MGDrivE: A modular simulation framework for the spread of gene drives through spatially-explicit mosquito populations

Sanchez, Corinne; Wu, Sean L.; Bennett, Jared B.; Marshall, John M.

doi:10.1101/350488

Cited by 30 publications

(37 citation statements)

References 53 publications

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“…The above mentioned theoretical approximation of the conditions for Wolbachia initiation and spread [61] assumes isotropic dispersal in a 2-dimensional habitat. Optimal release strategy for the Sterile Insect Technique programs [62], different suppression and replacement strategies [63,64], the effect of larval habitat fragmentation on population crash [65], and confinement and reversibility conditions for threshold-dependent gene drive systems [10] have all been simulated in the spatially explicit models of mosquito populations that applied the exponential dispersal kernel in a 2-dimensional landscape. The approximation of the parametrized dispersal kernel for high-rise landscapes could be achieved by considering the releases of mosquitoes from multiple floors rather than from the ground level only.…”

Section: Discussionmentioning

confidence: 99%

Using spatial genetics to quantify mosquito dispersal for control programs

Filipović

Hapuarachchi

Tien

et al. 2020

Preprint

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Background: Hundreds of millions of people get a mosquito-borne disease every year, of which nearly one million die. Mosquito-borne diseases are primarily controlled and mitigated through the control of mosquito vectors. Accurately quantified mosquito dispersal in a given landscape is critical for the design and optimization of the control programs, yet the field experiments that measure dispersal of mosquitoes recaptured at certain distances from the release point (markrelease-recapture MRR studies) are challenging for such small insects and often unrepresentative of the insect's true field behavior. Using Singapore as a study site, we show how mosquito dispersal patterns can be characterized from the spatial analyses of genetic relatedness among individuals sampled over a short time span without interruption of their natural behaviors. Methods and Findings:We captured ovipositing females of Aedes aegypti, a major arboviral disease vector, across floors of high-rise apartment blocks and genotyped them using thousands of genome-wide SNP markers. We developed a methodology that produces a dispersal kernel for distance that results from one generation of successful breeding (effective dispersal), using the distances separating full siblings, 2 nd and 3 rd degree relatives (close kin). In Singapore, the estimated dispersal distance kernel was exponential (Laplacian), giving the mean effective dispersal distance (and dispersal kernel spread σ) of 45.2 m (95%CI: 39.7-51.3 m), and 10% probability of dispersal >100 m (95%CI: 92-117 m). Our genetic-based estimates matched the parametrized dispersal kernels from the previously reported MRR experiments. If few close-kin are captured, a conventional genetic isolation-by-distance analysis can be used, and we show that it can produce σ estimates congruent with the close-kin method, conditioned on the accurate estimation of effective population density. We also show that genetic patch size, estimated with the spatial autocorrelation analysis, reflects the spatial extent of the dispersal kernel 'tail' that influences e.g. predictions of critical radii of release zones and Wolbachia wave speed in mosquito replacement programs. Conclusions:We demonstrate that spatial genetics (the newly developed close-kin analysis, and conventional IBD and spatial autocorrelation analyses) can provide a detailed and robust characterization of mosquito dispersal that can guide operational vector control decisions. With the decreasing cost of next generation sequencing, acquisition of spatial genetic data will become increasingly accessible, and given the complexities and criticisms of conventional MRR methods, but the central role of dispersal measures in vector control programs, we recommend genetic-based dispersal characterization as the more desirable means of parameterization.

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Section: Discussionmentioning

confidence: 99%

Using spatial genetics to quantify mosquito dispersal for control programs

Filipović

Hapuarachchi

Tien

et al. 2020

Preprint

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“…To model the expected performance of a split-drive functioning as a confinable and reversible gene-drive system and as a test system prior to the release of a linked homing drive for Ae. aegypti, we simulated release schemes for split-drive, linked homing drive, and inundative releases of males carrying a refractory allele using the MGDrivE simulation framework (79) (https://marshalllab.github.io/MGDrivE/). This framework models the egg, larval, pupal, and adult mosquito life stages (both male and female adults are modeled) implementing a daily time step, overlapping generations, and a mating structure in which adult males mate throughout their lifetime while adult females mate once upon emergence, retaining the genetic material of the adult male with whom they mate for the duration of their adult lifespan.…”

Section: Mathematical Modelingmentioning

confidence: 99%

“…Releases are carried out in a population with an equilibrium size of 10,000 adults that exchanges migrants with a neighboring population of the same equilibrium size at a rate of 1% per mosquito per generation. Model predictions were computed using 100 realizations of the stochastic implementation of the MGDrivE simulation framework (79). Weekly releases of 10,000 males homozygous for the split-drive system or disease-refractory gene were carried out over a 10 week period, while a single release was carried out for the linked homing drive system.…”

Section: Fig S9 Allele Frequencies For Best Performing Split-drive mentioning

confidence: 99%

Development of a Confinable Gene-Drive System in the Human Disease Vector,Aedes aegypti

Li¹,

Yang²,

Kandul³

et al. 2019

Preprint

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Aedes aegypti, the principal mosquito vector for many arboviruses that causes yellow fever, dengue, Zika, and chikungunya, increasingly infects millions of people every year. With an escalating burden of infections and the relative failure of traditional control methods, the development of innovative control measures has become of paramount importance. The use of gene drives has recently sparked significant enthusiasm for the genetic control of mosquito populations, however no such system has been developed in Ae. aegypti. To fill this void and demonstrate efficacy in Ae. aegypti, here we develop several CRISPR-based split-gene drives for use in this vector. With cleavage rates up to 100% and transmission rates as high as 94%, 2 mathematical models predict that these systems could spread anti-pathogen effector genes into wild Ae. aegypti populations in a safe, confinable and reversible manner appropriate for field trials and effective for controlling disease. These findings could expedite the development of effectorlinked gene drives that could safely control wild populations of Ae. aegypti to combat local pathogen transmission. Significance StatementAe. aegypti is a globally distributed arbovirus vector spreading deadly pathogens to millions of people annually. Current control methods are inadequate and therefore new technologies need to be innovated and implemented. With the aim of providing new tools for controlling this pest, here we engineered and tested several split gene drives in this species. These drives functioned at very high efficiency and may provide a tool to fill the void in controlling this vector. Taken together, our results provide compelling path forward for the feasibility of future effector-linked split-drive technologies that can contribute to the safe, sustained control and potentially the elimination of pathogens transmitted by this species.

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“…We modeled releases of Aedes aegypti, the mosquito vector of dengue, Zika, and chikungunya viruses, and simulated five weekly releases of 100 adult males homozygous for each system into a population with an equilibrium size of 10,000 adults. Model predictions were computed using 50 realizations of the stochastic implementation of the MGDrivE simulation framework 38 .…”

Section: Mathematical Modeling Predicts Tgd Alleles Would Collectivelmentioning

confidence: 99%

Split-gene drive system provides flexible application for safe laboratory investigation and potential field deployment

Amo

Bishop

C.³

et al. 2019

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CRISPR-based gene drives spread through populations bypassing the dictates of Mendelian genetics, offering a population-engineering tool for tackling vector-borne diseases, managing crop pests, and helping island conservation efforts; unfortunately, current technologies raise safety concerns for unintended gene propagation. Herein, we address this by splitting the two drive components, Cas9 and gRNAs, into separate alleles to form a novel trans-complementing split-genedrive (tGD) and demonstrate its ability to promote super-Mendelian inheritance of the separate transgenes. This bi-component nature allows for individual transgene optimization and increases safety by restricting escape concerns to experimentation windows. We employ the tGD and a smallmolecule-controlled version to investigate the biology of component inheritance and use our system to study the maternal effects on CRISPR inheritance, impaired homology on efficiency, and resistant allele formation. Lastly, mathematical modeling of tGD spread in a population shows potential advantages for improving current gene-drive technologies for field population modification. Figure 1 -The trans-complementing gene-drive system (tGD) features simultaneous super-Mendelian inheritance of two transgenes.(A) Schematic of the tGD genetic arrangement with two elements that can be kept separated as different transgenic lines. The Cas9 transgene is inserted in the genomic location targeted by the gRNA-A, while a separate cassette expressing a tandem gRNA construct (gRNA-A, gRNA-B) is inserted at the location targeted by gRNA-B. Upon genetic cross, each gRNA combines with Cas9 to generate a double-strand DNA break at each locus on the wild-type allele. Each break is then repaired by homology-directed repair (HDR) pathway using the intact chromosome carrying the transgene as a template. (B) Outline of the genetic cross used to demonstrate tGD in fruit flies. F0 males carrying a DsRed-marked Cas9 transgene inserted in the yellow locus were crossed to females carrying a GFP-marked cassette containing two gRNAs (y1-e1) inserted in the ebony coding sequence. Trans-heterozygous F1 females (carrying both Cas9 and gRNAs) were crossed to wild-type males to assess germline transmission rates of the fluorophores marking the transgenes in the F2 progeny. The conversion event is indicated by the red and green triangles in the F1 females (C) Single F1 female germline inheritance output measured as GFP and DsRed marker presence in the F2 progeny. The black bar represents the inheritance average. The blue shading represents the deviation from the expected 50% "Mendelian" inheritance. Inheritance average, standard deviation, number of samples (n) and total number of flies scored in each experiment are represented over the graph in line with the respective data.

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MGDrivE: A modular simulation framework for the spread of gene drives through spatially-explicit mosquito populations

Cited by 30 publications

References 53 publications

Using spatial genetics to quantify mosquito dispersal for control programs

Using spatial genetics to quantify mosquito dispersal for control programs

Development of a Confinable Gene-Drive System in the Human Disease Vector,Aedes aegypti

Split-gene drive system provides flexible application for safe laboratory investigation and potential field deployment

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