the releases of transgenic mosquitoes (with respect to the natural population), a limit exists above which performing more releases does not significantly increase the speed at which the transgene takes over the population. Additionally, we find that changes in the genetic standing variation do not affect the time to introgression; and that, even though sex of the released mosquitoes (mixed, gravid, or male-only) does impact the extent of the effects, their viability has to be assessed with respect to the necessary mosquito sex-sorting labour.
Héctor Manuel Sánchez Castellanos
added a research item
Interest in gene drive technology has continued to grow as promising new drive systems have been developed in the lab and discussions are moving towards implementing field trials. The prospect of field trials requires models that incorporate a significant degree of ecological detail, including parameters that change over time in response to environmental data such as temperature and rainfall, leading to seasonal patterns in mosquito population density. Epidemiological outcomes are also of growing importance, as: i) the suitability of a gene drive construct for release will depend on its expected impact on disease transmission, and ii) initial field trials are expected to have a measured entomological outcome and a modeled epidemiological outcome. We present MGDrivE 2 (Mosquito Gene Drive Explorer 2): an extension of and development from the MGDrivE 1 simulation framework that investigates the population dynamics of a variety of gene drive architectures and their spread through spatially-explicit mosquito populations. Key strengths and improvements of the MGDrivE 2 framework are: i) the ability of parameters to vary with time and induce seasonal population dynamics, ii) an epidemiological module accommodating reciprocal pathogen transmission between humans and mosquitoes, and iii) an implementation framework based on stochastic Petri nets that enables efficient model formulation and flexible implementation. Example MGDrivE 2 simulations are presented to demonstrate the application of the framework to a CRISPR-based homing gene drive system intended to drive a disease-refractory gene into a population, incorporating time-varying temperature and rainfall data, and predict impact on human disease incidence and prevalence. Further documentation and use examples are provided in vignettes at the project's CRAN repository. MGDrivE 2 is an open-source R package freely available on CRAN. We intend the package to provide a flexible tool capable of modeling gene drive constructs as they move closer to field application and to infer their expected impact on disease transmission.
Héctor Manuel Sánchez Castellanos
added a research item
Comparing mosquito replacement gene-drive technology against population suppression in São Tomé and Príncipe in the presence of genetic standing variation and resistant allele formation rates. https://chipdelmal.github.io/MGDrivE_Presentations/MMC2020/
Héctor Manuel Sánchez Castellanos
added 2 research items
The discovery of CRISPR-based gene editing and its application to homing-based gene drive systems has been greeted with excitement, for its potential to control mosquito-borne diseases on a wide scale, and concern, for the invasiveness and potential irreversibility of a release. Gene drive systems that display threshold-dependent behavior could potentially be used during the trial phase of this technology, or when localized control is otherwise desired, as simple models predict them to spread into partially isolated populations in a confineable manner, and to be reversible through releases of wild-type organisms. Here, we model hypothetical releases of two recently engineered threshold-dependent gene drive systems-reciprocal chromosomal translocations and a form of toxin-antidote-based underdominance known as UD MEL-to explore their ability to be confined and remediated. We simulate releases of Aedes aegypti, the mosquito vector of dengue, Zika, and other arboviruses, in Yorkeys Knob, a suburb of Cairns, Australia, where previous biological control interventions have been undertaken on this species. We monitor spread to the neighboring suburb of Trinity Park to assess confinement. Results suggest that translocations could be introduced on a suburban scale, and remediated through releases of non-disease-transmitting male mosquitoes with release sizes on the scale of what has been previously implemented. UD MEL requires fewer releases to introduce, but more releases to remediate, including of females capable of disease transmission. Both systems are expected to be confineable to the release site; however, spillover of translocations into neighboring populations is less likely. Our analysis supports the use of translocations as a threshold-dependent drive system capable of spreading disease-refractory genes into Ae. aegypti populations in a confineable and reversible manner. It also highlights increased release requirements when incorporating life history and population structure into models. As the technology nears implementation, further ecological work will be essential to enhance model predictions in preparation for field trials.
Héctor Manuel Sánchez Castellanos
added a research item
1.Malaria, dengue, Zika, and other mosquito‐borne diseases continue to pose a major global health burden through much of the world, despite the widespread distribution of insecticide‐based tools and antimalarial drugs. The advent of CRISPR/Cas9‐based gene editing and its demonstrated ability to streamline the development of gene drive systems has reignited interest in the application of this technology to the control of mosquitoes and the diseases they transmit. The versatility of this technology has enabled a wide range of gene drive architectures to be realized, creating a need for their population‐level and spatial dynamics to be explored. 2.We present MGDrivE (Mosquito Gene Drive Explorer): a simulation framework designed to investigate the population dynamics of a variety of gene drive architectures and their spread through spatially‐explicit mosquito populations. A key strength of the MGDrivE framework is its modularity: a) a genetic inheritance module accommodates the dynamics of gene drive systems displaying userdefined inheritance patterns, b) a population dynamic module accommodates the life history of a variety of mosquito disease vectors and insect agricultural pests, and c) a landscape module generates the metapopulation model by which insect populations are connected via migration over space. 3.Example MGDrivE simulations are presented to demonstrate the application of the framework to CRISPR/Cas9‐based homing gene drive for: a) driving a disease‐refractory gene into a population (i.e. population replacement), and b) disrupting a gene required for female fertility (i.e. population suppression), incorporating homing‐resistant alleles in both cases. Further documentation and use examples are provided at the project's Github repository. 4.MGDrivE is an open‐source R package freely available on CRAN. We intend the package to provide a flexible tool capable of modeling novel inheritance‐modifying constructs as they are proposed and become available. The field of gene drive is moving very quickly, and we welcome suggestions for future development.
Héctor Manuel Sánchez Castellanos
added 11 research items
The recent development of a CRISPR-Cas9-based homing system for the suppression of Anopheles gambiae is encouraging; however, with current designs, the slow emergence of homing-resistant alleles is expected to result in suppressed populations rapidly rebounding, as homing-resistant alleles have a significant fitness advantage over functional, population-suppressing homing alleles. To explore this concern, we develop a mathematical model to estimate tolerable rates of homing-resistant allele generation to suppress a wild population of a given size. Our results suggest that, to achieve meaningful population suppression, tolerable rates of resistance allele generation are orders of magnitude smaller than those observed for current designs for CRISPR-Cas9-based homing systems. To remedy this, we theoretically explore a homing system architecture in which guide RNAs (gRNAs) are multiplexed, increasing the effective homing rate and decreasing the effective resistant allele generation rate. Modeling results suggest that the size of the population that can be suppressed increases exponentially with the number of multiplexed gRNAs and that, with four multiplexed gRNAs, a mosquito species could potentially be suppressed on a continental scale. We also demonstrate successful proof-of-principle use of multiplexed ribozyme flanked gRNAs to induce mutations in vivo in Drosophila melanogaster – a strategy that could readily be adapted to engineer stable, homing-based drives in relevant organisms.
Héctor Manuel Sánchez Castellanos
added a research item
The recent discovery of CRISPR-Cas9 and its use in gene drive systems has sparked global interest in their use to control the spread of mosquito-borne pathogens. In particular, the discovery of the Mutagenic Chain Reaction (MCR), which ensures homozygous inheritance of a desired homing allele, has rendered gene drive as a viable technology. However, the dynamics of gene drive in realistic ecological settings is not well understood. Many in silico experiments involving gene drive simulations consider mosquito populations to be a single, well-mixed population over some area of interest. Other experiments attempt to make generalizations about gene drive dynamics without considering how features of the habitat distribution used in the experiments may have affected the outcome. Therefore, it is currently unclear how spatial variation in mosquito habitat distributions affects the dynamics of gene drive. Yet, this understanding is vital to gene drive's feasibility as an eradication tool. In this work, we analyze the relationship between habitat clustering and homing drive fixation in an Aedes aegypti mosquito population. Using the Area Interaction Point Process, simulated habitat distributions with varying degrees of clustering were generated. A CRISPR-Cas9 Mutagenic Chain Reaction gene drive system was simulated on each landscape over three years simulation time. The results showed that relationship between habitat clustering and homing drive fixation is likely to be quadratic, with certain highly clustered habitat distributions behaving similarly to habitat distributions where the habitats repulse one another. Our findings suggest that landscapes most amenable to fixation of the homing allele are those with homogeneous distribution of mosquito habitats. These experiments enabled us to develop the first methodology for analyzing the relationship between landscape heterogeneity and homing allele fixation in a quantitative way. In particular, it shows that landscape heterogeneity cannot be ignored in evaluating the likelihood of success of a gene drive system.
Héctor Manuel Sánchez Castellanos
added 2 research items
Presentation of our work: "Confinement and reversibility of threshold-dependent gene drive systems in spatially-explicit Aedes aegypti populations" (https://www.researchgate.net/publication/332380657_Confinement_and_reversibility_of_threshold-dependent_gene_drive_systems_in_spatially-explicit_Aedes_aegypti_populations); as part of the DARPA: "Safe Genes" project.
Héctor Manuel Sánchez Castellanos
added a research item
The discovery of CRISPR-based gene editing and its application to homing-based gene drive systems has been greeted with excitement, for its potential to control mosquito-borne diseases on a wide scale, and concern, for the invasiveness and potential irreversibility of a release. Gene drive systems that display threshold-dependent behavior could potentially be used during the trial phase of this technology, or when localized control is otherwise desired, as simple models predict them to: a) effectively spread into partially isolated populations in a confineable manner, and b) be reversible through releases of wild-type organisms. Here, we model hypothetical releases of two recently-engineered threshold-dependent gene drive systems - reciprocal chromosomal translocations and a form of toxin-antidote-based underdominance known as UDMEL - to explore their ability to be confined and remediated. We simulate releases of Aedes aegypti, the mosquito vector of dengue, Zika and other arboviruses, in Yorkeys Knob, a suburb of Cairns, Australia, where previous biological control interventions have been undertaken on this species. We monitor spread to the neighboring suburb of Trinity Park, to assess confinement. Our results suggest that translocations could be introduced on a suburban scale, and remediated through releases of non-disease-transmitting male mosquitoes with release sizes on the scale of what has been previously implemented. UDMEL requires fewer releases to introduce, but more releases to remediate, including of females capable of disease transmission. Both systems are expected to be confineable to the release site; however, spillover of translocations into neighboring populations is less likely. https://youtu.be/lNcIHcJYI_0
Héctor Manuel Sánchez Castellanos
added a research item
In this work, we present our framework with applications to various novel gene-drive systems such as: reciprocal chromosomal translocations, toxin-antidote-based underdominant systems. In doing so, we show how our model can be used to answer relevant questions in the field of mosquito-borne diseases elimination, such as: how to make fair comparisons of gene drive constructs, how can we predict the spread/confinement of our genotypes, and how we can measure the impact of our interventions in the presence of realistic spatial interactions. https://chipdelmal.github.io/MGDrivE_Presentations/CompBio2018/#/
Héctor Manuel Sánchez Castellanos
added a research item
Malaria, dengue, Zika, and other mosquito-borne diseases continue to pose a major global health burden through much of the world. The advent of CRISPR/Cas9-based gene editing and its demonstrated ability to streamline the development of gene drive systems has reignited interest in the application of this technology to the control of mosquitoes and the diseases they transmit. The versatility of CRISPR technology has also enabled a wide range of gene drive architectures to be realized, creating a need for their population-level and spatial dynamics to be explored. To this end, we present MGDrivE (Mosquito Gene Drive Explorer): a simulation framework designed to investigate the population dynamics of a variety of gene drive architectures and their spread through spatially-explicit mosquito populations. A key strength of the MGDrivE modeling framework is its modularity: a) a genetic inheritance module accommodates the dynamics of gene drive systems displaying user-defined inheritance patterns, b) a population dynamic module accommodates the life history of a variety of mosquito disease vectors, and c) a landscape module accommodates the distribution of mosquito metapopulations connected by migration in space. To demonstrate the functionality of the software package, we present example MGDrivE simulations for threshold-dependent drive systems: a) reciprocal chromosomal translocations, and b) toxin-antidote-based underdominant systems. These systems are particularly suited to field trials and other local releases as they are expected to: a) spread at their release site following an intentional release, b) only spread to low levels in neighboring populations, and c) be eliminated through dilution with wild-type organisms. Using the MGDrivE framework and metrics from network theory, we describe design criteria for these systems. In closing, we describe other systems to which the MGDrivE framework applies, and future directions for its development.
Héctor Manuel Sánchez Castellanos
added a research item
In this work, we present MGDrivE with example applications to threshold-dependent drives (reciprocal chromosomal translocations and toxin-antidote-based underdominant systems). We show how the timing of the releases can be optimized for the drives to fixate in the population with a minimum cost, and how this information can be applied to simulate releases in a specific town in Australia where other similar mosquito-borne diseases control interventions have been studied in the past.
Héctor Manuel Sánchez Castellanos
added a research item
Malaria, dengue, Zika, and other mosquito-borne diseases continue to pose a major global health burden through much of the world, despite the widespread distribution of insecticide-based tools and antimalarial drugs. The advent of CRISPR/Cas9-based gene editing and its demonstrated ability to streamline the development of gene drive systems has reignited interest in the application of this technology to the control of mosquitoes and the diseases they transmit. The versatility of this technology has also enabled a wide range of gene drive architectures to be realized, creating a need for their population-level and spatial dynamics to be explored. To this end, we present MGDrivE (Mosquito Gene Drive Explorer): a simulation framework designed to investigate the population dynamics of a variety of gene drive architectures and their spread through spatially-explicit mosquito populations. A key strength of the MGDrivE framework is its modularity: a) a genetic inheritance module accommodates the dynamics of gene drive systems displaying user-defined inheritance patterns, b) a population dynamic module accommodates the life history of a variety of mosquito disease vectors and insect agricultural pest species, and c) a landscape module accommodates the distribution of insect metapopulations connected by migration in space. Example MGDrivE simulations are presented to demonstrate the application of the framework to CRISPR/Cas9-based homing gene drive for: a) driving a disease-refractory gene into a population (i.e. population replacement), and b) disrupting a gene required for female fertility (i.e. population suppression), incorporating homing-resistant alleles in both cases. We compare MGDrivE with other genetic simulation packages, and conclude with a discussion of future directions in gene drive modeling.
Héctor Manuel Sánchez Castellanos
added 4 research items
Our goal for each of these species is to use mathematical models to determine optimal CRISPR-Cas9-based gene drive architectures that could be successful in controlling their agricultural impact while ensuring biosafety through the ability to remediate them from the environment in the event of negative consequences or a change in public opinion.
Mosquito-borne diseases, such as dengue, Zika, chikungunya, and yellow fever, pose significant health problems in tropical regions of the world. Control of the main vector for these diseases, the Aedes aegypti mosquito, remains elusive despite extensive efforts using traditional vector control interventions. Recent development in gene-drive technologies provide complementary control methods for population reduction or immunization against disease transmission. However, questions about fixation within a population, confinement (containing a gene-drive in the designated population), and remediation (removing the gene-drive from a population after introduction), remain to be answered. Using a class-based, spatially-explicit model (MGDrivE), we explored the fixation, confinement, and remediation characteristics of two traditional gene-drives; translocations and UDmel. Our network represents two abstract, neighboring cities, where we tested male-only releases for fixation (complete replacement of the wild-type mosquito population within a city), confinement (amount of spillover into the second city), and remediation (complete removal of gene-drive mosquitoes from both populations). Videos Playlist: https://www.youtube.com/playlist?list=PLRzY6w7pvIWqKYnJno8xGCOrPNDQBlvQE
Recent developments of CRISPR-Cas9 based homing endonuclease gene drive systems for the suppression or replacement of mosquito populations have generated much interest in their use for control of mosquito-borne diseases (such as dengue, malaria, chikungunya and Zika). This is because genetic control of pathogen transmission may complement or even substitute traditional vector-control interventions, which have had limited success in bringing the spread of these diseases to a halt. Despite excitement for the use of gene drives for mosquito control, current modeling efforts have analyzed only a handful of these new approaches (usually studying just one per framework). Moreover, these models usually consider well-mixed populations with no explicit spatial dynamics. To this end, we are developing MGDrivE (Mosquito Gene DRIVe Explorer), in cooperation with the ``UCI Malaria Elimination Initiative’’, as a flexible modeling framework to evaluate a variety of drive systems in spatial networks of mosquito populations. This framework provides a reliable testbed to evaluate and optimize the efficacy of gene drive mosquito releases. What separates MGDrivE from other models is the incorporation of mathematical and computational mechanisms to simulate a wide array of inheritance-based technologies within the same, coherent set of equations. We do this by treating the population dynamics, genetic inheritance operations, and migration between habitats as separate processes coupled together through the use of mathematical tensor operations. This way we can conveniently swap inheritance patterns whilst still making use of the same set of population dynamics equations. This is a crucial advantage of our system, as it allows other research groups to test their ideas without developing new models and without the need to spend time adapting other frameworks to suit their needs. Full presentation available at: https://chipdelmal.github.io/MGDrivE/Documents/NCCB_MGDrivE/#/
Héctor Manuel Sánchez Castellanos
added a project goal
Creating a flexible and comprehensive framework in which gene-drive releases can be simulated and assessed.