Keywords: Modeling
Modelling Aedes albopictus management, incorporating immigration and bi-directional Wolbachia interactions
35520Ryan, M., Mendiolar, M., Pagendam, D. et al., J Pest Sci, 99. 2026-03-10 09:16:51.
Aedes albopictus mosquitoes are competent vectors for the spread of at least 24 different arboviruses, including dengue, Ross River, and Japanese encephalitis viruses. However, they remain less studied than their more urban cousins, Aedes aegypti. We model an incompatible insect technique (IIT) strategy for mosquito control, with bi-directional incompatibility between two strains of Wolbachia (wAlbA/wAlbB ARwP) and age-based cytoplasmic incompatibility decay in a well-mixed population. We include mosquito immigration to explore potential reversibility, an important consideration in bi-directional IIT control programs. We also explore the establishment probability after female contamination of an artificially-infected Wolbachia mosquito strain, consider the suppression dynamics and probability of mosquito management success for different release strategies, and determine a corresponding cost proxy for release (numbers of mosquitoes released). We found an establishment probability threshold of 40% in the absence of mating preferences, though this threshold needs validation in future field and laboratory experiments. We found differences in suppression success between release cessation and 6 months later for different immigration rates. There are similar short-term costs with differences in medium- and longer-term costs between release strategies. Our model suggests bi-directional IIT control programs are reversible with low amounts of wild-type immigration. This work demonstrates opportunities to optimise the suppression of these medically important mosquitoes.
Optimal spatial release strategies for confined gene drives and Wolbachia
35488Ziye Wang, Jackson Champer, bioRxiv, 2026-03-06 10:19:13.
Gene drives are genetic elements that can rapidly spread through populations, offering potential solutions for controlling disease vectors and pests. In some scenarios, it is necessary to utilize drives that can be confined to only target populations. The success of these threshold-dependent gene drives, which require a minimum local frequency to establish, depends critically on the spatial strategy used for introduction. Here, we use a reaction-diffusion model to systematically identify optimal release patterns that maximize the per-capita efficiency for four distinct gene drive designs as well as use of Wolbachia bacteria, which spread similarly to frequency-dependent gene drives. We find that the most efficient release strategy is highly dynamic, transitioning from a broad "everywhere" release for short timeframes to a "multiple-ring" pattern for intermediate times, and finally to a focused "center" release for longer timeframes. These timeframes depend on the specific type of drive, with more powerful variants transitioning more quickly to center releases. Our results demonstrate that these optimized, variable release strategies can be substantially more effective than simple uniform releases. This study provides a quantitative framework for designing effective gene drive implementations, highlighting that a carefully planned spatial strategy is essential for maximizing impact, making optimal use of available resources.
Stochastic dynamics at the back of a gene drive eradication wave
35468Léna Kläy, Léo Girardin, Florence Débarre, Vincent Calvez, Theoretical Population Biology, 168:44-64. 2026-02-24 14:22:40.
Gene drive alleles bias their own inheritance to offspring. They can fix in a wild-type population in spite of a fitness cost, and even lead to the eradication of the target population if the fitness cost is high. However, this outcome may be prevented or delayed if areas previously cleared by the drive are recolonised by wild-type individuals. Here, we investigate the conditions under which these stochastic wild-type recolonisation events are likely and when they are unlikely to occur in one spatial dimension. More precisely, we examine the conditions ensuring that the last individual carrying a wild-type allele is surrounded by a large enough number of drive homozygous individuals, resulting in a very low chance of wild-type recolonisation. To do so, we make a deterministic approximation of the distribution of drive alleles within the wave, and we split the distribution of wild-type alleles into a deterministic part and a stochastic part. Our analytical and numerical results suggest that the probability of wild-type recolonisation events increases with lower fitness of drive individuals and with smaller local carrying capacity. Numerical simulations show that these results extend to two spatial dimensions. The role of the migration rate however, is less clear but has a lower impact. We further demonstrate that, in the event of wild-type recolonisation, the probability of subsequent drive reinvasion decreases with smaller values of the intrinsic growth rate of the population. Overall, our study paves the way for further analysis of wild-type recolonisation at the back of eradication travelling waves.
Spatial confinement of gene drives: Assessing risk of failure using global sensitivity analysis
35459Cole D. Butler, Alun L. Lloyd, bioRxiv, 2026-02-19 09:59:30.
Gene drives allow pest populations to be genetically modified to reduce their harm on agriculture and human health. The genetic modification, or payload, spreads within a target population at rates exceeding normal Mendelian inheritance. While gene drives have demonstrated immense potential in laboratory populations, they present unique challenges. Foremost among these challenges is spatial confinement, or ensuring that the payload remains confined to target populations. However, there is an inherent tension between gene drive spread and spatial confinement: increasing the spreading efficiency of a gene drive increases the risk of escape, while engineering confinement mechanisms increases the risk of gene drive extinction. In this work, we explore spatial outcomes in gene drives designed for spatial confinement and the dependence of these outcomes on target organism dispersal and payload fitness cost. We use a stochastic spatial model to compute the probability of failure for each gene drive, and use techniques from global sensitivity analysis to quantify the contribution of dispersal and fitness cost to variance in gene drive performance. Our findings reveal how spatial outcomes are affected by key parameters, and how this sensitivity varies tremendously between different gene drives. These spatial properties can be used to classify gene drive behavior and are useful to determine suitability for a particular application.
Mathematical modelling of Wolbachia replacement in Aedes aegypti for dengue control: a scoping review
35445Katie Tiley, Laith Yakob, Kathleen O'Reilly, Oliver Brady, Proc Biol Sci, 293. 2026-02-12 17:52:03.
Wolbachia replacement in dengue virus vectors is a promising tool for controlling transmission, and models can explore its potential in novel and complex scenarios. We analyse how research questions in Wolbachia replacement modelling have developed over time and in response to empirical findings. A scoping review was conducted of Wolbachia replacement models. For each study, we extracted research questions, key findings and modelling methodology and thematically categorized research questions. From 726 search results, 115 studies met inclusion criteria. Four themes were identified: identifying key Wolbachia characteristics (n = 61, 53.0%), investigating effects of environmental heterogeneity (n = 21, 18.3%), estimating epidemiological impact (n = 25, 21.7%) and exploring Wolbachia replacement in combination with other arboviral control measures (n = 8, 7.0%). Models identify cytoplasmic incompatibility (CI) and maternal transmission (MT) as key for fixation success. However, less than 20% (n = 6) of studies parameterize CI and MT using empirical sources. Although models agree outbreaks may occur with fixation, few explore epidemiological outcomes of heterogeneous Wolbachia fixation or combined vector control. These findings highlight the need for empirical parameterization and incorporating environmental complexity for models to remain insightful for decision-making. Policymakers would benefit from future models exploring heterogeneous coverage and combined control strategies, given evidence of context-specific outcomes and diverse control tools.
Mapping Gene Drive Dynamics onto Mendelian Models
35414Zihang Wen, Monica Wan, Gili Greenbaum, Oana Carja, bioRxiv, 2026-01-30 16:46:40.
CRISPR-based gene drives bias their own transmission and can spread even when deleterious, giving rise to evolutionary dynamics that can be substantially more complex than those governed by standard Mendelian inheritance. Identifying conditions under which gene-drive dynamics can be faithfully approximated by Mendelian models would therefore enable the extensive theoretical toolkit of classical population genetics to be applied to gene-drive systems. Here, we develop a general mapping framework that translates gene-drive models into dynamically equivalent Mendelian models, allowing their behavior to be analyzed using classical theory. By deriving both haploid and diploid effective-parameter mappings, we identify Mendelian models that closely reproduce allele-frequency trajectories of gene drives across a wide range of conversion rates, fitness costs, and dominance effects. We delineate the regions of the parameter space where a one-parameter haploid approximation provides an accurate first-order representation, and where incorporating dominance in a diploid mapping substantially improves fidelity and recovers internal equilibria and threshold behavior. Analytic approximations yield efficient mappings across most of the drive parameter space, while a trajectory-based grid search further improves accuracy near nonlinear regime boundaries. To demonstrate the utility of this framework, we apply it to predicting gene swamping in a two-deme migration-selection model and show that the mapped Mendelian system accurately forecasts transitions between fixation and loss under three relevant release scenarios: environmental variation in fitness, engineered fitness asymmetries, and environment-dependent conversion. Together, these results establish a theoretical bridge between non-Mendelian gene drives and classical population genetic models, providing an interpretable and computationally efficient foundation for predicting gene-drive outcomes and guiding the design of gene drive systems and deployment strategies.
Genetic Allee Effects for Controlling Invasive Populations
35313Louis Nowell Nicolle, Alex Fournier-Level, Charles Robin, et al., Molecular Ecology, 2026-01-02 10:37:23.
Invasive pests threaten food security and devastate ecosystems. A universal problem in their management is that small populations can easily evade detection. This makes identifying new incursions challenging and complicates efforts to eradicate or contain established populations. If newly founded populations exhibited a strong Allee effect, small populations would tend towards extinction and most new incursions would go extinct without the need for detection or intervention. Of course, invasive species rarely exhibit strong Allee effects, but new genetic technologies make it conceivable to impose one. Here we consider how introduction of genetic load can cause a genetic Allee effect that reduces the establishment probability of small founder populations. Using numerical and individual-based modelling, we examine the fate of populations sampled from a larger invasive source population carrying deleterious recessive alleles. Our analysis reveals that the genetic load unmasked by founding can dramatically reduce the establishment probability of small populations across a wide range of parameter space. A sterile mutation effect is more effective than a lethal mutation effect, but X-linkage offers minimal benefit over autosomal inheritance. Although extinction of newly founded populations is a common outcome, it may be challenging to achieve in species with very high reproductive outputs. Distributing deleterious recessive alleles across a large number of loci at low frequencies was more effective than distributing them across fewer loci at higher frequencies. Our findings suggest that driving deleterious recessives into a source population may render it less prone to establish in new areas.
Analysis of a household-scale model for the invasion of Wolbachia into a resident mosquito population
35327Barlow, A., Penington, S. & Adams, B., Journal of Mathematical Biology, 92. 2025-12-22 12:18:25.
In areas infested with Aedes aegypti mosquitoes it may be possible to control dengue, and some other vector-borne diseases, by introducing Wolbachia-infected mosquitoes into the wildtype population. Thus far, empirical and theoretical studies of Wolbachia release have tended to focus on the dynamics at the community scale. However, Ae. aegypti mosquitoes typically dwell in and around the same houses as the people they bite and it can be insightful to explore what happens at the household scale where small population sizes lead to inherently stochastic dynamics. Here we use a continuous-time Markov framework to develop a stochastic household model for small populations of wildtype and Wolbachia-infected mosquitoes. We investigate the transient and long term dynamics of the system, in particular examining the impact of stochasticity on the Wolbachia invasion threshold and bistability between the wildtype-only and Wolbachia-only steady states previously observed in deterministic models. We focus on the influence of key parameters which determine the fitness cost of Wolbachia infection and the probability of Wolbachia vertical transmission. Using Markov and matrix population theory, we derive salient characteristics of the system including the probability of successful Wolbachia invasion, the expected time until invasion and the probability that a Wolbachia-infected population reverts to a wildtype population. These attributes can inform strategies for the release of Wolbachia-infected mosquitoes. In addition, we find that releasing the minimum number of Wolbachia-infected mosquitoes required to displace a resident wildtype population according to the deterministic model, only results in that outcome about 20% of the time in the stochastic model; a significantly larger release is required to reach a steady state composed entirely of Wolbachia-infected mosquitoes 90% of the time.
Improving Wolbachia-based control programs in urban settings: Insights from spatial modeling
35335Florez D, Cortez R, Hyman JM, Qu Z, PLoS Neglected Tropical Diseases, 19. 2025-12-12 11:08:20.
Arboviral diseases remain a major public health concern, particularly in tropical and subtropical regions where mosquito populations thrive. One promising strategy to curb transmission is the release of Aedes aegypti mosquitoes infected with Wolbachia, a bacterium that reduces their ability to spread viruses. However, past large-scale releases have not always been successful, especially in complex urban settings, where restricted access to certain areas often leads to infection establishment failures and wasted resources. To address this, we developed a spatial model that simulates how Wolbachia-infected mosquitoes are established in different urban environments. We also explored strategies to improve their success under constraints on release size and the efficacy level of insecticide used for pre-release interventions. Our findings suggest that targeted releases are most effective in areas with limited mosquito movement without additional insecticide use. In higher-dispersal areas, reducing at least 35% of wild mosquitoes before release significantly improves establishment within nine months. Additionally, distributing releases over 2-5 weekly batches enhances success more than a single large release, even without other interventions. These findings offer practical insights for designing cost-effective and efficient Wolbachia-based mosquito control programs, reducing the burden of mosquito-borne diseases on vulnerable communities.
Integrating mosquito genomics into simulation modeling: Opportunities for better-informed biocontrol
35282Gordana Rašić, John M. Marshall, Current Opinion in Insect Science, 2025-11-03 11:25:51.
Mosquito-borne diseases remain a major global health burden, and novel biocontrol tools are quickly advancing from the laboratory to the field. Mathematical models play a central role in evaluating these interventions, yet their predictive accuracy depends on robust parameterization. Population genomics presents a powerful opportunity to address this challenge. Here, we review progress at the interface between mosquito genomics and biocontrol modeling, highlighting how genomic data have informed our understanding of mosquito population structure, standing genetic variation at gene drive target sites, and sources of resurgence for suppressed populations. We also discuss frontiers, including new approaches to quantifying gene flow, mating behaviors, and inbreeding depression, all of which shape intervention outcomes. By tapping this potential to better quantify our understanding of mosquito ecology, modelers can develop context-specific models with better predictive accuracy, supporting efficacy and risk assessment, design of field trials and interventions, and promotion of regulation and public trust.
A male-drive female-sterile system for the self-limited control of the malaria mosquito Anopheles gambiae
35261Strampelli, A., Willis, K., Gulliford, H.R. et al., Nature Communications, 16. 2025-10-28 08:43:17.
Despite great leaps forward in preventing and treating malaria, several challenges, including insecticide resistance, have hindered progress in fighting the disease. Thus, there is a pressing need for new tools to control malaria, including the use of genetically modified mosquitoes (GMMs) in the field. Various genetic strategies for vector control are currently explored, ranging from self-sustaining GMMs with unrestricted geographic and temporal spread to self-limiting alternatives. Here, we describe a self-limiting gene drive strategy called Male Drive Female Sterile (MDFS) targeting Anopheles gambiae, a major malaria vector. The MDFS genetic construct causes dominant sterility in females, while transgenic males remain fertile, allowing them to transmit the female sterility trait at super-Mendelian rates. Laboratory studies show that repeated releases of MDFS can lead to elimination of caged mosquito populations. Based on these findings, modelling suggests MDFS could be a highly effective and self-limiting strategy for suppressing wild malaria mosquito populations.
Intermittent releases: a modelling approach for sterile insect technique in mosquito control
35255Bhattacharyya, J., Banerjee, M. & Banerjee, S, Journal of Mathematical Biology, 91. 2025-10-27 10:49:16.
An unconventional and environmentally friendly mosquito management approach offers a sustainable solution that protects both the environment and human health. One such method is the Sterile Insect Technique (SIT), which holds promise as a mosquito control strategy by releasing sterilized male mosquitoes into the wild-type (WT) mosquito population. Since the success of SIT depends on the strategic planning of sterile mosquito releases, this paper examines a stage-structured model for mosquito populations with a density-dependent threshold for sterile male mosquito release, where releases occur only when the ratio of WT to sterile mosquito populations exceeds a critical threshold. Using intermittent releases, the proposed SIT model is designed to optimally align the release of sterile male mosquitoes with WT and sterile mosquito population densities, maintaining WT mosquito suppression at a predefined threshold and offering a more effective alternative to continuous release strategies. We employ Filippov’s modelling approach to investigate how intermittent releases, represented by piecewise-smooth functions, affect the dynamics of the system, particularly when mosquito populations exceed the predefined threshold. To explore the dynamical complexities, we employ Filippov’s convex method by defining the vector field in the discontinuous region as convex combinations of adjacent fields, allowing for the analysis of sliding motion and the identification of discontinuity-induced bifurcations through differential inclusions. Our findings identify the minimum release rate of sterile mosquitoes required to achieve the desired suppression level, highlighting the need to increase this rate due to increased WT mosquito immigration, reduced survival and mating fitness of sterile mosquitoes, and limitations in mosquito surveillance accuracy.
Estimated cost and operational structure of pgSIT malaria vector control programs in selected West African countries
35203William A.C. Gendron, Robyn Raban, Agastya Mondal, et al., Scientific African, 29. 2025-09-30 15:35:38.
Malaria control has primarily been achieved through vector control, but current methods are insufficient to achieve elimination. Precision guided sterile insect technique (pgSIT) is a mosquito suppression technique that generates sterile male mosquitoes for mass release. Our previous studies showed that this intervention is expected to be highly cost-effective in a malaria endemic region of West Africa, but these estimates used only 15-31% capacity for sex sorting, which is the limiting production step and a primary cost. We, therefore, determined the most cost efficient facility size by calculating the cost per million Anopheles gambiae suppressed as the facility was scaled up to suppress more mosquitoes. We developed an optimized facility size per 9.2 million mosquitoes suppressed, which can be a framework for scaling and increases the cost effectiveness of this intervention. The development of this intervention can potentially interrupt malaria transmission, strengthen local public health institutions, create manufacturing capacity, provide local jobs, and enhance regional health security capabilities that are more resilient to disruptions in supply chains and malaria investment.
Experimental demonstration of daisy chain gene drive and modelling of daisy suppression systems
35147Jialiang Guo, Weizhe Chen, Jackson Champer, bioRxiv, 2025-09-22 10:06:58.
CRISPR-based gene drive can address ecological problems by biased inheritance coupled with an effector for either population modification of suppression. However, the potential risk of uncontrolled spread impedes some applications of gene drive. Daisy chain gene drives have received much attention as a potential approach to overcome this problem. They potentially allow the efficient spread of drive elements in a target population, but are ultimately self-limiting. This is achieved by splitting a normal gene drive system into multiple dependent drive elements, where each element can bias the inheritance of another, except one non-driving element. With the successive loss of each chain link, the spread of transgenic elements will slow down and eventually stop. Here, we use modelling to assess the population dynamics of daisy chain drives in both panmictic and continuous space models, focusing on suppression systems. We find that achieving population elimination through a single release of daisy chain gene drives is possible but difficult, with relatively high requirements for drive performance and release size. These effects are substantially amplified in spatial models. We also constructed two configurations of daisy chain gene drives in Drosophila melanogaster as a proof-of-principle. One is a rescue drive for population modification, and the other aims for population suppression by targeting a haplosufficient female fertility gene. These drives all functioned within expectations at moderate efficiency in individual crosses. However, the drive design failed to spread in cage populations because of higher than expected fitness costs. Overall, our study demonstrates that daisy chain systems may be promising candidates for both modification and suppression, but challenges remain in both construction and potential deployment in large regions.
Natural Selection of Synthetic Gene Drives for Population Suppression Can Favor an Intermediate Strength of Drive
35141P. J. Beaghton and Austin Burt, The American Naturalist, 206. 2025-09-16 15:55:03.
Synthetic gene drives are being investigated as tools to suppress pest populations, and it is important to understand how natural selection will act on variant drivers that may either arise by de novo mutation or be intentionally released. In this study, we extend previous spatially implicit stochastic models to examine the evolutionary dynamics of synthetic driving Y chromosomes in patchy environments when population size is responding dynamically to the spread of the driver and derive conditions for the existence of an evolutionarily stable strategy (ESS) for drive strength. Under broad conditions, an intermediate drive strength emerges as the ESS, capable of outcompeting both stronger and weaker variants. Additionally, we show how the intentional release of two drivers straddling the ESS can help stabilize population dynamics. Finally, inbreeding depression has the effect of expanding the range of conditions under which no intermediate ESS exists, with ever stronger drive being selected until the population is eliminated. These results provide insights into the expected evolutionary trajectories of gene drive systems, with important implications for the design and release of gene drives for pest and vector control.
Ecology and evolution in gene drive modeling
35060NSF-Simons NITMB, YouTube, 2025-08-25 16:09:18.
Speaker: Gili Greenbaum Title: Ecology and evolution in gene drive modeling This talk was recorded as part of the Modeling and Theory in Population Biology workshop at NITMB. The NSF-Simons National Institute for Theory and Mathematics in Biology (NITMB) aims to integrate the disciplines of mathematics and biology in order to transform the practice of biological research and to inspire new mathematical discoveries. NITMB is a partnership between Northwestern University and the University of Chicago. It is funded by the National Science Foundation DMS-2235451 and the Simons Foundations MP-TMPS-00005320. The mission of the NITMB is to create a nationwide collaborative research community that will generate new mathematical results and uncover the “rules of life” through theories, data-informed mathematical models, and computational and statistical tools. The NITMB leverages close collaborations between experimentalists and theorists to synergize discovery. The fundamental research done by NITMB will stimulate advances in areas as diverse as the environment, medicine, and technology development. NITMB members and visitors share space in downtown Chicago that is readily accessible to collaborators across the U.S. and the world. NITMB uses an interlocking set of strategies and initiatives aimed at broad impacts for the mathematical and biological research communities. Targeted research bringing together mathematicians and biologists to collaborate and train the next generation of interdisciplinary scientists. Scientific long programs, workshops, and conferences enhancing collaboration between mathematics and biology. An innovative research program organized around five interrelated themes, selected because they reflect key capabilities of biological systems and interconnect with open mathematical problems.
Novel stressors and trait variation determine X-linked meiotic drive frequency
35021Fisher Adam M., White Nicola, Bonsall Michael B., Price Tom AR. and Knell Robert J., Proc. R. Soc. B., 292. 2025-08-13 16:09:01.
Sex ratio meiotic drive alleles bias their transmission by impairing the viability of non-drive gametes, leading to skewed population sex ratios. Despite theoretical predictions that drive alleles should reach fixation causing population extinction, meiotic drive persists at intermediate frequencies in wild populations, though the reasons for this are unclear. Here, we investigate how novel environmental stress and genotype-specific fitness costs contribute to drive frequency. Using a suppression-free X-linked meiotic drive system in Drosophila pseudoobscura, we exposed flies to varying doses of the pesticide permethrin and measured mortality and fecundity across genotypes. We found that drive-bearing males (SR) and drive-homozygous females (SRSR) exhibited heightened mortality, both in the presence and absence of pesticide, while heterozygous (SRST) females exhibited superior fecundity. Using a mathematical model parametrized with our empirical findings, we explored the long-term population dynamics of meiotic drive under different conditions. Our model predicts that drive frequency has a concave relationship with pesticide dose and is strongly modulated by genotype-specific female fecundity. These results suggest that novel environmental stressors and drive-induced fitness effects play key roles in determining meiotic drive frequencies. Our findings improve our understanding of drive frequencies in the wild and have direct implications for drive-based pest control.
Spatiotemporal complexity in interacting wild and sterile mosquito populations
35005Mandal, G., Guin, L.N. & Chakravarty, S., Nonlinear Dyn, 2025-08-04 08:39:42.
In the present exploration, a mosquito population model is investigated that incorporates a non-linear, saturated release rate for sterile mosquitoes. The model framework leverages a reaction-diffusion system to generate spatiotemporal patterns. A thorough theoretical analysis is conducted to explore the model’s feasible equilibria, focusing on the phenomenon of bistability. Subsequently, the stability, instability, and potential bifurcation scenarios are examined rigorously. Each identified bifurcation is then utilized to elucidate the complex dynamical behaviour of the system. The entire parameter space is systematically partitioned by simultaneously varying two key parameters. This partitioned space can then be further analyzed in conjunction with one and two-parameter bifurcation diagrams. This approach facilitates a deeper understanding of the system’s dynamics within each identified region. In two dimensions (2D), the evolution of diffusion-driven pattern formation is presented for various scenarios, including spots, stripes, labyrinthine structures, combinations of stripes and holes, and hole replication. These spatial patterns are demonstrated to be influenced by critical system factors associated with the concept of Turing space. Sensitivity analysis reveals that the number of wild offspring produced per mating event is the most sensitive parameter within the model. Moreover, the present investigation admits dynamical codimension one and two bifurcations concerning the induced most sensitive parameter. The theoretical findings are consistently validated and corroborated by numerical simulations, which are further employed to evaluate the biological implications of the theoretical results.
CRISPR-GPT for agentic automation of gene-editing experiments
35077Qu, Y., Huang, K., Yin, M. et al., Nat. Biomed. Eng, 2025-07-30 12:34:29.
Performing effective gene-editing experiments requires a deep understanding of both the CRISPR technology and the biological system involved. Meanwhile, despite their versatility and promise, large language models (LLMs) often lack domain-specific knowledge and struggle to accurately solve biological design problems. We present CRISPR-GPT, an LLM agent system to automate and enhance CRISPR-based gene-editing design and data analysis. CRISPR-GPT leverages the reasoning capabilities of LLMs for complex task decomposition, decision-making and interactive human–artificial intelligence (AI) collaboration. This system incorporates domain expertise, retrieval techniques, external tools and a specialized LLM fine tuned with open-forum discussions among scientists. CRISPR-GPT assists users in selecting CRISPR systems, experiment planning, designing guide RNAs, choosing delivery methods, drafting protocols, designing assays and analysing data. We showcase the potential of CRISPR-GPT by knocking out four genes with CRISPR-Cas12a in a human lung adenocarcinoma cell line and epigenetically activating two genes using CRISPR-dCas9 in a human melanoma cell line. CRISPR-GPT enables fully AI-guided gene-editing experiment design and analysis across different modalities, validating its effectiveness as an AI co-pilot in genome engineering.
How population control of pests is modulated by density dependence: The perspective of genetic biocontrol
34993Cole D. Butler, Alun L. Lloyd, Journal of Theoretical Biology, 2025-07-30 11:07:06.
Managing pest species relies critically on mechanisms that regulate population dynamics, particularly those factors that change with population size. These density-dependent factors can help or hinder control efforts and are especially relevant considering recent advances in genetic techniques that allow for precise manipulation of the timing and sex-specificity of population suppression. Despite this importance, density dependence is often poorly characterized owing to limited data and an incomplete understanding of developmental ecology. To address this issue, we construct and analyze a mathematical model of a pest population with a general control under a wide range of density dependence scenarios. Using this model, we investigate how control performance is affected by the strength of density dependence. By modifying the timing and sex-specificity of the control, we tailor our analysis to simulate different pest control strategies, including conventional and genetic biocontrol methods. We pay particular attention to the latter as case studies by extending the baseline model to include genetic dynamics. Finally, we clarify past work on the dynamics of mechanistic models with density dependence. We find substantial differences in control performance for differing strengths of density dependence, with populations exhibiting strong density dependence being most resilient to suppression. However, these results change with the size and timing of the control load, as well as the target sex. Interestingly, we also find that the strength of density dependence affects population invasion by certain genetic biocontrol strategies. While the model is parameterized using the life history traits of the yellow fever mosquito, Aedes aegypti, the principles developed here apply to many pest species. We conclude by discussing what this means for pest population suppression moving forward.
Assessing the impact of the Wolbachia-based control of malaria
34962Zhuolin Qu, Lauren M. Childs, Mathematical Biosciences, 2025-07-08 13:34:58.
Malaria remains a significant infectious disease globally, causing hundreds of thousands of deaths each year. Traditional control methods, such as disease surveillance and mosquito control, along with the development of malaria vaccines, have made strides in reducing the disease’s impact, but new control methods are urgently needed. Wolbachia is a natural bacterium that can infect mosquitoes and reduce their ability to transmit diseases. While initially used to control dengue fever, recent research explored its potential for malaria control. In this study, we develop and analyze a novel mathematical model to assess the potential use of Wolbachia-based strategies for malaria control. The model describes the complex Wolbachia transmission dynamics among mosquitoes and incorporates key features of malaria transmission in humans with dynamical immunity feedback. We derive the basic reproduction number of the malaria disease transmission, which depends on the prevalence of Wolbachia in mosquitoes. Our findings reveal bifurcations in both Wolbachia transmission among mosquitoes and malaria transmission in humans, suggesting the potential for malaria elimination through Wolbachia-based interventions. The sensitivity analysis identifies the important parameters for the basic reproduction number and for malaria reduction and elimination. We numerically explore the integration of Wolbachia and other malaria controls. When control focuses on reducing the malaria burden in humans, there is a substantial rebound in malaria prevalence following the intervention in humans, and our results suggest post-Wolbachia malaria control leads to the greatest reduction in total days of infection. When Wolbachia release is integrated with pre-release mosquito control, there is a comparably large reduction in total days of infection if pre-release mosquito control occurs only a few days before Wolbachia release.
Dynamical analysis of a nonlocal delays spatial malaria model with Wolbachia-infected male mosquitoes release
34960Liping Wang, Runqi Liu, Yangyang Shi, Electronic Research Archive, 33:3177-3200. 2025-07-08 13:27:46.
Malaria continues to pose a considerable threat to global health. This study investigates the use of releasing Wolbachia-infected male mosquitoes as a method to mitigate the spread of malaria. We have formulated a reaction-diffusion model with nonlocal delays that includes the Wolbachia release strategy. The basic reproduction number R0 is defined within our model framework, serving as a critical threshold parameter that dictates the dynamic behavior of the model. A thorough dynamic analysis of the model reveals that when R0<1, a globally attractive infection-free steady state is established. In contrast, if R0>1, the disease persists uniformly. Numerical simulations are conducted to validate the theoretical results and to further illustrate the effectiveness of the Wolbachia release strategy on transmission and control of malaria. These simulations underscore the potential of using Wolbachia-infected male mosquitoes to significantly reduce spread of malaria.
Mozzie: a computationally efficient simulator for the spatio-temporal modelling of mosquitoes
34916Wilkins et al., Journal of Open Source Software, 10. 2025-06-16 13:04:27.
Mozzie enables simulation of the lifecycle and spatial spread of mosquitoes. Mozzie can be used to assess risks associated with disease-control strategies at local, regional or continental scales. Most particularly, strategies involving genetic alterations of mosquitoes to eliminate malaria, are of prime interest. More technically, Mozzie simulates a population-dynamics model that uses differential equations or delay differential equations (Bohner et al., 2018; El-Hachem & Beeton, 2024) to describe the spread and persistence of mosquitoes that may be genetically altered. Genetic alterations are flexibly modelled: these can involve any number of alleles; Mendelian or non-Mendelian inheritance, including gene drives; they can be self-limiting or self-sustaining; and can include the emergence of resistant allelles. The model allows simulation of 𝑁 mosquito species. It incorporates mate-choice, hybridisation and intra-specific competition that occur within complexes of mosquito species (Beeton et al., 2020). This fills a gap that currently exists among similar models, allowing researchers to assess potential transfer of the genetic alterations between (sub-)species. Mozzie supports spatial and temporal variations in lifecyle parameters, and local diffusion andwind-assisted, long range, advection. For example, wind patterns and the capacity of the landscape to support mosquitoes can vary spatially and temporally, reflecting daily variations, seasonality, and local conditions. Conversely, Mozzie does not contain human agents, nor does it consider the effect of genetic control strategies on the prevalence of pathogens such as the malaria parasite, among human or animal populations. Mozzie has been used by the authors to simulate the spread across sub-Saharan Africa of a theoretical, population-modifying, gene drive in Anopheles gambiae s.s. and Anopheles coluzzii (Beeton et al., 2022) (that paper also describes the mathematics of a particular mosquito lifecycle model that is contained in Mozzie). It has also been used to predict the spread of Target Malaria’s Paternal Male Bias construct (Galizi et al., 2014) following a proposed field-release of genetically modified Anopheles coluzzi male mosquitoes in Burkina Faso (Hosack et al., 2023).
Modelling and sensitivity analysis to control dengue through inclusion of genetically modified hybrid mosquitoes
34907Wasim, T., Ismaeel, T., Naseem, A., Abdeljawad, T., & Alqudah, M. A., Mathematical and Computer Modelling of Dynamical Systems, 31. 2025-06-15 18:50:47.
Dengue fever, an ancient yet persistent global health threat transmitted by mosquitoes, remains difficult to control. Recent advances propose genetically modified hybrid mosquitoes as a novel intervention. This study focuses on two primary control strategies: the Sterile Insect Technique (SIT) and genetic sterilization. SIT involves releasing sterile male mosquitoes to reduce populations through unsuccessful mating, while genetic sterilization targets mosquito reproduction or virus transmission capabilities. In our proposed model, modified mosquitoes are included in the susceptible vector compartment, denoted as ℧𝑚. Diagnosis and treatment are modeled with parameters 𝑑1 and 𝑑2. Field and laboratory studies suggest these methods effectively reduce mosquito populations and dengue incidence. A mathematical model is developed to study this strategy’s impact, incorporating the basic reproduction number 𝑅0 and equilibrium analysis. Numerical methods are used to assess system stability and compute sensitivity indices 𝒲ℋ𝜉, ultimately demonstrating the potential for effective dengue control.
Maximising Eradication Potential of Rat Gene Drives Using a Two-Target Homing Rescue Strategy: Spatial Modelling of Empirical Data
34817Birand, A., Gierus, L., Prowse, T., Cassey, P., Thomas, P.Q., Molecular Ecology, 2025-05-04 16:12:38.
Gene drives are genetic elements with positively biased transmission and may be useful tools to suppress mammalian pests that threaten biodiversity worldwide. While gene drives are progressing in mice, less is known about their potential for invasive rat control. A recent report has provided the first data on germline gene conversion in rats, demonstrating that modest homing rates (up to 67%) can be achieved in females. Here, we apply these empirically derived values to investigate the potential of various gene drive strategies to suppress an island population of 200,000 rats, using our stochastic, spatially explicit, individual-based modelling framework. Standard homing drives embedded in haplosufficient fertility or viability genes failed to eradicate, but achieved permanent population suppression. In contrast, a two-target design with a homing rescue (HR) drive embedded in a haplolethal gene that also targets an independent fertility or viability gene demonstrated considerable suppression potential. Remarkably, an HR drive targeting a haplosufficient female fertility gene showed robust eradication even at the relatively low homing rates previously demonstrated in rats. Interestingly, homing rate had a relatively low influence on eradication probability while cutting efficiency at the haplolethal gene was critical. Further, as long as the latter was similar to the cutting and subsequent knockout of the unlinked female fertility gene, then eradication could be achieved across a range of homing rates. Together, these results suggest that modest homing rates, such as have been demonstrated in rats and other species, can potentially be leveraged for population suppression, offering new opportunities for gene drive development.
Economic evaluation of Wolbachia deployment in Colombia: A modeling study
34812Shepard, D.S., Lee, S.R., Halasa-Rappel, Y.A., Rincon Perez, C.W., Harker Roa, A., PLoS One, 20. 2025-05-04 15:55:06.
Wolbachia are bacteria that inhibit dengue virus replication within the mosquito. A cluster-randomized trial in Indonesia found Wolbachia reduced virologically-confirmed dengue cases by 77.1%. Previous models predicted Wolbachia to be highly cost-effective in Indonesia, Vietnam, and Brazil. To inform decisions about future extensions in Colombia, we performed economic evaluations of potential Wolbachia deployments in 11 target cities. We assembled the numbers and distribution by severity of reported dengue cases from Colombia’s national disease surveillance system and the health service provision registry (RIPS). An epidemiological panel of three experts estimated the shares of dengue that were non-medical, under-reported, or misreported as another disease. We determined costs (in 2020 US dollars at market prices) of treating dengue illness from the benchmark insurance tariff and RIPS data on treatment services per symptomatic dengue case. Our central estimates projected 10 years of efficacy and focused on Cali, the target city with the highest number of dengue cases. For Cali, we estimated a net health-sector savings of US$4.95 per person and averting 369 disability-adjusted life years (DALYs) per 100,000 population. From a societal perspective, at 10 years Wolbachia deployment is expected to have highly favorable benefit-cost ratios, with benefits per dollar invested of US$5.50 in Cali and US$4.68 over all target cities. Over 10 years, Wolbachia is highly beneficial on economic grounds, and almost universally cost saving. The Wolbachia program’s economic benefits exceeded its costs in all 11 cities. The program’s savings in healthcare costs alone would more than offset deployment costs nationally and in 9 of 11 target cities. Wolbachia is likely to be the most cost-effective or cost-saving dengue control option in municipalities with both high incidence of dengue and high population density, whereas areas with high dengue incidence but low population density should consider vaccination.
An eco-epidemiological model for malaria with Microsporidia MB as bio-control agent
34793Mfangnia CNT, Tonnang HEZ, Tsanou B, Keith Herren J, Modeling Earth Systems and Environment, 11. 2025-04-23 10:24:11.
Microsporidia MB is an endosymbiont which naturally infects Anopheles mosquitoes. Due to its ability to block Plasmodium transmission, it shows potential as a bio-based agent for the control of malaria. Its self-sustainability is promising, as it can spread through both vertical and horizontal transmissions. However, its low prevalence in mosquito populations remains a challenge. We develop an eco-epidemiological mathematical model describing the co-dynamics of Microsporidia MB (within mosquito population) and malaria (within human population). The model is used to assess the potential of Microsporidia MB-infected mosquitoes on the control of malaria infection. The results on the basic reproduction numbers, the stability of the equilibria, and the existence of bifurcations are obtained, providing conditions for the extinction and persistence of MB-infected mosquitoes. We highlight relevant threshold parameters for the elimination and persistence of MB-infected mosquitoes and malaria-infected individuals. Using real data from Kenya, we found that, given a horizontal transmission rate between 0 and 0.5, a minimum vertical rate of 0.55 is required to avoid extinction of MB-infected mosquitoes. The predicted prevalence of MB-infected mosquitoes using transmission rates reported from lab experiments align with the observed low prevalence of MB-infected mosquitoes in the field, thereby validating our model and results. Finally, predictions indicate that increasing MB mosquito infection could effectively control malaria, with target prevalence varying by region: 15% in Highland, 40% on the coast, and 70% in the Lake region. This study offers insights into the use of bio-based vector population replacement solutions to reduce malaria incidence in regions where Microsporidia MB is prevalent.
Mathematically modelling the population dynamics of CRISPR gene drive systems in the pine pest Sirex noctilio
34779Strydom, H., Ouifki, R., Chapwanya, M., bioRxiv, 2025-04-18 10:34:17.
Sirex noctilio is an invasive pest of pine that has caused significant economic damage in South Africa and many other Southern Hemisphere countries. Current management tools are not efficient in all cases and consequently there is a need for more efficient and targeted control measures. An emerging tool for pest management is the use of gene editing and associated gene drive systems. In this study, we aim to investigate the use of CRISPR-Cas gene drive systems in the management of S. noctilio in South Africa. As a first step, we developed a model for the population dynamics of S. noctilio, using historical national population monitoring data and incorporating the influence of two main biological control agents of the pest. We then modelled the influence of two different CRISPR-Cas systems on the population dynamics of S. noctilio namely, a baseline CRISPR model and Complementary Sex Determination CRISPR (CSD) model. Each model is used to simulate a male and female only introduction strategy to estimate the effectiveness of different methods of introducing the gene drive system. The model calibration was achieved by optimizing the model fit to existing data using the least squares technique. Results suggest that both CRISPR gene drive systems would be effective at controlling the population growth of S. noctilio at high levels of introduction, but overall population control would be hindered by practical limitations. Although only two CRISPR models were explored, the underlying population model serves as a framework for further studies into the population dynamics of Sirex noctilio, as well as many other CRISPR-Cas gene drive systems.
Evolutionary consequences of long-distance dispersal in mosquitoes
34776Thomas L Schmidt, Current Opinion in Insect Science, 68. 2025-04-18 10:25:09.
Long-distance dispersal (LDD) provides a means for mosquitoes to invade new regions and spread adaptive alleles, including those conferring insecticide resistance. Most LDD takes place on human transport vessels and will typically be rarer and more directionally constrained than active flight but can connect populations and regions that are otherwise mutually inaccessible. These features make LDD worthy of specific consideration in mosquito research. This paper reviews recent evolutionary research on LDD and its consequences for mosquito populations and mosquito control. LDD is the main source of mosquito range expansions, and genomic methods can now trace the origins of new invasions to specific towns or cities. Genomic methods can also give a rough indication of the number of invaders, which if very small may lead to the stochastic loss of advantageous alleles during invasion bottlenecks. Once invasions are established, LDD spreads adaptive alleles between populations. Emerging insights into insecticide resistance evolution indicate that LDD has repeatedly spread resistance mutations across global species ranges, but these broad patterns are convoluted by two other evolutionary processes: parallel adaptation at the same gene or gene cluster and polygenic adaptation at different genes in different populations. Together, these processes have produced patterns of similarity and dissimilarity at resistance genes that are decoupled from geographical distance. LDD within cities is less well studied but is important for planning and evaluating local control efforts. Urban investigations of LDD may help identify areas experiencing weaker selection pressures from insecticides and isolated areas to target for control.
Anticipating evolutionary responses of mosquito mating systems to population suppression with mass-reared males
34745Bonsall, M.B., Cator, L.J., Current Opinion in Insect Science, 68. 2025-04-06 19:52:32.
Strategies that rely on the mass release of males to suppress mosquito populations will exert selective pressure on natural mating systems. Here, we investigate how mass releases might affect the mating behaviors of wild target populations. We highlight gaps in our understanding of both variation in these aspects of mosquito behavior and the evolutionary forces that maintain variation within and between populations. We provide a mathematical framework for integrating mosquito mating ecology into models of population suppression. Given that these strategies are being increasingly deployed, anticipating and managing evolutionary responses of target population behavior should be a priority for research.
A predatory gene drive for targeted control of self-transmissible plasmids
34734Ryan Tsoi et al., Science Advances, 11. 2025-04-03 17:09:42.
Suppressing plasmid transfer in microbial communities has profound implications due to the role of horizontal gene transfer (HGT) in spreading and maintaining diverse functional traits such as metabolic functions, virulence factors, and antibiotic resistance. However, existing tools for inhibiting HGT are limited in their modes of delivery, efficacy, and scalability. Here, we present a versatile denial-of-spread (DoS) strategy to target and eliminate specific conjugative plasmids. Our strategy exploits retrotransfer, whereby an engineered DoS plasmid is introduced into host cells containing a target plasmid. Acting as a predatory gene drive, DoS propagates itself at the expense of the target plasmid, through competition or active elimination. Once the target plasmid is eradicated, DoS is removed via induced plasmid suicide, resulting in a community containing neither plasmid. The strategy is tunable and scalable for various conjugative plasmids, different mechanisms of plasmid inheritance interruption, and diverse environmental contexts. DoS represents a new tool for precise control of gene persistence in microbial communities.
Global asymptotic stability in a delay stage structured model for mosquito population suppression
34720Huang, Mg., Yu, Js., Applied Mathematics, 40:112-136. 2025-03-31 14:42:25.
A promising avenue to control mosquito-borne diseases such as dengue, malaria, and Zika involves releasing male mosquitoes carrying the bacterium Wolbachia in wild areas to drive female sterility by a mechanism called cytoplasmic incompatibility (CI). In this work, we initiate a preliminary assessment of how the combined impact of dispersal, incomplete CI and mating competitiveness on mosquito population suppression by a delay differential equation model. Our theoretical analyses indicate that the immigration of eggs plays a significant role in the suppression dynamics. For the case without egg immigration, we identify a threshold dispersal rate v* of adult mosquitoes, threshold CI density ξ*, and threshold release ratio r*. A successful mosquito suppression would be established only when v < v*, ξ > ξ*, and r(t) ≥ r* uniformly. The immigration of eggs causes the threshold dynamics to be invalid, and warns an absolute failure of population suppression. The monotonicity of the adult steady-state in the dispersal rate and CI intensity indicates that choosing a suitable Wolbachia strain with strong CI intensity, or bringing down the dispersal rate of mosquitoes by blocking the suppression zones is a feasible strategy to obtain a better suppression level.
Exploring the ecology of malaria mosquitoes in São Tomé and Príncipe
34636Lisa Chamberland, Outreach Network for Gene Drive Research, 2025-03-21 14:28:58.
As part of our work to develop new genetic approaches for malaria control, the University of California Malaria Initiative (UCMI) is studying mosquito movement and breeding patterns in São Tomé and Príncipe. In a study published last year, we investigated the dispersal dynamics of Anopheles coluzzii – the only malaria vector on this island nation. Our recent study examines how environmental factors influence A. coluzzii breeding sites and shape mosquito dispersal across São Tomé and Príncipe. Understanding movement and interactions between mosquito populations is key to designing malaria control strategies. The data collected will also offer key insights that will guide the design of potential field evaluations of the technology we are working to develop. To determine the most suitable habitats for A. coluzzii, we used computer modeling to analyze environmental conditions such as temperature, elevation, and human population density. Our results show that the northeastern regions of both São Tomé and Príncipe islands provide the most suitable conditions for A. coluzzii larval development, with lower elevations and higher human population densities likely contributing to greater habitat availability. Interestingly, our climate modeling suggests that the mosquito’s geographic distribution on the islands will remain largely unchanged under current climate projections, even without additional interventions.
wStri spread dynamics in Nilaparvata lugens via discrete mathematical models
34574Zheng, B., Yang, H., Elaydi, S. et al., Journal of Mathematical Biology, 90. 2025-03-12 16:30:16.
Wolbachia, an intracellular bacterium, is well-known for inducing cytoplasmic incompatibility, which has become a promising and environmentally sustainable strategy for controlling pest populations. The strain wStri, specifically identified in Nilaparvata lugens (brown planthopper), has shown potential for such biocontrol applications. In this study, we develop a comprehensive discrete mathematical model to analyze the dynamics of wStri spread in a mixed population of wStri-infected, wLug-infected, and uninfected Nilaparvata lugens under both constant and periodically varying environmental conditions. Under a constant environment, the model identifies the critical threshold necessary for the successful establishment of wStri within the population. Our analysis reveals that the model exhibits a strong Allee effect, where a population must exceed a certain critical density-the Allee threshold-for the wStri strain to persist and spread. Below this threshold, the wStri strain is likely to be eliminated, failing in pest control efforts. When the environment varies periodically, the model transforms into a non-autonomous periodic discrete model, introducing additional complexity. In this scenario, we derive sufficient conditions that ensure the composition of finitely many Allee maps continues to function as an Allee map. Furthermore, we prove that a unique periodic orbit exists within such a periodic environment. This orbit is characterized as unstable and acts as a threshold, determining whether wStri will establish itself in the population or die out over time. The findings from this model provide critical insights into the conditions under which wStri can be effectively used to control Nilaparvata lugens, particularly in environments that are not constant but fluctuate periodically. These insights have significant implications for the practical deployment of Wolbachia-based biocontrol methods in pest management strategies.
Wolbachia-based mosquito control: Environmental perspectives on population suppression and replacement strategies
34543Bhattacharyya, J., Roelke, D.L., Acta Tropica, 262. 2025-02-25 10:59:30.
Mosquito-borne diseases pose a significant threat to global health, and traditional mosquito control methods often fall short of effectiveness. A promising alternative is the biological control strategy of transinfecting mosquitoes with Wolbachia, a bacterium capable of outcompeting harmful pathogens and reducing the ability of mosquitoes to transmit diseases. However, Wolbachia infections are sensitive to abiotic environmental factors such as temperature and humidity, which can affect their densities in mosquitoes and, consequently, their ability to block pathogens. This review evaluates the effectiveness of different Wolbachia strains transinfected into mosquitoes in reducing mosquito-borne diseases. It explores how Wolbachia contributes to mosquito population control and pathogen interference, highlighting the importance of mathematical models in understanding Wolbachia transmission dynamics. Additionally, the review addresses the potential impact on arboviral transmission and the challenges posed by environmental fluctuations in mosquito control programs.
Controlling the frequency dynamics of homing gene drives for intermediate outcomes
34494Camm B., Fournier-Level A., G3: Genes|Genomes|Genetics, 2025-02-04 17:53:42.
Gene drives have enormous potential for solving biological issues by forcing the spread of desired alleles through populations. However, to safeguard from the potentially irreversible consequences on natural populations, gene drives with intermediate outcomes that neither fixate nor get removed from the population are of outstanding interest. To elucidate the conditions leading to intermediate gene drive outcomes, a stochastic, individual allele-focused gene drive model was developed to simulate the diffusion of a homing gene drive in a population. The frequencies of multiple alleles at a locus targeted by a gene drive were tracked under various scenarios. These explored the effect of gene drive conversion efficiency, strength and frequency of resistance alleles, dominance and strength of a fitness cost for the gene drive, and the level of inbreeding. Four outcomes were consistently observed: fixation, loss, temporary, and equilibrium. The latter 2 are defined by the frequency of the gene drive peaking then crashing or plateauing, respectively. No single variable determined the outcome of a drive. The difference between the conversion efficiency and resistance level, modeled quantitatively, differentiated the temporary and equilibrium outcomes. The frequency dynamics of the gene drive within outcomes varied extensively, with different variables driving these dynamics between outcomes. These simulation results highlight the possibility of fine-tuning gene drive outcomes and frequency dynamics. To that end, we provide a web application implementing our model, which will guide the safer design of gene drives able to achieve a range of controllable outcomes tailored to population management needs.
A Y chromosome-linked genome editor for efficient population suppression in the malaria vector Anopheles gambiae
34215Tolosana, I., Willis, K., Gribble, M. et al., Nature Communications, 16:206. 2025-01-07 09:21:41.
Genetic control – the deliberate introduction of genetic traits to control a pest or vector population – offers a powerful tool to augment conventional mosquito control tools that have been successful in reducing malaria burden but that are compromised by a range of operational challenges. Self-sustaining genetic control strategies have shown great potential in laboratory settings, but hesitancy due to their invasive and persistent nature may delay their implementation. Here, instead, we describe a self-limiting strategy, designed to have geographically and temporally restricted effect, based on a Y chromosome-linked genome editor (YLE). The YLE comprises a CRISPR-Cas9 construct that is always inherited by males yet generates an autosomal dominant mutation that is transmitted to over 90% of the offspring and results in female-specific sterility. To our knowledge, our system represents a pioneering approach in the engineering of the Y chromosome to generate a genetic control strain for mosquitoes. Mathematical modelling shows that this YLE technology is up to seven times more efficient for population suppression than optimal versions of other self-limiting strategies, such as the widely used Sterile Insect Technique or the Release of Insects carrying a Dominant Lethal gene.
Wolbachia-based mosquito control: Environmental perspectives on population suppression and replacement strategies
34213Joydeb Bhattacharyya, Daniel L. Roelke, Acta Tropica, 262. 2025-01-07 09:07:50.
Mosquito-borne diseases pose a significant threat to global health, and traditional mosquito control methods often fall short of effectiveness. A promising alternative is the biological control strategy of transinfecting mosquitoes with Wolbachia, a bacterium capable of outcompeting harmful pathogens and reducing the ability of mosquitoes to transmit diseases. However, Wolbachia infections are sensitive to abiotic environmental factors such as temperature and humidity, which can affect their densities in mosquitoes and, consequently, their ability to block pathogens. This review evaluates the effectiveness of different Wolbachia strains transinfected into mosquitoes in reducing mosquito-borne diseases. It explores how Wolbachia contributes to mosquito population control and pathogen interference, highlighting the importance of mathematical models in understanding Wolbachia transmission dynamics. Additionally, the review addresses the potential impact on arboviral transmission and the challenges posed by environmental fluctuations in mosquito control programs.
Exploring The Dynamics of Gene Drive Mosquitoes Within Wild Populations Using an Agent-Based Simulation
33614S. Wickramasooriya, I. Mahmood, et al., IEEE Xplore, 2024-11-12 13:33:12.
Gene drive technology is emerging as a potentially powerful tool in combating vector-borne diseases – notably malaria. This study introduces an agent-based model (ABM) focused on the deployment of genetically engineered mosquitoes with gene drive (GEM) in Príncipe Island, Republic of São Tomé and Príncipe, an island nation in the Gulf of Guinea, West Africa. Grounded in empirical data from laboratory and field studies, our model forecasts the dynamics of mosquito populations central to devising efficacious GEM release strategies. The core objective is to evaluate the time required for GEMs to constitute 90% of the mosquito population and to elucidate their dispersal throughout the island. This research is instrumental in understanding GEM potential in controlling malaria vectors.
Improving the suppressive power of homing gene drive by co-targeting a distant-site female fertility gene
33386Faber, N.R., Xu, X., Chen, J. et al., Nature Communications, 15. 2024-11-04 17:07:21.
Gene drive technology has the potential to address major biological challenges. Well-studied homing suppression drives have been shown to be highly efficient in Anopheles mosquitoes, but for other organisms, lower rates of drive conversion prevent elimination of the target population. To tackle this issue, we propose a gene drive design that has two targets: a drive homing site where drive conversion takes place, and a distant site where cleavage induces population suppression. We model this design and find that the two-target system allows suppression to occur over a much wider range of drive conversion efficiency. Specifically, the cutting efficiency now determines the suppressive power of the drive, rather than the conversion efficiency as in standard suppression drives. We construct a two-target drive in Drosophila melanogaster and show that both components of the gene drive function successfully. However, cleavage in the embryo from maternal deposition as well as fitness costs in female drive heterozygotes both remain significant challenges for both two-target and standard suppression drives. Overall, our improved gene drive design has the potential to ease problems associated with homing suppression gene drives for many species where drive conversion is less efficient.
Exploring The Dynamics of Gene Drive Mosquitoes Within Wild Populations Using an Agent-Based Simulation
34602S. Wickramasooriya, I. Mahmood, A. Calinescu, M. Wooldridge and G. Lanzaro, 2024 Annual Modeling and Simulation Conference, Washington, D.C.:1-14. 2024-10-29 10:38:49.
Gene drive technology is emerging as a potentially powerful tool in combating vector-borne diseases – notably malaria. This study introduces an agent-based model (ABM) focused on the deployment of genetically engineered mosquitoes with gene drive (GEM) in Príncipe Island, Republic of São Tomé and Príncipe, an island nation in the Gulf of Guinea, West Africa. Grounded in empirical data from laboratory and field studies, our model forecasts the dynamics of mosquito populations central to devising efficacious GEM release strategies. The core objective is to evaluate the time required for GEMs to constitute 90% of the mosquito population and to elucidate their dispersal throughout the island. This research is instrumental in understanding GEM potential in controlling malaria vectors.
Wolbachia Invasion in Mosquitoes with Incomplete CI, Imperfect Maternal Transmission and Maturation Delay
32710Ma X, Su Y, Bulletin of Mathematical Biology, 2024-10-22 17:32:46.
The mechanism of cytoplasmic incompatibility (CI) is important in the study of Wolbachia invasion in wild mosquitoes. Su et al. (Bull Math Biol 84(9):95, 2022) proposed a delay differential equation model by relating the CI effect to maturation delay. In this paper, we investigate the dynamics of this model by allowing the same density-dependent death rate and distinct density-independent death rates. Through analyzing the existence and stability of equilibria, we obtain the parameter conditions for Wolbachia successful invasion if the maternal transmission is perfect. While if the maternal transmission is imperfect, we give the ranges of parameters to ensure failure invasion, successful invasion and partially suppressing, respectively. Meanwhile, numerical simulations indicate that the system may exhibit monostable and bistable dynamics when parameters vary. Particularly, in the bistable situation an unstable separatrix, like a line, exists when choosing constant functions as initial values; and the maturation delay affects this separatrix in an interesting way.
The potential of gene drives in malaria vector species to control malaria in African environments
32702Hancock, P.A., North, A., Leach, A.W. et al., Nature Communications, 15. 2024-10-22 14:44:25.
Gene drives are a promising means of malaria control with the potential to cause sustained reductions in transmission. In real environments, however, their impacts will depend on local ecological and epidemiological factors. We develop a data-driven model to investigate the impacts of gene drives that causes vector population suppression. We simulate gene drive releases in sixteen ~ 12,000 km2 areas of west Africa that span variation in vector ecology and malaria prevalence, and estimate reductions in vector abundance, malaria prevalence and clinical cases. Average reductions in vector abundance ranged from 71.6–98.4% across areas, while impacts on malaria depended strongly on which vector species were targeted. When other new interventions including RTS,S vaccination and pyrethroid-PBO bednets were in place, at least 60% more clinical cases were averted when gene drives were added, demonstrating the benefits of integrated interventions. Our results show that different strategies for gene drive implementation may be required across different African settings.
Practical Application of a Relationship-Based Model to Engagement for Gene-Drive Vector Control Programs
32533Ana Kormos, Lodney Nazaré, Adionilde Aguiar dos Santos, and Gregory C. Lanzaro, The American Journal of Tropical Medicine and Hygiene, 111:341-360. 2024-10-15 12:04:35.
Engagement is an important component in the advancement of gene-drive vector control research programs as developers look to transition the technology from the laboratory to the field. As research advances and engagement surrounding this novel technology is put into practice, knowledge can be gained from practical experiences and applications in the field. A relationship-based model (RBM) provides a framework for end-user development of engagement programs and strategies. The model places end users at the center of the engagement decision-making processes rather than as recipients of predetermined strategies, methods, and definitions. Successful RBM application for healthcare delivery has previously been demonstrated, and the University of California Malaria Initiative (UCMI) has applied this model to its gene-drive program in the Democratic Republic of São Tomé and Príncipe. The model emphasizes the importance of local leadership in the planning, development, and implementation of all phases of project engagement. The primary aim of this paper is to translate the model from paper to practice and provide a transparent description, using practical examples, of the UCMI program implementation of RBM at its field site. End-user development of the UCMI engagement program provides a unique approach to the development of ethical, transparent, and effective engagement strategies for malaria control programs. This paper may also serve as a reference and example for projects looking to establish an engagement program model that integrates end-user groups in the decision-making processes surrounding engagement.
Overcoming drug-resistant tumors with selection gene drives
31594Hui Wang, Mingqi Xie, Cell Genomics, 4. 2024-09-17 12:48:55.
Drug resistance is a major hurdle prohibiting effective treatment of many diseases, including cancer. Using model-guided designs, Leighow et al.1 engineered a dual-switch selection gene drive system custom designed to combat drug-resistant tumors. By demonstrating remarkable killing efficacies in preclinical models using human non-small lung cancer cells in vitro and in mice, this work describes an attractive mindset to develop next-generation anticancer therapies.
Applications of Mathematical Programming to Genetic Biocontrol
31592Váleri N. Vásquez, John M. Marshall, SIAM Journal on Applied Mathematics, 84. 2024-09-17 12:36:59.
We review existing approaches to optimizing the deployment of genetic biocontrol technologies—tools used to prevent vector-borne diseases such as malaria and dengue—and formulate a mathematical program that enables the incorporation of crucial ecological and logistical details. The model is comprised of equality constraints grounded in discretized dynamic population equations, inequality constraints representative of operational limitations including resource restrictions, and an objective function that jointly minimizes the count of competent mosquito vectors and the number of transgenic organisms released to mitigate them over a specified time period. We explore how nonlinear programming (NLP) and mixed integer nonlinear programming (MINLP) can advance the state of the art in designing the operational implementation of three distinct transgenic public health interventions, two of which are presently in active use around the world.
Deployment of tethered gene drive for confined suppression in continuous space requires avoiding drive wave interference
31622Ruobing Feng, Jackson Champer, Molecular Ecology, 33. 2024-09-16 21:13:35.
Gene drives have great potential for suppression of pest populations and removal of exotic invasive species. CRISPR homing suppression drive is a powerful but unconfined drive, posing risks of uncontrolled spread. Thus, developing methods for confining a gene drive is of great significance. Tethered drive combines a confined system such as Toxin-Antidote Recessive Embryo drive with a strong drive such as a homing suppression drive. It can prevent the homing drive from spreading beyond the confined drive and can be constructed readily, giving it good prospects for future development. However, we have found that care must be taken when deploying tethered drive systems in some scenarios. Simulations of tethered drive in a panmictic population model reveal that successful deployment requires a proper release ratio between the two components, tailored to prevent the suppression drive from eliminating the confined system before it has the chance to spread. Spatial models where the population moves over a one-dimensional landscape display a more serious phenomenon of drive wave interference between the two tethered drive components. If the faster suppression drive wave catches up to the confined drive wave, success is still possible, but it is dependent on drive performance and ecological parameters. Two-dimensional simulations further restrict the parameter range for drive success. Thus, careful consideration must be given to drive performance and ecological conditions, as well as specific release proposals for potential application of tethered drive systems.
Population suppression by release of insects carrying a dominant sterile homing gene drive targeting doublesex in Drosophila
34760Chen, W., Guo, J., Liu, Y. et al., Nature Communications, 15. 2024-09-14 09:17:45.
CRISPR homing gene drives can suppress pest populations by targeting female fertility genes, converting wild-type alleles into drive alleles in the germline of drive heterozygotes. fsRIDL (female-specific Release of Insects carrying a Dominant Lethal) is a self-limiting population suppression strategy involving continual release of transgenic males carrying female lethal alleles. Here, we propose an improved pest suppression system called “Release of Insects carrying a Dominant-sterile Drive” (RIDD), combining performance characteristics of homing drive and fsRIDL. We construct a split RIDD system in Drosophila melanogaster by creating a 3-gRNA drive disrupting the doublesex female exon. Drive alleles bias their inheritance in males, while drive alleles and resistance alleles formed by end-joining cause dominant female sterility. Weekly releases of RIDD males progressively suppressed and eventually eliminated cage populations. Modeling shows that RIDD is substantially stronger than SIT and fsRIDL. RIDD is also self-limiting, potentially allowing targeted population suppression.
Altering traits and fates of wild populations with Mendelian DNA sequence modifying Allele Sails
29102Michelle L. Johnson, Bruce A. Hay, Maciej Maselko, Nature Communications, 15. 2024-04-16 09:23:41.
Population-scale genome editing can be used to alter the composition or fate of wild populations. One approach to achieving these aims utilizes a synthetic gene drive element—a multi-gene cassette—to bring about an increase in the frequency of an existing allele. However, the use of gene drives is complicated by the multiple scientific, regulatory, and social issues associated with transgene persistence and gene flow. Alternatives in which transgenes are not driven could potentially avoid some of these issues. Here we propose an approach to population scale gene editing using a system we refer to as an Allele Sail. An Allele Sail consists of a genome editor (the Wind) that introduces DNA sequence edits (the Sail) at one or more sites, resulting in progeny that are viable and fertile. The editor, such as a sequence-specific nuclease, or a prime- or base-editor, is inherited in a Mendelian fashion. Meanwhile, the edits it creates experience an arithmetic, Super-Mendelian increase in frequency. We explore this system using agent-based modeling, and identify contexts in which a single, low frequency release of an editor brings edits to a very high frequency. We also identify conditions in which manipulation of sex determination can be used to bring about population suppression. Current regulatory frameworks often distinguish between transgenics as genetically modified organisms (GMOs), and their edited non-transgenic progeny as non-GMO. In this context an Allele Sail provides a path to alter traits and fates of wild populations in ways that may be considered more acceptable.
Population suppression with dominant female-lethal alleles is boosted by homing gene drive
28685Jinyu Zhu, Jingheng Chen, Yiran Liu, Xuejiao Xu, Jackson Champer, bioRxiv, 2023-12-07 10:24:25.
Methods to suppress pest insect populations using genetic constructs and repeated releases of male homozygotes have recently been shown to be an attractive alternative to older sterile insect technique based on radiation. Female-specific lethal alleles have substantially increased power, but still require large, sustained transgenic insect releases. Gene drive alleles bias their own inheritance to spread throughout populations, potentially allowing population suppression with a single, small-size release. However, suppression drives often suffer from efficiency issues, and the most well-studied type, homing drives, tend to spread without limit. In this study, we show that coupling female-specific lethal alleles with homing gene drive allowed substantial improvement in efficiency while still retaining the self-limiting nature (and thus confinement) of a lethal allele strategy. Using a mosquito model, we show the required releases sizes for population elimination in a variety of scenarios, including different density growth curves, with comparisons to other systems. Resistance alleles reduced the power of this method, but these could be overcome by targeting an essential gene with the drive while also providing rescue. A proof-of-principle demonstration of this system in Drosophila melanogaster was effective in both basing its inheritance and achieving high lethality among females that inherit the construct in the absence of antibiotic. Overall, our study shows that substantial improvements can be achieved in female-specific lethal systems for population suppression by combining them with a gene drive.
Incorporating ecology into gene drive modelling
28150J. Kim, K. D. Harris, I. K. Kim, S. Shemesh, P. W. Messer and G. Greenbaum, Ecology Letters, 26:S62-S80. 2023-10-23 11:37:54.
Abstract Gene drive technology, in which fast-spreading engineered drive alleles are introduced into wild populations, represents a promising new tool in the fight against vector-borne diseases, agricultural pests and invasive species. Due to the risks involved, gene drives have so far only been tested in laboratory settings while their population-level behaviour is mainly studied using mathematical and computational models. The spread of a gene drive is a rapid evolutionary process that occurs over timescales similar to many ecological processes. This can potentially generate strong eco-evolutionary feedback that could profoundly affect the dynamics and outcome of a gene drive release. We, therefore, argue for the importance of incorporating ecological features into gene drive models. We describe the key ecological features that could affect gene drive behaviour, such as population structure, life-history, environmental variation and mode of selection. We review previous gene drive modelling efforts and identify areas where further research is needed. As gene drive technology approaches the level of field experimentation, it is crucial to evaluate gene drive dynamics, potential outcomes, and risks realistically by including ecological processes.
Expansions to the MGDrivE suite for simulating the efficacy of novel gene-drive constructs in the control of mosquito-borne diseases
28003J. B. Bennett, S. L. Wu, P. R. Chennuri, K. M. Myles and M. L. Ndeffo-Mbah, BMC Research Notes, 16:258. 2023-10-05 08:39:23.
The MGDrivE (MGDrivE 1 and MGDrivE 2) modeling framework provides a flexible and expansive environment for testing the efficacy of novel gene-drive constructs for the control of mosquito-borne diseases. However, the existing model framework did not previously support several features necessary to simulate some types of intervention strategies. Namely, current MGDrivE versions do not permit modeling of small molecule inducible systems for controlling gene expression in gene drive designs or the inheritance patterns of self-eliminating gene drive mechanisms. Here, we demonstrate a new MGDrivE 2 module that permits the simulation of gene drive strategies incorporating small molecule-inducible systems and self-eliminating gene drive mechanisms. Additionally, we also implemented novel sparsity-aware sampling algorithms for improved computational efficiency in MGDrivE 2 and supplied an analysis and plotting function applicable to the outputs of MGDrivE 1 and MGDrivE 2.
MGDrivE 3: A decoupled vector-human framework for epidemiological simulation of mosquito genetic control tools and their surveillance
27894A. Mondal, C. H. M. Sanchez and J. M. Marshall, bioRxiv, 2023.09.09.556958. 2023-09-12 08:11:56.
We present MGDrivE 3 (Mosquito Gene Drive Explorer 3), a new version of a previously-developed framework, MGDrivE 2, that investigates the spatial population dynamics of mosquito genetic control systems and their epidemiological implications. The new framework incorporates three major developments: i) a decoupled sampling algorithm allowing the vector portion of the MGDrivE framework to be paired with a more detailed epidemiological framework, ii) a version of the Imperial College London malaria transmission model, which incorporates age structure, various forms of immunity, and human and vector interventions, and iii) a surveillance module that tracks mosquitoes captured by traps throughout the simulation. Example MGDrivE 3 simulations are presented demonstrating the application of the framework to a CRISPR-based homing gene drive linked to dual disease-refractory genes and their potential to interrupt local malaria transmission. Simulations are also presented demonstrating surveillance of such a system by a network of mosquito traps. MGDrivE 3 is freely available as an open-source R package on CRAN (https://cran.r-project.org/package=MGDrivE2) (version 2.1.0), and extensive examples and vignettes are provided.
A migration-selection model in genetic engineering
27690Y. Qi and L. Su, Nonlinear Analysis: Real World Applications, 75:103983. 2023-08-31 08:48:22.
We investigate a migration-selection system arising from CRISPR-Cas9 genetic engineering, which describes the evolution of the frequencies of a wild allele O, a drive allele D, and a brake allele B. The purpose is to see whether the drive allele D can persist in the population and whether its spread can be limited or stopped by the brake allele B when necessary. We give a complete classification of the dynamics of this system when there is no migration. We further show that migration may cause complex spatiotemporal patterns by demonstrating the existence of spatially inhomogeneous periodic solutions and steady state solutions.
Female meiotic drive shapes the distribution of rare inversion polymorphisms in Drosophila melanogaster
27674S. A. Koury, Genetics, 2023-08-24 07:04:55.
In all species, new chromosomal inversions are constantly being formed by spontaneous rearrangement and then stochastically eliminated from natural populations. In Drosophila, when new chromosomal inversions overlap with a pre-existing inversion in the population, their rate of elimination becomes a function of the relative size, position, and linkage phase of the gene rearrangements. These altered dynamics result from complex meiotic behavior wherein overlapping inversions generate asymmetric dyads that cause both meiotic drive/drag and segmental aneuploidy. In this context, patterns in rare inversion polymorphisms of a natural population can be modeled from the fundamental genetic processes of forming asymmetric dyads via crossing-over in meiosis I and preferential segregation from asymmetric dyads in meiosis II. Here, a mathematical model of crossover-dependent female meiotic drive is developed and parameterized with published experimental data from Drosophila melanogaster laboratory constructs. This mechanism is demonstrated to favor smaller, distal inversions and accelerate the elimination of larger, proximal inversions. Simulated sampling experiments indicate that the paracentric inversions directly observed in natural population surveys of Drosophila melanogaster are a biased subset that both maximizes meiotic drive and minimizes the frequency of lethal zygotes caused by this cytogenetic mechanism. Incorporating this form of selection into a population genetic model accurately predicts the shift in relative size, position, and linkage phase for rare inversions found in this species. The model and analysis presented here suggest that this weak form of female meiotic drive is an important process influencing the genomic distribution of rare inversion polymorphisms.
Gene drives for invasive wasp control: Extinction is unlikely, with suppression dependent on dispersal and growth rates
27669P. J. Lester, D. O'Sullivan and G. L. W. Perry, Ecological Applications, 2023-08-24 06:36:30.
Abstract Gene drives offer a potentially revolutionary method for pest control over large spatial extents. These genetic modifications spread deleterious variants through a population and have been proposed as methods for pest suppression or even eradication. We examined the influence of local dispersal, long-distance and/or human-mediated dispersal, and variation in population growth, on the success of a gene drive for the control of invasive social wasps (Vespula vulgaris). Our simulations incorporated a spatially realistic environment containing variable habitat quality in New Zealand. Pest eradication was not observed, except in extreme and unrealistic scenarios of constant, widespread, and spatially intense releases of genetically modified individuals every year for decades. Instead, the regional persistence of genetically modified and wild-type wasps was predicted. Simulations using spatially homogeneous versus realistic landscapes (incorporating uninhabitable areas and dispersal barriers) showed little difference in overall population dynamics. Overall, little impact on wasp abundance was observed in the first 15?years post-introduction. After 25?years, populations were suppressed to levels <95% of starting populations. Populations exhibited ?chase dynamics? with population cycles in space, with local extinction occurring in some areas while wasps became abundant in others. Increasing the wasps' local dispersal distance increased the spatial and temporal variability of the occupied area and population suppression. Varying levels of human-associated long-distance dispersal had little effect on population dynamics. Increasing intrinsic population growth rates interacted with local dispersal to cause higher mean populations and substantially higher levels of variation in population suppression and the total amount of landscape occupied. Gene drives appear unlikely to cause a rapid and widespread extinction of this and probably other pests, but could offer long-term and cost-effective methods of pest suppression. The predicted level of <95% pest suppression would substantially reduce the predation pressure and competitive interactions of this invasive wasp on native species. However, the predicted long-term persistence of genetically modified pests will influence the ethics and likelihood of using gene drives for pest control, especially given concerns that modified wasps would eventually be transported back to their home range.
The impact of predators of mosquito larvae on Wolbachia spreading dynamics
27651Z. Zhu, Y. Hui and L. Hu, Journal of Biological Dynamics, 17:2249024. 2023-08-21 07:05:13.
Dengue fever creates more than 390 million cases worldwide yearly. The most effective way to deal with this mosquito-borne disease is to control the vectors. In this work we consider two weapons, the endosymbiotic bacteria Wolbachia and predators of mosquito larvae, for combating the disease. As Wolbachia-infected mosquitoes are less able to transmit dengue virus, releasing infected mosquitoes to invade wild mosquito populations helps to reduce dengue transmission. Besides this measure, the introduction of predators of mosquito larvae can control mosquito population. To evaluate the impact of the predators on Wolbachia spreading dynamics, we develop a stage-structured five-dimensional model, which links the predator-prey dynamics with the Wolbachia spreading. By comparatively analysing the dynamics of the models without and with predators, we observe that the introduction of the predators augments the number of coexistence equilibria and impedes Wolbachia spreading. Some numerical simulations are presented to support and expand our theoretical results.
Optimizing the delivery of self-disseminating vaccines in fluctuating wildlife populations
27639C. Schreiner, A. Basinski, C. Remien and S. Nuismer, PLOS Neglected Tropical Diseases, 17:e0011018. 2023-08-18 07:45:43.
Author summary Pathogens such as Ebola, rabies, and Lassa virus that usually infect wildlife can jump to the human population. In the worst case, this can lead to outbreaks or pandemics such as happened in 2014 with Ebola and 2019 with SARS-CoV-2. One approach to mitigate the threat of pathogens spilling into the human population is to proactively vaccinate wildlife harboring these pathogens before the pathogens infect humans. With traditional vaccines, administering enough vaccines to the wildlife population to limit pathogen spread is challenging. To address this challenge, recent technological advances have allowed the development of vaccines that allow some degree of spread of the vaccine from animal to animal. However, for a vaccination campaign using these self-disseminating vaccines to be implemented successfully, we need to know when vaccines should be administered. We used mathematical models to explore how the reservoir host’s population ecology and properties of the vaccine affect the success of a vaccination campaign. Our results demonstrate that the timing of vaccine delivery relative to seasonal reproduction can make or break the success of vaccination programs. The effectiveness of self-disseminating vaccines is optimized by introducing vaccine after the peak of seasonal reproduction when the number of animals available for vaccination is highest.
Population suppression by release of insects carrying a dominant sterile homing gene drive targeting doublesex in Drosophila
26903C. Weizhe, G. Jialiang, L. Yiran and C. Jackson, bioRxiv, 2023.07.17.549342. 2023-07-17 11:00:13.
Gene drive alleles, which bias their own inheritance and increase in frequency, show great promise for blocking disease transmission or directly suppressing pest populations. The most common engineered drive system is the CRISPR homing drive, which converts wild-type alleles to drive alleles in the germline of drive heterozygotes by homology-directed repair after CRISPR cleavage. One successful homing drive example targets a female-specific exon in doublesex in Anopheles mosquitos, suppressing the population by inducing recessive sterility in female drive homozygotes. We found that in Drosophila melanogaster, a 3-gRNA drive disrupting the doublesex female exon resulted in a masculine phenotype and dominant female sterility. Resistance alleles formed by end-joining repair were also dominant sterile. This was likely caused by expression of male-specific transcripts in females with drive and resistance alleles, disrupting sex development. Based on this construct, we proposed a new pest suppression system called Release of Insects carrying a Dominant-sterile Drive (RIDD). This entails continuously releasing drive heterozygous males, with drive and resistance alleles causing sterility in females. The drive remains at high frequency longer than currently used dominant female-lethal alleles (RIDL) due to drive conversion in males, and drive alleles also cause sterility based on resistance, both substantial advantages. With weekly releases of drive males into a cage population with overlapping generations, our RIDD system targeting dsx reached 100% prevalence within 27 weeks, progressively reducing egg production and eventually causing total population collapse. RIDD combines the merits of homing gene drive and RIDL. It is powerful but self-limiting, unlike unconfined standard homing drives, allowing for targeted population suppression.Competing Interest StatementThe authors have declared no competing interest.
Modeling the Impact of Migration on Mosquito Population Suppression
27422M. Huang and J. Yu, Qualitative Theory of Dynamical Systems, 22:134. 2023-07-17 08:45:23.
The Wolbachia-induced incompatible insect technique is a promising strategy for controlling wild mosquito populations. However, recent experimental studies have shown that mosquito migration into target areas dilutes the strategy’s effectiveness. In this work, we formulate a delay differential equation model to assess the impact of migration on mosquito population suppression. We identify that mosquito migration into an idealized target area makes it impossible to eliminate the target population completely. Our analysis identifies a lower bound of the suppression rate $$gamma ^*$$for a given migration number, which reveals the possible maximum reduction of wild population size in the peak season. For a given suppression rate target $$gamma _0>gamma ^*$$, we identify the permitted maximum migration number $$D(gamma _0)$$, above which is impossible to reduce the field mosquito density up to $$(1-gamma _0)times 100%$$in peak season. To reduce more than $$95%$$of Aedes albopictus population during its peak season in Guangzhou within six weeks, the required minimum release number of Wolbachia-infected males climbs steeply as the migration number increases to D(0.05).
Estimating mosquito abundance and population suppression in an incompatible insect technique study
26901L. Griffin, D. Pagendam, C. Drovandi, B. Trewin and N. W. Beebe, Journal of Applied Ecology, 2023-07-10 10:53:08.
Our model can provide valuable insights that can shape decision support systems in sterile insect technique and incompatible insect technique programmes operating over large geographical scales. The model helps determine how many sterile/incompatible insects should be released over time and how population control is progressing (via use of counterfactual scenarios). These outcomes are achieved because the model provides estimates of wild-type populations over time, even when there has been no differentiation between sterile/incompatible and wild-type insects caught in trap
Threshold dynamics of a stochastic mathematical model for Wolbachia infections
26546J. Yang, Z. Chen, Y. Tan, Z. Liu and R. A. Cheke, Journal of Biological Dynamics, 17:2231967. 2023-07-07 08:51:13.
A stochastic mathematical model is proposed to study how environmental heterogeneity and the augmentation of mosquitoes with Wolbachia bacteria affect the outcomes of dengue disease. The existence and uniqueness of the positive solutions of the system are studied. Then the V-geometrically ergodicity and stochastic ultimate boundedness are investigated. Further, threshold conditions for successful population replacement are derived and the existence of a unique ergodic steady-state distribution of the system is explored. The results show that the ratio of infected to uninfected mosquitoes has a great influence on population replacement. Moreover, environmental noise plays a significant role in control of dengue fever.
MGSurvE: A framework to optimize trap placement for genetic surveillance of mosquito population
26616C. H. Sánchez, D. L. Smith and J. M. Marshall, bioRxiv, 2023-06-23 13:35:51.
Genetic surveillance of mosquito populations is becoming increasingly relevant as genetics-based mosquito control strategies advance from laboratory to field testing. Especially applicable are mosquito gene drive projects, the potential scale of which leads monitoring to be a significant cost driver. For these projects, monitoring will be required to detect unintended spread of gene drive mosquitoes beyond field sites, and the emergence of alternative alleles, such as drive-resistant alleles or non-functional effector genes, within intervention sites. This entails the need to distribute mosquito traps efficiently such that an allele of interest is detected as quickly as possible - ideally when remediation is still viable. Additionally, insecticide-based tools such as bednets are compromised by insecticide-resistance alleles for which there is also a need to detect as quickly as possible. To this end, we present MGSurvE (Mosquito Gene SurveillancE): a computational framework that optimizes trap placement for genetic surveillance of mosquito populations such that the time to detection of an allele of interest is minimized. A key strength of MGSurvE is that it allows important biological features of mosquitoes and the landscapes they inhabit to be accounted for, namely: i) resources required by mosquitoes (e.g., food sources and aquatic breeding sites) can be explicitly distributed through a landscape, ii) movement of mosquitoes may depend on their sex, the current state of their gonotrophic cycle (if female) and resource attractiveness, and iii) traps may differ in their attractiveness profile. Example MGSurvE analyses are presented to demonstrate optimal trap placement for: i) an Aedes aegypti population in a suburban landscape in Queensland, Australia, and ii)an Anopheles gambiae population on the island of São Tomé, São Tomé and Príncipe. Further documentation and use examples are provided in project's documentation. MGSurvE is freely available as an open-source Python package on pypi ( https://pypi.org/project/MGSurvE/ ). It is intended as a resource for both field and computational researchers interested in mosquito gene surveillance. AUTHOR SUMMARY: Mosquito-borne diseases such as malaria and dengue fever continue to pose a major health burden throughout much of the world. The impact of currently-available tools, such as insecticides and antimalarial drugs, is stagnating, and gene drive-modified mosquitoes are considered a novel tool that could contribute to continuing reductions in disease transmission. Gene drive approaches are unique in the field of vector control in that they involve transgenes that could potentially spread on a wide scale, and consequently, surveillance is expected to be a major cost driver for the technology. This is needed to monitor for unintended spread of intact drive alleles, and the emergence of alternative alleles such as homing-resistance alleles and non-functional effector genes. Additionally, surveillance of insecticide-resistance alleles is of interest to support the impact of insecticide-based tools such as bednets. Here, we present MGSurvE, a computational framework that optimizes trap placement for genetic surveillance of mosquito populations in order to minimize the time to detection for an allele of interest. MGSurvE has been tailored to various features of mosquito ecology, and is intended as a resource for researchers to optimize the efficiency of limited surveillance resources.
Modeling emergence of Wolbachia toxin-antidote protein functions with an evolutionary algorithm
26277J. Beckmann, J. Gillespie and D. Tauritz, Front Microbiol, 14:1116766. 2023-06-09 10:36:38.
Evolutionary algorithms (EAs) simulate Darwinian evolution and adeptly mimic natural evolution. Most EA applications in biology encode high levels of abstraction in top-down population ecology models. In contrast, our research merges protein alignment algorithms from bioinformatics into codon based EAs that simulate molecular protein string evolution from the bottom up. We apply our EA to reconcile a problem in the field of Wolbachia induced cytoplasmic incompatibility (CI). Wolbachia is a microbial endosymbiont that lives inside insect cells. CI is conditional insect sterility that operates as a toxin antidote (TA) system. Although, CI exhibits complex phenotypes not fully explained under a single discrete model. We instantiate in-silico genes that control CI, CI factors (cifs), as strings within the EA chromosome. We monitor the evolution of their enzymatic activity, binding, and cellular localization by applying selective pressure on their primary amino acid strings. Our model helps rationalize why two distinct mechanisms of CI induction might coexist in nature. We find that nuclear localization signals (NLS) and Type IV secretion system signals (T4SS) are of low complexity and evolve fast, whereas binding interactions have intermediate complexity, and enzymatic activity is the most complex. Our model predicts that as ancestral TA systems evolve into eukaryotic CI systems, the placement of NLS or T4SS signals can stochastically vary, imparting effects that might impact CI induction mechanics. Our model highlights how preconditions and sequence length can bias evolution of cifs toward one mechanism or another.
The optimal strategy of incompatible insect technique (IIT) using Wolbachia and the application to malaria control
25203T. Matsufuji and S. Seirin-Lee, Journal of Theoretical Biology, 569:111519. 2023-05-29 09:18:33.
For decades, techniques to control vector population with low environmental impact have been widely explored in both field and theoretical studies. The incompatible insect technique (IIT) using Wolbachia, based on cytoplasmic incompatibility, is a technique that Wolbachia-infected male mosquitoes are incapable of producing viable offspring after mating with wild-type female mosquitoes. While the IIT method experimentally ensured its effectiveness in several field works, the failure of female mosquito population control by replacement owing to the accidental contamination of Wolbachia-infected female mosquitoes has been a concern and an obstacle in implementing the IIT method in nature. In this study, we develop a population-based IIT mathematical model using cytoplasmic incompatibility and evaluate the effectiveness of the IIT method in scenarios where contamination is present or absent. In addition, by extending the model to assess the disease infection status of the human population with malaria, we evaluate the optimal release strategy and cost for successful disease control. Our study proves that IIT could be a promising method to control mosquito-borne diseases without perfect suppression of vector mosquito population regardless of contamination.
Leveraging eco-evolutionary models for gene drive risk assessment
25157M. A. Combs, A. J. Golnar, J. M. Overcash, A. L. Lloyd, K. R. Hayes, D. A. O’Brochta and K. M. Pepin, Trends in Genetics, 2023-05-15 15:09:00.
As development of gene drive systems accelerates and diversifies, predicting outcomes for target populations and the potential for human and environmental risks requires accounting for numerous eco-evolutionary processes.Gene drive dynamic models quantify the influence of features across genetics (e.g., resistance development and standing genetic diversity), demographics (e.g., mating systems and inbreeding), spatial ecology (e.g., dispersal and competition), biotic and abiotic environments (e.g., climate variation and landscape structure), and implementation strategies (e.g., introduction size and timing) on gene drive outcomes.Synthesizing published gene drive models reveals research trends, knowledge gaps, and emergent principles. Modeling limitations and tradeoffs are discussed.Integrating an iterative modeling approach within the existing phased pathway for gene drive research improves utility for risk assessment.
Mathematical modeling of the performance of wild and transgenic mosquitoes in malaria transmission
25861A. P. Wyse, A. J. B. dos Santos, J. D. Azevedo, A. C. de Meneses and V. M. D. Santos, Plos One, 18:23. 2023-04-28 08:20:19.
A mathematical model that simulates malaria transmission under the influence of transgenic mosquitoes refractory to malaria is presented in this paper. The zygosity of transgenic mosquitoes is taken into account and, consequently, the total population of mosquitoes is comprised of wild type and heterozygous and homozygous transgenic mosquitoes. These three mosquito varieties interact by mating and competition, and the genetic characteristics of their resulting offspring are in accordance with Mendelian genetics or the mutagenic chain reaction (MCR) technique. Although the incorporation of transgenic mosquitoes into the ecosystem reduces the incidence of malaria, the model also takes into account the importance of completing treatment in individuals with confirmed infection and the imminent risk of increased environmental temperature.
Modelling the effect of migration on the localisation and spread of a gene drive
24955C. Benjamin James and F.-L. Alexandre Jules Hen, bioRxiv, 2023.04.02.535303. 2023-04-04 14:22:19.
Gene drives have the potential to address pressing ecological issues. Through the super-Mendelian inheritance of a gene drive, a trait can be spread through a population even in spite of a fitness cost. This ability to spread is both its greatest quality and detractor. We may not want a gene drive to spread universally. If a gene drive were designed to cause the collapse of a pest population, it may inadvertently cause the collapse of the entire species. Migration is the mechanism through which a gene drive can spread to distant populations. Understanding its effect on the progression of a gene drive is crucial to our ability to control a gene drive. While migration can spread the gene drive to other populations, equally it can bring in other alleles to the population that may disrupt the progression of the gene drive. Through our deterministic migration gene drive model we can assess the conditions in which a gene drive is likely to spread to unintended populations, and if a gene drive is likely to be displaced by incoming alleles.Competing Interest StatementThe authors have declared no competing interest.
Modelling Emergence of Wolbachia Toxin-Antidote Protein Functions with an Evolutionary Algorithm
24926J. Beckmann, J. Gillespie and D. Tauritz, bioRxiv, 2023-03-25 13:50:46.
Evolutionary algorithms (EAs) simulate Darwinian evolution and adeptly mimic natural evolution. Most EA applications in biology encode high levels of abstraction in top-down ecological population models. In contrast, our research merges protein alignment algorithms from bioinformatics into codon based EAs that simulate molecular protein string evolution from the bottom up. We apply our EA to reconcile a problem in the field of Wolbachia induced cytoplasmic incompatibility (CI). Wolbachia is a microbial endosymbiont that lives inside insect cells. CI is conditional insect sterility that operates as a toxin antidote (TA) system. Although, CI exhibits complex phenotypes not fully explained under a single discrete model. We instantiate in-silico genes that control CI, CI factors ( cifs ), as strings within the EA chromosome. We monitor the evolution of their enzymatic activity, binding, and cellular localization by applying selective pressure on their primary amino acid strings. Our model helps rationalize why two distinct mechanisms of CI induction might coexist in nature. We find that nuclear localization signals (NLS) and Type IV secretion system signals (T4SS) are of low complexity and evolve fast, whereas binding interactions have intermediate complexity, and enzymatic activity is the most complex. Our model predicts that as ancestral TA systems evolve into eukaryotic CI systems, the placement of NLS or T4SS signals can stochastically vary, imparting effects that might impact CI induction mechanics. Our model highlights how preconditions, genetic diversity, and sequence length can bias evolution of cifs towards one mechanism or another.
Modeling Sustained Transmission of Wolbachia among Anopheles Mosquitoes: Implications for Malaria Control in Haiti
24916D. Florez, A. J. Young, K. J. Bernabé, J. M. Hyman and Z. Qu, Trop Med Infect Dis, 8. 2023-03-09 12:09:17.
Wolbachia infection in Anopheles albimanus mosquitoes can render mosquitoes less capable of spreading malaria. We developed and analyzed a mechanistic compartmental ordinary differential equation model to evaluate the effectiveness of Wolbachia-based vector control strategies among wild Anopheles mosquitoes in Haiti. The model tracks the mosquito life stages, including egg, larva, and adult (male and female). It also accounts for critical biological effects, such as the maternal transmission of Wolbachia through infected females and cytoplasmic incompatibility, which effectively sterilizes uninfected females when they mate with infected males. We derive and interpret dimensionless numbers, including the basic reproductive number and next-generation numbers. The proposed system presents a backward bifurcation, which indicates a threshold infection that needs to be exceeded to establish a stable Wolbachia infection. The sensitivity analysis ranks the relative importance of the epidemiological parameters at baseline. We simulate different intervention scenarios, including prerelease mitigation using larviciding and thermal fogging before the release, multiple releases of infected populations, and different release times of the year. Our simulations show that the most efficient approach to establishing Wolbachia is to release all the infected mosquitoes immediately after the prerelease mitigation process. Moreover, the model predicts that it is more efficient to release during the dry season than the wet season.
A mosquito population suppression model with a saturated Wolbachia release strategy in seasonal succession
24814Z. Zhang, L. Chang, Q. Huang, R. Yan and B. Zheng, J Math Biol, 86:51. 2023-03-06 08:55:06.
Releasing Wolbachia-infected male mosquitoes to suppress wild female mosquitoes through cytoplasmic incompatibility has shown great promise in controlling and preventing mosquito-borne diseases. To make the release logistically and economically feasible, we propose a saturated release strategy, which is only implemented during the epidemic season of mosquito-borne diseases. Under this assumption, the model becomes a seasonally switching ordinary differential equation model. The seasonal switch brings rich dynamics, including the existence of a unique periodic solution or exactly two periodic solutions, which are proved by using the qualitative property of the Poincaré map. Sufficient conditions are also obtained for determining the stability of the periodic solutions.
Hybrid incompatibilities in the anopheles gambiae species complex
24968A. Kriezis, Imperial College London, 2023-03-01 10:47:20.
Malaria is an infectious disease caused by parasites of the genus Plasmodium which is responsible for approximately 400,000 deaths annually, primarily in sub-Saharan Africa. Malaria is transmitted by mosquitoes belonging to the Anopheles gambiae species complex. While progress has been made to reduce the incidence of malaria, the emergence of insecticide resistance necessitates the development of novel vector control strategies. Gene drive technologies have seen significant advances in recent years, providing hope for their implementation in the near future. While gene flow has been identified between sibling species of the An. gambiae species complex, they are reproductively isolated by both pre- and post-zygotic isolation mechanisms. Interspecific crosses between most member species produce sterile hybrid males, in accordance with Haldane’s rule of speciation. The aim of this project was to support the development of gene drive technologies by investigating hybrid incompatibilities between two of the most significant vector species, Anopheles gambiae and Anopheles arabiensis. The potential for the introgression of genomic regions from one species into the genetic background of the other was investigated to help inform models regarding the spread of gene drives between sibling species. In addition, the identification of genetic elements involved in hybrid male sterility could provide potential targets for vector control strategies. Large autosomal regions were found to introgress and persist in interspecific genomes without a detectable fertility cost. In addition, the introduction of distinct autosomal regions of conspecific DNA into otherwise heterospecific genomes of hybrid males was found to overcome hybrid incompatibilities and partially restore fertility. While no specific genetic factors involved in hybrid incompatibilities could be identified, the results indicate that such factors are present at least on the X chromosome. Furthermore, the evidence suggests that asynapsis between interspecific homologous autosomes during gametogenesis plays a role in the manifestation of hybrid male sterility.
Simulations Reveal High Efficiency and Confinement of a Population Suppression CRISPR Toxin-Antidote Gene Drive
24791Y. Zhu and J. Champer, ACS Synthetic Biolog, 2023-02-24 09:56:44.
Though engineered gene drives hold great promise for spreading through and suppressing populations of disease vectors or invasive species, complications such as resistance alleles and spatial population structure can prevent their success. Additionally, most forms of suppression drives, such as homing drives or driving Y chromosomes, will generally spread uncontrollably between populations with even small levels of migration. The previously proposed CRISPR-based toxin-antidote system called toxin-antidote dominant embryo (TADE) suppression drive could potentially address the issues of confinement and resistance. However, it is a relatively weak form of drive compared to homing drives, which might make it particularly vulnerable to spatial population structure. In this study, we investigate TADE suppression drive using individual-based simulations in a continuous spatial landscape. We find that the drive is actually more confined than in simple models without space, even in its most efficient form with low cleavage rate in embryos from maternally deposited Cas9. Furthermore, the drive performed well in continuous space scenarios if the initial release requirements were met, suppressing the population in a timely manner without being severely affected by chasing, a phenomenon in which wild-type individuals avoid the drive by recolonizing empty areas. At higher embryo cut rates, the drive loses its ability to spread, but a single, widespread release can often still induce rapid population collapse. Thus, if TADE suppression gene drives can be successfully constructed, they may play an important role in control of disease vectors and invasive species when stringent confinement to target populations is desired.
Review of gene drive modelling and implications for risk assessment of gene drive organisms
24722J. L. Frieß, C. R. Lalyer, B. Giese, S. Simon and M. Otto, Ecological Modelling, 478:110285. 2023-02-13 09:34:10.
Synthetic gene drive (GD) systems constitute a form of novel invasive environmental biotechnology with far-reaching consequences beyond those of other known genetically modified organisms (GMOs). During the last 10 years, the development of GD systems has been closely linked to mathematical modelling which can provide feedback on how to achieve gene drive spread but also may be used to predict the ecological consequences of a gene drive release. GMOs, thus also GD systems, need to pass an environmental risk assessment (ERA) prior to a release into the environment. Models in this respect may play an important role because a release of GD organisms, even at a small scale, may not be reversible. In our review, we analyse the scope and structure of existing models to examine how they may assist the ERA. Our analysis reveals that a majority of models so far are deterministic, non-spatial and not tailored for a specific target organism. Models often use simplified assumptions on the biology of the species and seem to be made to test the effectiveness of the drive. Few models go beyond this and verify whether model predictions may be realistic under field conditions. We identified four advanced models that we judged to be the most ecologically realistic and compared the implemented parameters with ERA requirements by the European Food Safety Authority (EFSA) and World Health Organization (WHO) for genetically modified insects and mosquitoes. Although a number of abiotic and biotic factors are already considered in these models, mating-related factors and traits relevant to the interactions between the GMO and target organisms and with other species are largely excluded. Overall, our results show that biological and ecological realism are still poorly realized in current models and that most models aim to predict efficacy rather than ecological effects. Given the complexity of natural ecosystems, it may not be possible to compile a single model to cover all complexities. Thus, models should be further developed with the purpose to assist specific questions related to the risk assessment of GDs. Moreover, uncertainty will be a key issue for any model used in RA and we see the need to improve this aspect when modelling gene drives.
Dynamics of an impulsive reaction-diffusion mosquitoes model with multiple control measures
24571Y. Li, H. Zhao and K. Wang, Mathematical Biosciences and Engineering, 20:775-806. 2023-01-14 08:34:08.
It is well-known that mosquito control is one of the effective methods to reduce and prevent the transmission of mosquito-borne diseases. In this paper, we formulate a reaction-diffusion impulsive hybrid model incorporating Wolbachia, impulsively spraying of insecticides, spatial heterogeneity, and seasonality to investigate the control of mosquito population. The sufficient conditions for mosquito extinction or successful Wolbachia persistence in a population of natural mosquitoes are derived. More importantly, we give the estimations of the spraying times of insecticides during a period for achieving the mosquito extinction and population replacement in a special case. A global attractivity of the positive periodic solution is analyzed under appropriate conditions. Numerical simulations disclose that spatial heterogeneity and seasonality have significant impacts on the design of mosquitoes control strategies. It is suggested to combine biological control and chemical pulse control under certain situations to reduce the natural mosquitoes. Further, our results reveal that the establishment of a higher level of population replacement depends on the strain type of the Wolbachia and the high initial occupancy of the Wolbachia-infected mosquitoes.
Gene drive designs for efficient and localisable population suppression using Y-linked editors
24339R. Geci, K. Willis and A. Burt, PLOS Genetics, 18:e1010550. 2022-12-27 08:45:03.
Author summary Some pest populations can be successfully controlled by the inundative release of sterile males, but this approach is not practicable when the target population is large or the species difficult to rear. Computer modelling has previously demonstrated that releasing males with a genomic editor on their Y chromosome that kills or sterilises female descendants could be much more efficient, particularly if combined with a sex ratio distorter. Here we extend this work to show that Y-linked editors can also be used in even more efficient gene drive designs that would spread over successive generations beyond the region of release. Such spread could nonetheless be controlled by exploiting relatively small pre-existing differences in gene frequency between populations to restrict the spread and impact of the constructs, if desired. The proposed design does not require high rates of recombinational repair of DNA breaks or expression off the Y chromosome during meiosis, potentially expanding the range of species in which such low release rate control is possible. Y-linked editors may therefore form the basis of a highly flexible set of genetic strategies for population control.
Performance characteristics allow for confinement of a CRISPR toxin-antidote gene drive designed for population suppression
24272S. Zhang and J. Champer, bioRxiv, 2022.12.13.520356. 2022-12-15 14:08:18.
Gene drives alleles that can bias their own inheritance are a promising way to engineer populations for control of disease vectors, invasive species, and agricultural pests. Recent advancements in the field have yielded successful examples of powerful suppression type drives and confined modification type drives, but developing confined suppression drives has proven more difficult. This is because the necessary power for strong suppression is often incompatible with the characteristics needed for drive confinement. However, one type of CRISPR toxin-antidote drive may be strong enough and confined, the TADE (Toxin-Antidote Dominant Embryo) suppression drive. By disrupting a haplolethal target gene and a haplosufficient female fertility gene, this drive quickly eliminates wild-type alleles and eventually induces population suppression. It has been shown to perform effectively in panmictic populations. However, confinement in spatial scenarios may be substantially different. Here, we use a reaction-diffusion model to assess the performance of TADE suppression drive in continuous space. We measure the drive wave advance speed while varying several performance parameters and find that moderate fitness costs or embryo cutting (from maternally deposited nuclease) can eliminate the drive’s ability to form a wave of advance. We assess the release size required for the drive to propagate, and finally, we investigate migration corridor scenarios. Depending on the corridor size and dispersal, it is often possible for the drive to suppress one population and then persist in the corridor without invading the second population. This prevents re-invasion by wild-type, which may be a particularly desirable outcome in some scenarios. Thus, even imperfect variants of TADE suppression drive may be excellent candidates for confined population suppression.Competing Interest StatementThe authors have declared no competing interest.
Tolerance-conferring defensive symbionts and the evolution of parasite virulence
24126C. A. Smith and B. Ashby, bioRxiv, 2022-12-05 09:03:54.
Defensive symbionts in the host microbiome can confer protection from infection or reduce the harms of being infected by a parasite. Defensive symbionts are therefore promising agents of biocontrol that could be used to control or ameliorate the impact of infectious diseases. Previous theory has shown how symbionts can evolve along the parasitism-mutualism continuum to confer greater or lesser protection to their hosts, and in turn how hosts may coevolve with their symbionts to potentially form a mutualistic relationship. However, the consequences of introducing a defensive symbiont for parasite evolution and how the symbiont may coevolve with the parasite have yet to be explored theoretically. Here, we investigate the ecological and evolutionary implications of introducing a tolerance-conferring defensive symbiont into an established host-parasite system. We show that while the defensive symbiont may initially have a positive impact on the host population, parasite and symbiont evolution tend to have a net negative effect on the host population in the long-term. This is because the introduction of the defensive symbiont always selects for an increase in parasite virulence and may cause diversification into high- and low-virulence strains. Even if the symbiont experiences selection for greater host protection, this simply increases selection for virulence in the parasite, resulting in a net negative effect on the host population. Our results therefore suggest that tolerance-conferring defensive symbionts may be poor biocontrol agents for population-level infectious disease control.Competing Interest StatementThe authors have declared no competing interest.
Modeling-informed Engineered Genetic Incompatibility strategies to overcome resistance in the invasive Drosophila suzukii
28350A. Sychla, N. R. Feltman, W. D. Hutchison and M. J. Smanski, Frontiers in Insect Science, 2. 2022-11-22 10:46:03.
Engineered Genetic Incompatibility (EGI) is an engineered extreme underdominance genetic system wherein hybrid animals are not viable, functioning as a synthetic speciation event. There are several strategies in which EGI could be leveraged for genetic biocontrol of pest populations. We used an agent-based model of Drosophila suzukii (Spotted Wing Drosophila) to determine how EGI would fare with high rates of endemic genetic resistance alleles. We discovered a surprising failure mode wherein field-generated females convert an incompatible male release program into a population replacement gene drive. Local suppression could still be attained in two seasons by tailoring the release strategy to take advantage of this effect, or alternatively in one season by altering the genetic design of release agents. We show in this work that data from modeling can be utilized to recognize unexpected emergent phenomena and a priori inform genetic biocontrol treatment design to increase efficacy.
The effect of mating complexity on gene drive dynamics
23967P. Verma, R. G. Reeves, S. Simon, M. Otto and C. S. Gokhale, The American Naturalist, 2022-11-15 12:33:47.
Gene drive technology promises to deliver on some of the global challenges humanity faces today in health care, agriculture, and conservation. However, there is a limited understanding of the consequences of releasing self-perpetuating transgenic organisms into wild populations under complex ecological conditions. In this study, we analyze the impact of three such complexities—mate choice, mating systems, and spatial mating network—on the population dynamics for two distinct classes of modification gene drive systems. All three factors had a high impact on the modeling outcome. First, we demonstrate that distortion-based gene drives appear to be more robust against mate choice than viability-based gene drives. Second, we find that gene drive spread is much faster for higher degrees of polygamy. Including a fitness cost, the drive is fastest for intermediate levels of polygamy. Finally, the spread of a gene drive is faster and more effective when the individuals have fewer connections in a spatial mating network. Our results highlight the need to include mating complexities when modeling the properties of gene drives, such as release thresholds, timescales, and population-level consequences. This inclusion will enable a more confident prediction of the dynamics of engineered gene drives and possibly even inform about the origin and evolution of natural gene drives.
Gene drive technology to suppress invasive mice
23843University of Adelaide, Phys Org, 2022-11-09 09:55:57.
Researchers at the University of Adelaide have released their first findings on the potential effectiveness of revolutionary gene drive technology to control invasive mice. The team has developed a world-first proof of concept for the technology—called t-CRISPR—using laboratory mice. Using sophisticated computer modeling performed by co-first author Dr. Aysegul Birand, the researchers also found about 250 gene-modified mice could eradicate an island population of 200,000 mice in around 20 years. The results of the study have been published today in Proceedings of the National Academy of Sciences.
Leveraging a natural murine meiotic drive to suppress invasive populations
23835L. Gierus, A. Birand, M. D. Bunting, G. I. Godahewa, S. G. Piltz, K. P. Oh, A. J. Piaggio, D. W. Threadgill, J. Godwin, O. Edwards, P. Cassey, J. V. Ross, T. A. A. Prowse and P. Q. Thomas, Proceedings of the National Academy of Sciences, 119:e2213308119. 2022-11-08 09:36:13.
Invasive rodents are a major cause of environmental damage and biodiversity loss, particularly on islands. Unlike insects, genetic biocontrol strategies including population-suppressing gene drives with biased inheritance have not been developed in mice. Here, we demonstrate a gene drive strategy (t(CRISPR)) that leverages super-Mendelian transmission of the t haplotype to spread inactivating mutations in a haplosufficient female fertility gene (Prl). Using spatially explicit individual-based in silico modeling, we show that t(CRISPR) can eradicate island populations under a range of realistic field-based parameter values. We also engineer transgenic t(CRISPR) mice that, crucially, exhibit biased transmission of the modified t haplotype and Prl mutations at levels our modeling predicts would be sufficient for eradication. This is an example of a feasible gene drive system for invasive alien rodent population control.
Making waves: Comparative analysis of gene drive spread characteristics in a continuous space model
23816M. Pan and J. Champer, bioRxiv, 2022.11.01.514650. 2022-11-02 10:23:47.
With their ability to rapidly increase in frequency, gene drives can be used to modify or suppress target populations after an initial release of drive-containing individuals. Recent advances in this field have revealed many possibilities for different types of drives, and several of these have been realized in experimental demonstrations. These drives all have unique advantages and disadvantages related to their ease of construction, confinement, and capacity to act as a modification or suppression system. While many properties of these drives have been explored in modelling studies, assessment of these drives in continuous space environments has been limited, often focusing on outcomes rather than fundamental properties. Here, we conduct a comparative analysis of many different gene drive types that have the capacity to form a wave of advance against wild-type alleles in one-dimensional continuous space. We evaluate the drive wave speed as a function of drive performance and ecological parameters, which reveals substantial differences between drive performance in panmictic versus spatial environments. In particular, we find that suppression drive waves are uniquely vulnerable to fitness costs and undesired CRISPR cleavage activity that can form resistance alleles in embryos by maternal deposition. Some drives, though, retain robust characteristics even with widely varying performance characteristics. To gain a better understanding of drive waves, we compare panmictic performance of drives across the full range of drive frequencies. We find that rates of wild-type allele removal in panmictic setting is correlated with drive wave speed, though this is also affected by a range of other factors. Overall, our results provide a useful resource for understanding the performance of drives in continuous spatial environments, which may be most representative of potential drive deployment in many relevant scenarios.Competing Interest StatementThe authors have declared no competing interest.
Modeling the efficacy of CRISPR gene drive for snail immunity on schistosomiasis control
23810R. E. Grewelle, J. Perez-Saez, J. Tycko, E. K. O. Namigai, C. G. Rickards and G. A. De Leo, PLOS Neglected Tropical Diseases, 16:e0010894. 2022-10-31 09:02:03.
CRISPR gene drives could revolutionize the control of infectious diseases by accelerating the spread of engineered traits that limit parasite transmission in wild populations. Gene drive technology in mollusks has received little attention despite the role of freshwater snails as hosts of parasitic flukes causing 200 million annual cases of schistosomiasis. A successful drive in snails must overcome self-fertilization, a common feature of host snails which could prevents a drive's spread. Here we developed a novel population genetic model accounting for snails' mixed mating and population dynamics, susceptibility to parasite infection regulated by multiple alleles, fitness differences between genotypes, and a range of drive characteristics. We integrated this model with an epidemiological model of schistosomiasis transmission to show that a snail population modification drive targeting immunity to infection can be hindered by a variety of biological and ecological factors; yet under a range of conditions, disease reduction achieved by chemotherapy treatment of the human population can be maintained with a drive. Alone a drive modifying snail immunity could achieve significant disease reduction in humans several years after release. These results indicate that gene drives, in coordination with existing public health measures, may become a useful tool to reduce schistosomiasis burden in selected transmission settings with effective CRISPR construct design and evaluation of the genetic and ecological landscape.
Monotonicity properties arising in a simple model of Wolbachia invasion for wild mosquito populations
24568D. Vicencio, O. Vasilieva and P. Gajardo, Mathematical Biosciences and Engineering, 20:1148-1175. 2022-10-25 08:23:57.
Using tools borrowed from monotone dynamical system theory, in the proposed model, we prove the existence of an invariant threshold manifold that allows us to provide practical recommendations for performing single and periodic releases of Wolbachia-carrying mosquitoes, seeking the eventual elimination of wild insects that are capable of transmitting infections to humans. We illustrate these findings with numerical simulations using parameter values corresponding to the wMelPop strain of Wolbachia that is considered the best virus blocker but induces fitness loss in its carriers. In these tests, we considered multiple scenarios contrasting a periodic release strategy against a strategy with a single inundative release, comparing their effectiveness. Our study is presented as an expository and mathematically accessible tool to study the use of Wolbachia-based biocontrol versus more complex models.
Pulled, pushed or failed: the demographic impact of a gene drive can change the nature of its spatial spread
23805L. Kläy, L. Girardin, V. Calvez and F. Débarre, arXiv, 2022-10-25 07:50:10.
Understanding the temporal spread of gene drive alleles -- alleles that bias their own transmission -- through modeling is essential before any field experiments. In this paper, we present a deterministic reaction-diffusion model describing the interplay between demographic and allelic dynamics, in a one-dimensional spatial context. We focused on the traveling wave solutions, and more specifically, on the speed of gene drive invasion (if successful). We considered various timings of gene conversion (in the zygote or in the germline) and different probabilities of gene conversion (instead of assuming 100% conversion as done in a previous work). We compared the types of propagation when the intrinsic growth rate of the population takes extreme values, either very large or very low. When it is infinitely large, the wave can be either successful or not, and, if successful, it can be either pulled or pushed, in agreement with previous studies (extended here to the case of partial conversion). In contrast, it cannot be pushed when the intrinsic growth rate is vanishing. In this case, analytical results are obtained through an insightful connection with an epidemiological SI model. We conducted extensive numerical simulations to bridge the gap between the two regimes of large and low growth rate. We conjecture that, if it is pulled in the two extreme regimes, then the wave is always pulled, and the wave speed is independent of the growth rate. This occurs for instance when the fitness cost is small enough, or when there is stable coexistence of the drive and the wild-type in the population after successful drive invasion. Our model helps delineate the conditions under which demographic dynamics can affect the spread of a gene drive.
Anopheles homing suppression drive candidates exhibit unexpected performance differences in simulations with spatial structure
23734S. E. Champer, I. K. Kim, A. G. Clark, P. W. Messer and J. Champer, eLife, 11:e79121. 2022-10-14 06:37:55.
Recent experiments have produced several Anopheles gambiae homing gene drives that disrupt female fertility genes, thereby eventually inducing population collapse. Such drives may be highly effective tools to combat malaria. One such homing drive, based on the zpg promoter driving CRISPR/Cas9, was able to eliminate a cage population of mosquitoes. A second version, purportedly improved upon the first by incorporating an X-shredder element (which biases inheritance towards male offspring), was similarly successful. Here, we analyze experimental data from each of these gene drives to extract their characteristics and performance parameters and compare these to previous interpretations of their experimental performance. We assess each suppression drive within an individual-based simulation framework that models mosquito population dynamics in continuous space. We find that the combined homing/X-shredder drive is actually less effective at population suppression within the context of our mosquito population model. In particular, the combined drive often fails to completely suppress the population, instead resulting in an unstable equilibrium between drive and wild-type alleles. By contrast, otherwise similar drives based on the nos promoter may prove to be more promising candidates for future development than originally thought.
Mitotic exchange in female germline stem cells is the major source of Sex Ratio chromosome recombination in Drosophila pseudoobscura
23719S. Koury, G3 Genes|Genomes|Genetics, 2022-10-04 06:48:20.
Sex Ratio chromosomes in Drosophila pseudoobscura are selfish X chromosome variants associated with three non-overlapping inversions. In the male germline, Sex Ratio chromosomes distort segregation of X and Y chromosomes (99:1), thereby skewing progeny sex ratio. In the female germline, segregation of Sex Ratio chromosomes is mendelian (50:50), but non-overlapping inversions strongly suppress recombination establishing a 26 Megabase haplotype (constituting ∼20% of the haploid genome). Rare crossover events located between non-overlapping inversions can disrupt this haplotype, and recombinants have sometimes been found in natural populations. We recently reported on the first lab-generated Sex Ratio recombinants occurring at a rate of 0.0012 crossovers per female meiosis. An improved experimental design presented here reveals these recombination events were at least 4-fold more frequent than previously estimated. Furthermore, recombination events were strongly clustered, indicating the majority arose from mitotic exchange in female germline stem cells and not from meiotic crossing-over in primary oocytes. Finally, asymmetric recovery of complementary recombinants was consistent with unequal exchange causing the recombination-induced viability defects. Incorporating these experimental results into population models for Sex Ratio chromosome evolution provided a substantially better fit to natural population frequencies and allowed maintenance of the highly differentiated 26 Megabase Sex Ratio haplotype without invoking strong epistatic selection. This study provides the first estimate of spontaneous mitotic exchange for naturally-occurring chromosomes in Drosophila female germline stem cells, reveals a much higher Sex Ratio chromosome recombination rate, and develops a mathematical model that accurately predicts the rarity of recombinant Sex Ratio chromosomes in natural populations.
Externalities modulate the effectiveness of the Wolbachia release programme
23611E. E. Ooi and A. Wilder-Smith, The Lancet Infectious Diseases, 2022-09-28 09:16:47.
Despite the remarkable outcome in Yogyakarta, the wMel approach also has some challenges. In particular, the extent to which ecological, weather, and other external factors influence the dissemination and establishment of wMel in complex urban environments remains unclear. Whether the high and sustained penetration rate of wMel and the efficacy in preventing dengue that was observed in Yogyakarta are readily reproducible in other regions of the world that are vulnerable to repeated outbreaks of such viral diseases is also unclear. We therefore welcome the study into the real-world effectiveness of large-scale wMel release in the urban setting of Rio de Janeiro.3 The study assessed the rate of wMel introgression at the neighbourhood level and its effect on the localised incidence of dengue and chikungunya. Mosquitoes were released over a 2·5-year period starting in August, 2017.
Estimating the effect of the wMel release programme on the incidence of dengue and chikungunya in Rio de Janeiro, Brazil: a spatiotemporal modelling study
23608G. Ribeiro dos Santos, B. Durovni, V. Saraceni, T. I. Souza Riback, S. B. Pinto, K. L. Anders, et al., The Lancet Infectious Diseases, 2022-09-28 09:07:02.
Summary Background Introgression of genetic material from species of the insect bacteria Wolbachia into populations of Aedes aegypti mosquitoes has been shown in randomised and non-randomised trials to reduce the incidence of dengue; however, evidence for the real-world effectiveness of large-scale deployments of Wolbachia-infected mosquitoes for arboviral disease control in endemic settings is still scarce. A large Wolbachia (wMel strain) release programme was implemented in 2017 in Rio de Janeiro, Brazil. We aimed to assess the effect of this programme on the incidence of dengue and chikungunya in the city. Methods 67 million wMel-infected mosquitoes were released across 28 489 locations over an area of 86·8 km2 in Rio de Janeiro between Aug 29, 2017 and Dec 27, 2019. Following releases, mosquitoes were trapped and the presence of wMel was recorded. In this spatiotemporal modelling study, we assessed the effect of the release programme on the incidence of dengue and chikungunya. We used spatiotemporally explicit mathematical models applied to geocoded dengue cases (N=283 270) from 2010 to 2019 and chikungunya cases (N=57 705) from 2016 to 2019. Findings On average, 32% of mosquitoes collected from the release zones between 1 month and 29 months after the initial release tested positive for wMel. Reduced wMel introgression occurred in locations and seasonal periods in which cases of dengue and chikungunya were historically high, with a decrease to 25% of mosquitoes testing positive for wMel during months in which disease incidence was at its highest. Despite incomplete introgression, we found that the releases were associated with a 38% (95% CI 32–44) reduction in the incidence of dengue and a 10% (4–16) reduction in the incidence of chikungunya. Interpretation Stable establishment of wMel in the geographically diverse, urban setting of Rio de Janeiro seems to be more complicated than has been observed elsewhere. However, even intermediate levels of wMel seem to reduce the incidence of disease caused by two arboviruses. These findings will help to guide future release programmes. Funding Bill & Melinda Gates Foundation and the European Research Council.
Daisy-chain gene drives: The role of low cut-rate, resistance mutations, and maternal deposition
23623S. A. N. Verkuijl, M. A. E. Anderson, L. Alphey and M. B. Bonsall, PLOS Genetics, 18:e1010370. 2022-09-19 14:37:34.
Author summary Reducing the harm of pest species by the introgression of traits into a wild population is often limited by the difficulties of mass rearing and release of modified individuals. Gene drives present an opportunity to substantially reduce the release frequencies required to spread a particular modification. However, uniform modification of a target species is, with a few specific exceptions, not necessary or desirable. Self-limiting gene drives, such as daisy-chain gene drives, have been widely discussed as a potential solution, allowing the invasiveness of a drive release to be tuned to the target population. Here, we investigate through computational modelling how daisy-chain gene drives perform when subjected to commonly observed inefficiencies associated with CRISPR-Cas9-based inheritance biasing. Compared to a self-perpetuating drive, daisy-chain gene drives are sensitive to factors that cause their separate elements to segregate prematurely. In particular, a reduction in the DNA cut-rate and an increase in the formation of resistance alleles. We find that the effect of inefficiencies in the drive mechanism is generally more pronounced when the drive is at low frequencies. With low rates of migration, this substantially reduces daisy-chain gene drives spread into a neighbouring non-target population.
An optimal control problem for dengue transmission model with Wolbachia and vaccination
23694J. Zhang, L. L. Liu, Y. Z. Li and Y. Wang, Communications In Nonlinear Science and Numerical Simulation, 116. 2022-09-02 07:47:59.
The release of Wolbachia-infected mosquitoes into the wild mosquitoes population is an excellent biological control strategy which can be effective against mosquito-borne infections. In this work, we propose a dengue transmission model that incorporates releasing Wolbachia into the wild mosquito population and vaccinating human population. We analyze the basic reproduction number, the existence and stability of the equilibria, and carry out the sensitivity analysis to quantify the effects of parameters on the basic reproduction number. The analysis shows that the basic reproduction number determines the stability of two equilibria, and two transmission probabilities are positively correlated with the basic reproduction number, especially, the transmission probability of human being infected byWolbachia-infected mosquitoes is more sensitive than that of wild mosquitoes. Based on an integrated control strategy for the prevention of dengue fever (vaccination, using mosquito nets, improved treatment of dengue and spraying insecticides), we derive the necessary conditions for the optimal control problem using Pontryagin's Maximum Principle and carry out numerical simulations by MATLAB. Finally, the cost-effectiveness analysis of several control strategies is examined to determine the most feasible strategy. It shows that the most cost-effective integrated strategy is vaccination, using mosquito nets and spraying insecticides. (c) 2022 Elsevier B.V. All rights reserved.
A confinable female-lethal population suppression system in the malaria vector, Anopheles gambiae
23500A. L. Smidler, J. J. Pai, R. A. Apte, H. M. Sánchez C, R. M. Corder, E. J. Gutiérrez, N. Thakre, I. Antoshechkin, J. M. Marshall and O. S. Akbari, bioRxiv, 2022.08.30.505861. 2022-08-30 19:10:47.
Malaria is among the world’s deadliest diseases, predominantly affecting sub-Saharan Africa, and killing over half a million people annually. Controlling the principal vector, the mosquito Anopheles gambiae, as well as other anophelines, is among the most effective methods to control disease spread. Here we develop an innovative genetic population suppression system termed Ifegenia (Inherited Female Elimination by Genetically Encoded Nucleases to Interrupt Alleles) in this deadly vector. In this bicomponent CRISPR-based approach, we disrupt a female-essential gene, femaleless (fle), demonstrating complete genetic sexing via heritable daughter gynecide. Moreover, we show that Ifegenia males remain reproductively viable, and can load both fle mutations and CRISPR machinery to induce fle mutations in subsequent generations, resulting in sustained population suppression. Through modeling, we demonstrate that iterative releases of non-biting Ifegenia males can act as an effective, confinable, controllable, and safe population suppression and elimination system.
Environmentally appropriate vector control is facilitated by standard metrics for simulation-based evaluation
23443V. N. Vásquez, M. R. Reddy and J. M. Marshall, Frontiers in Tropical Diseases, 3. 2022-08-17 08:44:11.
As anthropogenic factors contribute to the introduction and expansion of new and established vector species, the geographic incidence of mosquito-borne disease is shifting. Computer simulations, informed by field data where possible, facilitate the cost-effective evaluation of available public health interventions and are a powerful tool for informing appropriate policy action. However, a variety of measurements are used in such assessments; this can complicate direct comparisons across both vector control technologies and the models used to simulate them. The expansion of biocontrol to include genetically engineered organisms is now prompting additional metrics with no analogy to traditional measurement approaches. We propose Standard Entomological Metrics (SEMs) to facilitate the model-based appraisal of both existing and novel intervention tools and define two examples: Suppression Efficacy Score and Time to Reduction Target. We formulate twelve synthetic case studies featuring two vector control technologies over three years of observed daily temperature in Cairns, Australia. After calculating Suppression Efficacy Score and Time to Reduction Target results, we apply these example outcomes to a discussion of health policy decision-making using SEMs. We submit that SEMs such as Suppression Efficacy Score and Time to Reduction Target facilitate the wholistic and environmentally appropriate simulation-based evaluation of intervention programs and invite the community to further discussion on this topic.
Harnessing Wolbachia cytoplasmic incompatibility alleles for confined gene drive: a modeling study
23424J. Li and J. Champer, bioRxiv, 2022.08.09.503337. 2022-08-11 07:25:47.
By using both mathematical and simulation models, we found that a drive containing CifA and CifB together create a confined drive with a moderate to high introduction threshold. When introduced separately, they act as a self-limiting drive. We observed that the performance of these drives is substantially influenced by various ecological parameters and drive characteristics. Extending our models to continuous space, we found that the drive individual release distribution has a critical impact on drive persistence.
Wolbachia Dynamics in Mosquitoes with Incomplete CI and Imperfect Maternal Transmission by a DDE System
23393Y. Su, B. Zheng and X. Zou, Bulletin of Mathematical Biology, 84:95. 2022-08-01 08:09:11.
In this paper, we propose a delay differential equation model to describe the Wolbachia infection dynamics in mosquitoes in which the key factor of cytoplasmic incompactibility (CI) is incorporated in a more natural way than those in the literature. By analyzing the dynamics of the model, we are able to obtain some information on the impact of four important parameters: the competition capabilities of the wild mosquitoes and infected mosquitoes, the maternal transmission level and the CI level. The analytic results show that there are ranges of parameters that support competition exclusion principle, and there are also ranges of parameters that allow co-persistence for both wild and infected mosquitoes. These ranges account for the scenarios of failure of invasion, invasion and suppressing the wild mosquitoes, and invasion and replacing the wild mosquitoes. We also discuss some possible future problems both in mathematics and in modeling.
A theory of resistance to multiplexed gene drive demonstrates the significant role of weakly deleterious natural genetic variation
23362B. S. Khatri and A. Burt, Proceedings of the National Academy of Sciences, 119:e2200567119. 2022-08-01 07:26:58.
CRISPR-based gene drives have the potential for controlling natural populations of disease vectors, such as malaria-carrying mosquitoes in sub-Saharan Africa. If successful, they hold promise of significantly reducing the burden of disease and death from malaria and many other vector-borne diseases. A significant challenge to success is the evolution of resistance. Here, we develop a theory of resistance for multiplexed drive, which shows the importance of weakly deleterious naturally occurring genetic variation, whose effect is significantly amplified compared to de novo mutation. These results provide a fundamental basis to estimate how many guide RNAs are required to prevent resistance in the face of natural genetic variation. Evolution of resistance is a major barrier to successful deployment of gene-drive systems to suppress natural populations, which could greatly reduce the burden of many vector-borne diseases. Multiplexed guide RNAs (gRNAs) that require resistance mutations in all target cut sites are a promising antiresistance strategy since, in principle, resistance would only arise in unrealistically large populations. Using stochastic simulations that accurately model evolution at very large population sizes, we explore the probability of resistance due to three important mechanisms: 1) nonhomologous end-joining mutations, 2) single-nucleotide mutants arising de novo, or 3) single-nucleotide polymorphisms preexisting as standing variation. Our results explore the relative importance of these mechanisms and highlight a complexity of the mutation?selection?drift balance between haplotypes with complete resistance and those with an incomplete number of resistant alleles. We find that this leads to a phenomenon where weakly deleterious naturally occurring variants greatly amplify the probability of multisite resistance compared to de novo mutation. This key result provides design criterion for antiresistance multiplexed systems, which, in general, will need a larger number of gRNAs compared to de novo expectations. This theory may have wider application to the evolution of resistance or evolutionary rescue when multiple changes are required before selection can act.
Robust control strategy by the Sterile Insect Technique for reducing epidemiological risk in presence of vector migration
23331P.-A. Bliman and Y. Dumont, Mathematical Biosciences, 350:108856. 2022-07-28 08:36:35.
The Sterile Insect Technique (SIT) is a promising technique to control mosquitoes, vectors of diseases, like dengue, chikungunya or Zika. However, its application in the field is not easy, and its success hinges upon several constraints, one of them being that the treated area must be sufficiently isolated to limit migration or re-invasion by mosquitoes from the outside. In this manuscript we study the impact of males and (fertile) females migration on SIT. We show that a critical release rate for sterile males exists for every migration level, in the context of continuous or periodic releases. In particular, when (fertile) females migration is sufficiently low, then SIT can be conducted successfully using either open-loop control or closed-loop control (or a combination of both methods) when regular measurements of the wild population are completed. Numerical simulations to illustrate our theoretical results are presented and discussed. Finally, we derive a threshold value for the females migration rate, when viruses are circulating, under which it is possible to lower the epidemiological risk in the treated area, according to the size of the human population.
Population replacement gene drive characteristics for malaria elimination in a range of seasonal transmission settings: a modelling study
23307S. Leung, N. Windbichler, E. A. Wenger, C. A. Bever and P. Selvaraj, Malaria Journal, 21:226. 2022-07-26 07:49:07.
BACKGROUND: Gene drives are a genetic engineering method where a suite of genes is inherited at higher than Mendelian rates and has been proposed as a promising new vector control strategy to reinvigorate the fight against malaria in sub-Saharan Africa. METHODS: Using an agent-based model of malaria transmission with vector genetics, the impacts of releasing population-replacement gene drive mosquitoes on malaria transmission are examined and the population replacement gene drive system parameters required to achieve local elimination within a spatially-resolved, seasonal Sahelian setting are quantified. The performance of two different gene drive systems-"classic" and "integral"-are evaluated. Various transmission regimes (low, moderate, and high-corresponding to annual entomological inoculation rates of 10, 30, and 80 infectious bites per person) and other simultaneous interventions, including deployment of insecticide-treated nets (ITNs) and passive healthcare-seeking, are also simulated. RESULTS: Local elimination probabilities decreased with pre-existing population target site resistance frequency, increased with transmission-blocking effectiveness of the introduced antiparasitic gene and drive efficiency, and were context dependent with respect to fitness costs associated with the introduced gene. Of the four parameters, transmission-blocking effectiveness may be the most important to focus on for improvements to future gene drive strains because a single release of classic gene drive mosquitoes is likely to locally eliminate malaria in low to moderate transmission settings only when transmission-blocking effectiveness is very high (above ~ 80-90%). However, simultaneously deploying ITNs and releasing integral rather than classic gene drive mosquitoes significantly boosts elimination probabilities, such that elimination remains highly likely in low to moderate transmission regimes down to transmission-blocking effectiveness values as low as ~ 50% and in high transmission regimes with transmission-blocking effectiveness values above ~ 80-90%. CONCLUSION: A single release of currently achievable population replacement gene drive mosquitoes, in combination with traditional forms of vector control, can likely locally eliminate malaria in low to moderate transmission regimes within the Sahel. In a high transmission regime, higher levels of transmission-blocking effectiveness than are currently available may be required.
Adaptive meiotic drive in selfing populations with heterozygote advantage
23271E. Brud, Theoretical Population Biology, 146:61-70. 2022-07-13 07:46:37.
The egalitarian allotment of gametes to each allele at a locus (Mendel's law of segregation) is a near-universal phenomenon characterizing inheritance in sexual populations. As exceptions to Mendel's law are known to occur, one can investigate why non-Mendelian segregation is not more common using modifier theory. Earlier work assuming sex-independent modifier effects in a random mating population with heterozygote advantage concluded that equal segregation is stable over long-term evolution. Subsequent investigation, however, demonstrated that the stability of the Mendelian scheme disappears when sex-specific modifier effects are allowed. Here I derive invasion conditions favoring the repeal of Mendelian law in mixed and obligate selfing populations. Oppositely-directed segregation distortion in the production of male and female gametes is selected for in the presence of overdominant fitness. The conditions are less restrictive than under panmixia in that strong selection can occur even without differential viability of reciprocal heterozygotes (i.e. in the absence of parent-of-origin effects at the overdominant fitness locus). Generalized equilibria are derived for full selfing.
Scalability of genetic biocontrols for eradicating invasive alien mammals
23159A. Birand, P. Cassey, J. V. Ross, P. Q. Thomas and T. A. A. Prowse, NeoBiota, 74:93-103. 2022-07-07 09:59:20.
CRISPR-based gene drives offer novel solutions for controlling invasive alien species, which could ultimately extend eradication efforts to continental scales. Gene drives for suppressing invasive alien vertebrates are now under development. Using a landscape-scale individual-based model, we present the first estimates of times to eradication for long-lived alien mammals. We show that demography and life-history traits interact to determine the scalability of gene drives for vertebrate pest eradication. Notably, optimism around eradicating smaller-bodied pests (rodents and rabbits) with gene-drive technologies does not easily translate into eradication of larger-bodied alien species (cats and foxes).
Slow and steady wins the race: spatial and stochastic processes and the failure of suppression gene drives
23117J. F. Paril and B. L. Phillips, Molecular Ecology, 2022-07-05 08:47:10.
Gene drives that skew sex ratios offer a new management tool to suppress or eradicate pest populations. Early models and empirical work suggest that these suppression drives can completely eradicate well-mixed populations, but models that incorporate stochasticity and space (i.e., drift, and recolonization events) often result in loss or failure of the drive. We developed a stochastic model to examine these processes in a simple 1-dimensional space. This simple space allows us to map the events and outcomes that emerged and examine how properties of the drive's wave of invasion affect outcomes. Our simulations, across a biologically-realistic section of parameter space, suggest that drive failure might be a common outcome in spatially explicit, stochastic systems, and that properties of the drive wave appear to mediate outcomes. Surprisingly, the drives that would be considered fittest in an aspatial model were strongly associated with failure in the spatial setting. The fittest drives cause relatively fast moving, and narrow waves that have a high chance of being penetrated by wild-types leading to wild-type recolonization, leading to failure. Our results also show that high rates of dispersal reduce the chance of failure because drive waves get disproportionately wider than wild-type waves as dispersal rates increase. Overall, wide, slow-moving drive waves were much less prone to failure. Our results point to the complexity inherent in using a genetic system to effect demographic outcomes and speak to a clear need for ecological and evolutionary modelling to inform the drive design process.
The suppressive potential of a gene drive in populations of invasive social wasps is currently limited
23091A. B. Meiborg, N. R. Faber, B. A. Taylor, B. A. Harpur and G. Gorjanc, bioRxiv, 2022.06.27.497711. 2022-06-30 07:33:43.
Social insects are very successful invasive species, and the continued increase of global trade and transportation has exacerbated this problem. The yellow-legged hornet, Vespa velutina nigrithorax (henceforth Asian hornet), is drastically expanding its range in Western Europe. As an apex insect predator, this hornet poses a serious threat to the honey bee industry and endemic pollinators. Current suppression methods have proven too inefficient and expensive to limit its spread. Gene drives might be an effective tool to control this species, but their use has not yet been thoroughly investigated in social insects. Here, we built a model that matches the hornet’s life history and modelled the effect of different gene drive scenarios on an established invasive population. To test the broader applicability and sensitivity of the model, we also incorporated the invasive European paper wasp Polistes dominula. We find that although a gene drive can spread through a social wasp population, it can only do so under stringent gene drive-specific conditions. The main issue is that the large number of offspring that social wasp colonies produce guarantees that, even with very limited formation of resistance alleles, such alleles will quickly spread and rescue the population. Furthermore, we find that only a gene drive targeting female fertility is promising for population control due to the haplodiploidy of social insects. Nevertheless, continued improvements in gene drive technology may make it a promising method for the control of invasive social insects.Competing Interest StatementThe authors have declared no competing interest.
DriverSEAT: A spatially-explicit stochastic modelling framework for the evaluation of gene drives in novel target species
23008M. Legros and L. G. Barrett, bioRxiv, 2022.06.13.496025. 2022-06-16 08:19:49.
Gene drives represent a potentially ground breaking technology for the control of undesirable species or the introduction of desirable traits in wild population, and there is strong interest in applying these technologies to a wide range of species across many domains including agriculture, health, conservation and biosecurity. There remains however considerable uncertainty regarding the feasibility and efficacy of gene drives in various species, based in particular on biological and ecological specificities of each target. In this paper we introduce DriverSEAT, a new spatial, modular modelling framework designed to assess the outcome of gene drives in a range of target species based on their specific ecological dynamics and genetics. In addition to the main structure and characteristics of the model, we present an example of its application on scenarios of genetic control of weeds, a potential candidate for gene drive control that presents significant challenges associated with plant population dynamics. We illustrate here how the results from DriverSEAT can inform on the potential value of gene drives in this specific context, and generally provide ecologically informed guidance for the development and feasibility of gene drives as a control method in new target species.Competing Interest StatementThe authors have declared no competing interest.
Unbalanced selection: the challenge of maintaining a social polymorphism when a supergene is selfish
22895A. G. Tafreshi, S. P. Otto and M. Chapuisat, Philos Trans R Soc Lond B Biol Sci, 377:20210197. 2022-06-13 06:11:36.
Supergenes often have multiple phenotypic effects, including unexpected detrimental ones, because recombination suppression maintains associations among co-adapted alleles but also allows the accumulation of recessive deleterious mutations and selfish genetic elements. Yet, supergenes often persist over long evolutionary periods. How are such polymorphisms maintained in the face of selection, drive and drift? We present a population genetic model that investigates the conditions necessary for a stable polymorphic equilibrium when one of the supergene haplotypes is a selfish genetic element. The model fits the characteristics of the Alpine silver ant, Formica selysi, in which a large supergene underlies colony social organization, and one haplotype distorts Mendelian transmission by killing progeny that did not inherit it. The model shows that such maternal-effect killing strongly limits the maintenance of social polymorphism. Under random mating, transmission ratio distortion prevents rare single-queen colonies from invading populations of multiple-queen colonies, regardless of the fitness of each genotype. A stable polymorphic equilibrium can, however, be reached when high rates of assortative mating are combined with large fitness differences among supergene genotypes. The model reveals that the persistence of the social polymorphism is non-trivial and expected to occur only under restrictive conditions that deserve further empirical investigation. This article is part of the theme issue 'Genomic architecture of supergenes: causes and evolutionary consequences'.
Modeling the impact of genetically modified male mosquitoes in the spatial population dynamics of Aedes aegypti
23212M. R. da Silva, P. H. G. Lugão, F. Prezoto and G. Chapiro, Scientific Reports, 12:9112. 2022-06-01 06:29:36.
The mosquito Aedes aegypti is the primary vector of diseases such as dengue, Zika, chikungunya, and yellow fever. Improving control techniques requires a better understanding of the mosquito’s life cycle, including spatial population dynamics in endemic regions. One of the most promising techniques consists of introducing genetically modified male mosquitoes. Several models proposed to describe this technique present mathematical issues or rely on numerous parameters, making their application challenging to real-world situations. We propose a model describing the spatial population dynamics of the Aedes aegypti in the presence of genetically modified males. This model presents some mathematical improvements compared to the literature allowing deeper mathematical analysis. Moreover, this model relies on few parameters, which we show how to obtain or estimate from the literature. Through numerical simulations, we investigate the impacts of environmental heterogeneity, the periodicity of genetically modified male releases, and released genetically modified males quantity on the population dynamics of Aedes aegypti. The main results point to that the successful application of this vector control technique relies on releasing more than a critical amount of modified males with a frequency exceeding a specific critical value.
Combined Trojan Y Chromosome Strategy and Sterile Insect Technique to Eliminate Mosquitoes: Modelling and Analysis
23051J. Lyu, M. Gu, S. Wang and K. Cheng, Mathematical Problems in Engineering, 2022:2373350. 2022-05-27 15:09:13.
Sterile insect technique has been successfully applied in the control of agricultural pests; however, it has a limited ability to control mosquitoes. A promising alternative approach is the Trojan Y Chromosome strategy, which works by manipulating the sex ratio of a population through the introduction of YY supermales that guarantee male offspring. To take the advantages of both approaches, a combined Trojan Y chromosome strategy and sterile insect technique (TYC-SIT) strategy considering intraspecies competition is modeled. The pure TYC method is compared with the pure SIT method by cancelling one-state variable. The dynamical analysis leads to results on both local and global stabilities of this combined TYC-SIT model. Optimal control analysis is also implemented to investigate the optimal mechanisms for extinction of mosquitoes. In particular, the numerical results affirm that the combined TYC-SIT enables near elimination of mosquitoes and works better than the pure TYC or pure SIT method. These conclusions have great significance for species controls with an XX-XY sex determinism system or ZZ-ZW system.
Recommendations for environmental risk assessment of gene drive applications for malaria vector control
22586J. B. Connolly, J. D. Mumford, D. C. M. Glandorf, S. Hartley, O. T. Lewis, S. W. Evans, G. Turner, C. Beech, N. Sykes, M. B. Coulibaly, J. Romeis, J. L. Teem, W. Tonui, B. Lovett, A. Mankad, A. Mnzava, S. Fuchs, T. D. Hackett, W. G. Landis, J. M. Marshall, Malar J, 21:152. 2022-05-25 09:36:02.
Building on an exercise that identified potential harms from simulated investigational releases of a population suppression gene drive for malaria vector control, a series of online workshops identified nine recommendations to advance future environmental risk assessment of gene drive applications.
Perplexing dynamics of Wolbachia proteins for cytoplasmic incompatibility
22582T. Harumoto and T. Fukatsu, PLOS Biology, 20:e3001644. 2022-05-25 09:23:59.
The mechanism of symbiont-induced cytoplasmic incompatibility has been a long-lasting mystery. This Primer explores a new study on Wolbachia’s Cif proteins in PLOS Biology that provides supportive evidence for the “Host-Modification Model,” although the alternative “Toxin-Antidote Model” is still in the running.
Adversarial interspecies relationships facilitate population suppression by gene drive in spatially explicit models
22288Y. Liu, W. Teo, H. Yang and J. Champer, bioRxiv, 2022.05.08.491087. 2022-05-08 08:15:29.
Suppression gene drives are designed to bias their inheritance and increase in frequency in a population, disrupting an essential gene in the process. When the frequency is high enough, the population will be unable to reproduce above the replacement level and could be eliminated. CRISPR suppression drives based on the homing mechanism have already seen success in the laboratory, particularly in malaria mosquitoes. However, several models predict that the use of these drives in realistic populations with spatial structure may not achieve complete success. This is due to the ability of wild-type individuals to escape the drive and reach empty areas with reduced competition, allowing them to achieve high reproductive success and leading to extinction-recolonization cycles across the landscape. Here, we extend our continuous space gene drive framework to include two competing species or predator-prey species pairs. We find in both discrete-generation and mosquito-specific models that the presence of a competing species or predator can greatly facilitate drive-based suppression, even for drives with modest efficiency. However, the presence of a competing species also substantially increases the frequency of outcomes in which the drive is lost before suppression is achieved. These results are robust in models with seasonal population fluctuations. We also found that suppression can be somewhat more difficult if targeting a predator with strong predator-prey interactions. Our results illustrate the difficulty of predicting outcomes of interventions that could substantially affect the populations of interacting species in complex ecosystems. However, our results are also potentially promising for the prospects of less powerful gene drives in achieving successful elimination of target pest populations.Competing Interest StatementThe authors have declared no competing interest.
A metapopulation approach to identify targets for Wolbachia-based dengue control
22221A. Reyna-Lara, D. Soriano-Paños, J. H. Arias-Castro, H. J. Martínez and J. Gómez-Gardeñes, Chaos, 32:041105. 2022-04-18 15:42:29.
Over the last decade, the release of Wolbachia-infected Aedes aegypti into the natural habitat of this mosquito species has become the most sustainable and long-lasting technique to prevent and control vector-borne diseases, such as dengue, zika, or chikungunya. However, the limited resources to generate such mosquitoes and their effective distribution in large areas dominated by the Aedes aegypti vector represent a challenge for policymakers. Here, we introduce a mathematical framework for the spread of dengue in which competition between wild and Wolbachia-infected mosquitoes, the cross-contagion patterns between humans and vectors, the heterogeneous distribution of the human population in different areas, and the mobility flows between them are combined. Our framework allows us to identify the most effective areas for the release of Wolbachia-infected mosquitoes to achieve a large decrease in the global dengue prevalence.
The sterile insect technique is protected from evolution of mate discrimination
21768J. J. Bull and R. Gomulkiewicz, PeerJ, 10:e13301. 2022-04-18 07:53:47.
Background The sterile insect technique (SIT) has been used to suppress and even extinguish pest insect populations. The method involves releasing artificially reared insects (usually males) that, when mating with wild individuals, sterilize the broods. If administered on a large enough scale, the sterility can collapse the population. Precedents from other forms of population suppression, especially chemicals, raise the possibility of resistance evolving against the SIT. Here, we consider resistance in the form of evolution of female discrimination to avoid mating with sterile males. Is resistance evolution expected? Methods We offer mathematical models to consider the dynamics of this process. Most of our models assume a constant-release protocol, in which the same density of males is released every generation, regardless of wild male density. A few models instead assume proportional release, in which sterile releases are adjusted to be a constant proportion of wild males. Results We generally find that the evolution of female discrimination, although favored by selection, will often be too slow to halt population collapse when a constant-release implementation of the SIT is applied appropriately and continually. The accelerating efficacy of sterile males in dominating matings as the population collapses works equally against discriminating females as against non-discriminating females, and rare genes for discrimination are too slow to ascend to prevent the loss of females that discriminate. Even when migration from source populations sustains the treated population, continued application of the SIT can prevent evolution of discrimination. However, periodic premature cessation of the SIT does allow discrimination to evolve. Likewise, use of a ‘proportional-release’ protocol is also prone to escape from extinction if discriminating genotypes exist in the population, even if those genotypes are initially rare. Overall, the SIT is robust against the evolution of mate discrimination provided care is taken to avoid some basic pitfalls. The models here provide insight for designing programs to avoid those pitfalls.
Propagation of seminal toxins through binary expression gene drives could suppress populations
21691J. Hurtado, S. Revale and L. M. Matzkin, Scientific Reports, 12:6332. 2022-04-15 08:22:57.
Gene drives can be highly effective in controlling a target population by disrupting a female fertility gene. To spread across a population, these drives require that disrupted alleles be largely recessive so as not to impose too high of a fitness penalty. We argue that this restriction may be relaxed by using a double gene drive design to spread a split binary expression system. One drive carries a dominant lethal/toxic effector alone and the other a transactivator factor, without which the effector will not act. Only after the drives reach sufficiently high frequencies would individuals have the chance to inherit both system components and the effector be expressed. We explore through mathematical modeling the potential of this design to spread dominant lethal/toxic alleles and suppress populations. We show that this system could be implemented to spread engineered seminal proteins designed to kill females, making it highly effective against polyandrous populations.
Mathematical modelling to assess the feasibility of Wolbachia in malaria vector biocontrol
22650S. Andreychuk and L. Yakob, Journal of Theoretical Biology, 542. 2022-03-29 06:30:06.
Releasing mosquitoes transinfected with the endosymbiotic bacterium Wolbachia is a novel strategy for interrupting vector-borne pathogen transmission. Following its success in controlling arboviruses spread by Aedes aegypti, this technology is being adapted for anopheline malaria vectors. However, antagonistic interactions between Wolbachia and naturally resident Asaia bacteria in malaria vectors have been demonstrated experimentally, potentially jeopardising Wolbachia biocontrol. We developed the first mathematical model accounting for interspecific competition between endosymbionts to assess the feasibility of this novel strategy for controlling malaria. First, Asaia prevalences among natural mosquito populations were compared with simulations parametrized with rates of Asaia transmission reported from laboratory studies. Discrepancies between projections and natural Asaia prevalences indicated potential overestimation of Asaia transmissibility in artificial laboratory settings. With parametrization that matches natural Asaia prevalence, simulations identified redundancies in Asaia's many infection routes (vertical, sexual and environmental). This resilience was only overcome when Wolbachia conferred very high resistance to environmental infection with Asaia, resulting in Wolbachia fixation and Asaia exclusion. Wolbachia's simulated spread was prevented when its maternal transmission was impeded in coinfected mosquitoes and the pre-control Asaia prevalence was beyond a threshold of 60-75%. This theoretical assessment highlights critical next steps in laboratory experiments to inform this strategy's feasibility. (c) 2022 The Author(s). Published by Elsevier Ltd.
Finding the strongest gene drive: Simulations reveal unexpected performance differences between Anopheles homing suppression drive candidates
21566S. E. Champer, I. K. Kim, A. G. Clark, P. W. Messer and J. Champer, bioRxiv, 2022.03.28.486009. 2022-03-28 12:29:28.
Recent experiments have produced several Anopheles gambiae homing gene drives that disrupt female fertility genes, thereby eventually inducing population collapse. Such drives may be highly effective tools to combat malaria. One such homing drive, based on the zpg promoter driving CRISPR/Cas9, was able to eliminate a cage population of mosquitoes. A second version, purportedly improved upon the first by incorporating an X-shredder element (which biases inheritance towards male offspring), was similarly successful. Here, we re-analyze the data of each of these gene drives and suggest an alternative interpretation of their performance. We assess each suppression drive within an individual-based simulation framework that models mosquito population dynamics in continuous space. We find that the combined homing/X-shredder drive is actually less effective at population suppression within the context of our mosquito population model. In particular, the combined drive often fails to completely suppress the population, instead resulting in an unstable equilibrium between drive and wild-type alleles. By contrast, otherwise similar drives based on the nos promoter may prove to be more promising candidates for future development due to potentially superior performance.Competing Interest StatementThe authors have declared no competing interest.
Modelling homing suppression gene drive in haplodiploid organisms
21016Y. Liu and J. Champer, bioRxiv, 2021.10.12.464047. 2022-03-15 06:38:01.
Gene drives have shown great promise for suppression of pest populations. These engineered alleles can function by a variety of mechanisms, but the most common is the CRISPR homing drive, which converts wild-type alleles to drive alleles in the germline of heterozygotes. Some potential target species are haplodiploid, in which males develop from unfertilized eggs and thus have only one copy of each chromosome. This prevents drive conversion, a substantial disadvantage compared to diploids where drive conversion can take place in both sexes. Here, we study homing suppression gene drives in haplodiploids and find that a drive targeting a female fertility gene could still be successful. However, such drives are less powerful than in diploids and suffer more from functional resistance alleles. They are substantially more vulnerable to high resistance allele formation in the embryo due to maternally deposited Cas9 and gRNA and also to somatic cleavage activity. Examining spatial models where organisms move over a continuous landscape, we find that haplodiploid suppression drives surprisingly perform nearly as well as in diploids, possibly due to their ability to spread further before inducing strong suppression. Together, these results indicate that gene drive can potentially be used to effectively suppress haplodiploid populations.Competing Interest StatementThe authors have declared no competing interest.
Rescue by gene swamping as a gene drive deployment strategy
20587K. D. Harris and G. Greenbaum, bioRxiv, 2022.03.08.483503. 2022-03-08 11:25:49.
Gene drives are genetic constructs that can spread deleterious alleles with potential application to population suppression of harmful species. Given that a gene drive can potentially spill over to other populations or even other species, control measures and fail-safes strategies must be considered. Gene drives are designed to generate a rapid demographic decline, while at the same time generating a dynamic change in the population’s genetics. Since these evolutionary and demographic processes are linked and are expected to occur at a similar time-scale during gene drive spread, feedback between these processes may significantly affect the outcome of deployment. To study this feedback and to understand how it affects gene drive spillovers, we developed a gene drive model that combines evolutionary and demographic dynamics in a two-population setting. The model demonstrates how feedback between evolutionary and demographic dynamics can generate additional outcomes to those generated by the evolutionary dynamics alone. We identify an outcome of particular interest, where the short-term suppression of the target population is followed by gene swamping and loss of the gene drive. This outcome could be useful for designing gene drive deployments that temporarily suppress the population, but ultimately do not remain in the population. Using our model, we demonstrate the robustness of this outcome to spillover and to the evolution of resistance, and suggest that it could be used as a fail-safe strategy for gene drive deployment.Competing Interest StatementThe authors have declared no competing interest.
Selfish migrants: How a meiotic driver is selected to increase dispersal
20575J. N. Runge, H. Kokko and A. K. Lindholm, J Evol Biol, 2022-03-07 10:54:44.
Meiotic drivers are selfish genetic elements that manipulate meiosis to increase their transmission to the next generation to the detriment of the rest of the genome. One example is the t haplotype in house mice, which is a naturally occurring meiotic driver with deleterious traits-poor fitness in polyandrous matings and homozygote inviability or infertility-that prevent its fixation. Recently, we discovered and validated a novel effect of t in a long-term field study on free-living wild house mice and with experiments: t-carriers are more likely to disperse. Here, we ask what known traits of the t haplotype can select for a difference in dispersal between t-carriers and wildtype mice. To that end, we built individual-based models with dispersal loci on the t and the homologous wildtype chromosomes. We also allow for density-dependent expression of these loci. The t haplotype consistently evolves to increase the dispersal propensity of its carriers, particularly at high densities. By examining variants of the model that modify different costs caused by t, we show that the increase in dispersal is driven by the deleterious traits of t, disadvantage in polyandrous matings and lethal homozygosity or male sterility. Finally, we show that an increase in driver-carrier dispersal can evolve across a range of values in driver strength and disadvantages.
Gene drives and population persistence vs elimination: The impact of spatial structure and inbreeding at low density
20529P. J. Beaghton and A. Burt, Theoretical Population Biology, 2022-03-03 08:28:52.
Synthetic gene drive constructs are being developed to control disease vectors, invasive species, and other pest species. In a well-mixed random mating population a sufficiently strong gene drive is expected to eliminate a target population, but it is not clear whether the same is true when spatial processes play a role. In species with an appropriate biology it is possible that drive-induced reductions in density might lead to increased inbreeding, reducing the efficacy of drive, eventually leading to suppression rather than elimination, regardless of how strong the drive is. To investigate this question we analyse a series of explicitly solvable stochastic models considering a range of scenarios for the relative timing of mating, reproduction, and dispersal and analyse the impact of two different types of gene drive, a Driving Y chromosome and a homing construct targeting an essential gene. We find in all cases a sufficiently strong Driving Y will go to fixation and the population will be eliminated, except in the one life history scenario (reproduction and mating in patches followed by dispersal) where low density leads to increased inbreeding, in which case the population persists indefinitely, tending to either a stable equilibrium or a limit cycle. These dynamics arise because Driving Y males have reduced mating success, particularly at low densities, due to having fewer sisters to mate with. Increased inbreeding at low densities can also prevent a homing construct from eliminating a population. For both types of drive, if there is strong inbreeding depression, then the population cannot be rescued by inbreeding and it is eliminated. These results highlight the potentially critical role that low-density-induced inbreeding and inbreeding depression (and, by extension, other sources of Allee effects) can have on the eventual impact of a gene drive on a target population.
Uniqueness and stability of periodic solutions for an interactive wild and Wolbachia-infected male mosquito model
20438R. Yan and Q. Sun, Journal of Biological Dynamics, 2022-02-15 09:03:48.
We investigate a mosquito population suppression model, which includes the release of Wolbachia-infected males causing incomplete cytoplasmic incompatibility (CI). The model consists of two sub-equations by considering the density-dependent birth rate of wild mosquitoes. By assuming the release waiting period T is larger than the sexual lifespan T¯ of Wolbachia-infected males, we derive four thresholds: the CI intensity threshold sh∗, the release amount thresholds g∗ and c∗, and the waiting period threshold T∗. From a biological view, we assume sh > sh∗ throughout the paper. When g∗ < c < c∗, we prove the origin E0 is locally asymptotically stable iff T < T∗, and the model admits a unique T-periodic solution iff T ≥ T∗, which is globally asymptotically stable. When c ≥ c∗, we show the origin E0 is globally asymptotically stable iff T ≤ T∗, and the model has a unique T-periodic solution iff T > T∗, which is globally asymptotically stable. Our theoretical results are confirmed by numerical simulations.
A gene drive does not spread easily in populations of the honey bee parasite Varroa destructor
20173N. R. Faber, A. B. Meiborg, G. R. McFarlane, G. Gorjanc and B. A. Harpur, Apidologie, 52:1112-1127. 2022-01-25 09:13:37.
Varroa mites (Varroa destructor) are the most significant threat to beekeeping worldwide. They are directly or indirectly responsible for millions of colony losses each year. Beekeepers are somewhat able to control varroa populations through the use of physical and chemical treatments. However, these methods range in effectiveness, can harm honey bees, can be physically demanding on the beekeeper, and do not always provide complete protection from varroa. More importantly, in some populations varroa mites have developed resistance to available acaricides. Overcoming the varroa mite problem will require novel and targeted treatment options. Here, we explore the potential of gene drive technology to control varroa. We show that spreading a neutral gene drive in varroa is possible but requires specific colony-level management practices to overcome the challenges of both inbreeding and haplodiploidy. Furthermore, continued treatment with acaricides is necessary to give a gene drive time to fix in the varroa population. Unfortunately, a gene drive that impacts female or male fertility does not spread in varroa. Therefore, we suggest that the most promising way forward is to use a gene drive which carries a toxin precursor or removes acaricide resistance alleles. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13592-021-00891-5.
Gene drives for vertebrate pest control: realistic spatial modelling of eradication probabilities and times for island mouse populations
20171A. Birand, P. Cassey, J. V. Ross, J. C. Russell, P. Thomas and T. A. A. Prowse, Molecular Ecology, 2022-01-24 09:06:03.
Abstract Invasive alien species continue to threaten global biodiversity. CRISPR-based gene drives, which can theoretically spread through populations despite imparting a fitness cost, could be used to suppress or eradicate pest populations. We develop an individual-based, spatially explicit, stochastic model to simulate the ability of CRISPR-based homing and X-chromosome shredding drives to eradicate populations of invasive house mice (Mus muculus) from islands. Using the model, we explore the interactive effect of the efficiency of the drive constructs and the spatial ecology of the target population on the outcome of a gene-drive release. We also consider the impact of polyandrous mating and sperm competition, which could compromise the efficacy of some gene-drive strategies. Our results show that both drive strategies could be used to eradicate large populations of mice. Whereas parameters related to drive efficiency and demography strongly influence drive performance, we find that sperm competition following polyandrous mating is unlikely to impact the outcome of an eradication effort substantially. Assumptions regarding the spatial ecology of mice influenced the probability of and time required for eradication, with short-range dispersal capacities and limited mate-search areas producing `chase' dynamics across the island characterised by cycles of local extinction and recolonization by mice. We also show that highly efficient drives are not always optimal, when dispersal and mate-search capabilities are low. Rapid local population suppression around the introduction sites can cause loss of the gene drive before it can spread to the entire island. We conclude that, although the design of efficient gene drives is undoubtedly critical, accurate data on the spatial ecology of target species is critical for predicting the result of a gene-drive release.
Effects of Sterile Males and Fertility of Infected Mosquitoes on Mosquito-Borne Disease Dynamics
20097X. L. Sun, S. Q. Liu, Y. F. Lv and Y. Z. Pei, Bulletin of Mathematical Biology, 84:33. 2022-01-13 09:37:31.
By studying an infection-age structured model, we consider the effects of releasing sterile males and the fertility of infected mosquitoes on the mosquito-borne diseases transmission including the extinction of mosquitoes, the elimination and persistence of diseases. Firstly, equivalent integral equations are established to prove the well-posedness of solutions. Then, the main results of disease dynamics are given. By taking chikungunya as a numerical simulation example, an optimal releasing threshold is given according to our presupposed control standard. When the fertility disturbance of infected mosquitoes is small, the high releasing amount plays a main role on the control of the disease; however, when the fertility disturbance is large, the initial distributions and the fertility of infected mosquitoes are the key factors to control the disease. Mathematically, the fertility of infected mosquitoes makes the system have complex dynamics with multiple positive equilibria and bistability.
The prince, the mayor, and the U.S. fish that ate Japan
20103C. Elliot, National Geographic, 2022-01-11 16:44:32.
When Crown Prince Akihito visited Chicago on October 3, 1960, his sole request was to visit Shedd Aquarium. Then Mayor Richard J. Daley, an avid angler, presented the prince with a gift that he scooped with a net from one of the tanks himself: 18 bluegills, the official Illinois state fish. The 26-year-old future emperor was already a passionate ichthyologist, and he planned to stock the exotic fish in the moat surrounding his palace, according to accounts in the Chicago Tribune at the time. At windy Chicago O’Hare International Airport the next day with Princess Michiko, Akihito bid the city farewell, carrying a gift that he couldn’t have imagined would cause a decades-long ecological crisis in his homeland. In the intervening six decades, the bluegills became an invasive, species-destroying nightmare, crowding Japanese freshwater lakes and rivers and destroying native fish biodiversity, says Kenji Saitoh, a researcher at the country’s Fisheries Resources and Education Agency. Fortunately, science has marched on in 60 years. Now, Japanese geneticists are experimenting with the gene editing wizardry of CRISPR to sterilize the invasive bluegills. If the initiative succeeds, wildlife managers could use the same technique to rid the U.S. of damaging aquatic invasives such as the Asian carp.
Modeling CRISPR gene drives for suppression of invasive rodents using a supervised machine learning framework
19764S. E. Champer, N. Oakes, R. Sharma, P. García-Díaz, J. Champer and P. W. Messer, PLoS Comput Biol, 17:e1009660. 2021-12-29 13:01:20.
Invasive rodent populations pose a threat to biodiversity across the globe. When confronted with these invaders, native species that evolved independently are often defenseless. CRISPR gene drive systems could provide a solution to this problem by spreading transgenes among invaders that induce population collapse, and could be deployed even where traditional control methods are impractical or prohibitively expensive. Here, we develop a high-fidelity model of an island population of invasive rodents that includes three types of suppression gene drive systems. The individual-based model is spatially explicit, allows for overlapping generations and a fluctuating population size, and includes variables for drive fitness, efficiency, resistance allele formation rate, as well as a variety of ecological parameters. The computational burden of evaluating a model with such a high number of parameters presents a substantial barrier to a comprehensive understanding of its outcome space. We therefore accompany our population model with a meta-model that utilizes supervised machine learning to approximate the outcome space of the underlying model with a high degree of accuracy. This enables us to conduct an exhaustive inquiry of the population model, including variance-based sensitivity analyses using tens of millions of evaluations. Our results suggest that sufficiently capable gene drive systems have the potential to eliminate island populations of rodents under a wide range of demographic assumptions, though only if resistance can be kept to a minimal level. This study highlights the power of supervised machine learning to identify the key parameters and processes that determine the population dynamics of a complex evolutionary system.
Cytoplasmic incompatibility in hybrid zones: infection dynamics and resistance evolution
19742E. S. Røed and J. Engelstädter, Journal of Evolutionary Biology, 2021-12-25 13:16:15.
Cytoplasmic incompatibility is an endosymbiont-induced mating incompatibility common in arthropods. Unidirectional cytoplasmic incompatibility impairs crosses between infected males and uninfected females, whereas bidirectional cytoplasmic incompatibility occurs when two host lineages are infected with reciprocally in compatible endosymbionts. Bidirectional cytoplasmic incompatibility is unstable in unstructured populations, but may be stable in hybrid zones. Stable coexistence of incompatible host lineages should generate frequent incompatible crosses. Therefore, hosts are expected to be under selection to resist their endosymbionts. Here, we for mulate a mathematical model of hybrid zones where two bidirectionally incompatible host lineages meet. We expand this model to consider the invasion of a hypothetical resistance allele. To corroborate our mathematical predictions, we test each prediction with stochastic, individual-based simulations. Our models suggest that hybrid zones may sustain stable coinfections of bidirectionally incompatible endosymbiont strains. Over a range of conditions, host are under selection for resistance against cytoplasmic incompatibility. Under asymetric migration, a resistance allele can facilitate infection turnover and subsequently either persist or become lost. The predictions we present may inform our understanding of the cophylogenetic relationship between the endosym biont Wolbachia and its hosts.
Weakly deleterious natural genetic variation amplifies probability of resistance in multiplexed gene drive systems
19904B. S. Khatri and A. Burt, bioRxiv, 2021.12.23.473701. 2021-12-23 08:31:18.
Evolution of resistance is a major barrier to successful deployment of gene drive systems to suppress natural populations. Multiplexed guide RNAs that require resistance mutations in all target cut sites is a promising strategy to overcome resistance. Using novel stochastic simulations that accurately model evolution at very large population sizes, we explore the probability of resistance due to three important mechanisms: 1) non-homologous end-joining mutations, 2) single nucleotide mutants arising de novo or, 3) single nucleotide polymorphisms pre-existing as standing variation. If the fraction of functional end-joining mutants is rare, we show that standing variation dominates, via a qualitatively new phenomenon where weakly deleterious variants significantly amplify the probability of multi-site resistance. This means resistance can be probable even with many target sites in not very large populations. This result has broad application to resistance arising in multi-site evolutionary scenarios including the evolution of vaccine escape mutations in large populations.Competing Interest StatementThe authors have declared no competing interest.
Modeling impact and cost-effectiveness of driving-Y gene drives for malaria elimination in the Democratic Republic of the Congo
19594N. Metchanun, C. Borgemeister, G. Amzati, J. von Braun, M. Nikolov, P. Selvaraj and J. Gerardin, Evolutionary Applications, 2021-12-07 17:59:09.
Malaria elimination will be challenging in countries that currently continue to bear high malaria burden. Sex-ratio distorting gene drives, such as driving-Y, could play a role in an integrated elimination strategy if they can effectively suppress vector populations. Using a spatially explicit, agent-based model of malaria transmission in eight provinces spanning the range of transmission intensities across the Democratic Republic of the Congo, we predict the impact and cost-effectiveness of integrating driving-Y gene drive mosquitoes in malaria elimination strategies that include existing interventions such as insecticide-treated nets and case management of symptomatic malaria. Gene drive mosquitoes could eliminate malaria and were the most cost-effective intervention overall if the drive component was highly effective with at least 95% X-shredder efficiency at relatively low fertility cost, and associated cost of deployment below 7.17 $int per person per year. Suppression gene drive could be a cost-effective supplemental intervention for malaria elimination, but tight constraints on drive effectiveness and cost ceilings may limit its feasibility.
Propagation of seminal toxins through binary expression gene drives can suppress polyandrous populations
19953J. Hurtado, S. Revale and L. M. Matzkin, bioRxiv, 2021.11.23.469777. 2021-11-24 09:48:59.
Gene drives can be highly effective in controlling a target population by disrupting a female fertility gene. To spread across a population, these drives require that disrupted alleles be largely recessive so as not to impose too high of a fitness penalty. We argue that this restriction may be relaxed by using a double gene drive design to spread a split binary expression system. One drive carries a dominant lethal/toxic effector alone and the other a transactivator factor, without which the effector will not act. Only after the drives reach sufficiently high frequencies would individuals have the chance to inherit both system components and the effector be expressed. We explore through mathematical modeling the potential of this design to spread dominant lethal/toxic alleles and suppress populations. We show that this system could be implemented to spread engineered seminal proteins designed to kill females, making it highly effective against polyandrous populations.Competing Interest StatementThe authors have declared no competing interest.
Malaria modeling and optimal control using sterile insect technique and insecticide-treated net
19230L. Cai, L. Bao, L. Rose, J. Summers and W. Ding, Applicable Analysis, 2021-11-05 21:55:36.
We investigate a malaria transmission model with SEIR (susceptible-exposed-infected-recovered) classes for the human population, SEI (susceptible-exposed-infected) classes for the wild mosquitoes and an additional class for the sterile mosquitoes. The basic reproduction number of the disease transmission is obtained, and a release threshold of the sterile mosquitoes is provided. We formulate an optimal control problem in which the goal is to minimize both the infected human populations and the cost to implement two control strategies: the release of sterile mosquitoes and the usage of insecticide-treated nets to reduce the malaria transmission. Adjoint equations are derived, and the characterization of the optimal controls is established. Finally, we quantify the effectiveness of the two interventions aimed at limiting the spread of malaria transmission. A combination of both strategies leads to more rapid elimination of the wild mosquito population that can suppress malaria transmission. Numerical simulations are provided to illustrate the results.
Population replacement gene drive characteristics for malaria elimination in a range of seasonal transmission settings: a modeling study
19134S. Leung, N. Windbichler, E. Wenger, C. Bever and P. Selvaraj, bioRxiv, 2021.11.01.466856. 2021-11-03 14:42:23.
Genetically engineering mosquitoes is a promising new vector control strategy to reinvigorate the fight against malaria in Sub-Saharan Africa. Using an agent-based model of malaria transmission with vector genetics, we examine the impacts of releasing population-replacement gene drive mosquitoes on malaria transmission and quantify the gene drive system parameters required to achieve local elimination within a spatially-resolved, seasonal Sahelian setting. We evaluate the performance of two different gene drive systems: "classic" and "integral". Various transmission regimes (low, moderate, and high - corresponding to annual entomological inoculation rates of 10, 30, and 80 infectious bites per person) and other simultaneous interventions, including deployment of insecticide-treated nets (ITNs) and passive healthcare seeking, are also simulated. Local elimination probabilities decreased with pre-existing population target site resistance frequency, increased with transmission-blocking effectiveness of the introduced antiparasitic gene and drive efficiency, and were context dependent with respect to fitness costs associated with the introduced gene. Of the four parameters, transmission-blocking effectiveness may be the most important to focus on for improvements to future gene drive strains because a single release of classic gene drive mosquitoes is likely to locally eliminate malaria in low to moderate transmission settings only when transmission-blocking effectiveness is very high (above approximately 80-90‰). However, simultaneously deploying ITNs and releasing integral rather than classic gene drive mosquitoes significantly boosts elimination probabilities, such that elimination remains highly likely in low to moderate transmission regimes down to transmission-blocking effectiveness values as low as approximately 50‰ and in high transmission regimes with transmission-blocking effectiveness values above approximately 80-90‰. Thus, a single release of currently achievable population replacement gene drive mosquitoes, in combination with traditional forms of vector control, can likely locally eliminate malaria in low to moderate transmission regimes within the Sahel. In a high transmission regime, higher levels of transmission-blocking effectiveness than are currently available may be required.Competing Interest StatementThe authors have declared no competing interest.
Modeling the efficacy of CRISPR gene drive for schistosomiasis control
19109R. E. Grewelle, J. Perez-Saez, J. Tycko, E. K. O. Namigai, C. G. Rickards and G. A. De Leo, bioRxiv, 2021.10.29.466423. 2021-11-01 14:51:40.
CRISPR gene drives could revolutionize the control of infectious diseases by accelerating the spread of engineered traits that limit parasite transmission in wild populations. While much effort has been spent developing gene drives in mosquitoes, gene drive technology in molluscs has received little attention despite the role of freshwater snails as obligate, intermediate hosts of parasitic flukes causing schistosomiasis -- a disease of poverty affecting more than 200 million people worldwide. A successful drive in snails must overcome self-fertilization, which prevents a drive's spread. Simultaneous hermaphroditism is a feature of snails -- distinct from gene drive model organisms -- and is not yet incorporated in gene drive models of disease control. Here we developed a novel population genetic model accounting for snails' sexual and asexual reproduction, susceptibility to parasite infection regulated by multiple alleles, fitness differences between genotypes, and a range of drive characteristics. We then integrated this model with an epidemiological model of schistosomiasis transmission and snail population dynamics. Simulations showed that gene drive establishment can be hindered by a variety of biological and ecological factors, including selfing. However, our model suggests that, under a range of conditions, gene drive mediated immunity in snails could maintain rapid disease reduction achieved by annual chemotherapy treatment of the human population, leading to long-term elimination. These results indicate that gene drives, in coordination with existing public health measures, may become a useful tool to reduce schistosomiasis burden in selected transmission settings with effective CRISPR construct design and close evaluation of the genetic and ecological landscape.Competing Interest StatementJT and EKON were seed funded by the Merck Innovation Cup 2016 for research on schistosomiasis, and previously employed as external consultants to the Global Health Institute of Merck (KGaA) which produces treatments for schistosomiasis. REG and GADL were partially supported by the National Science Foundation's grants DEB-2011179 and ICER-2024383.
Modeling homing suppression gene drive in haplodiploid organisms
18986Y. Liu and J. Champer, bioRxiv, 2021.10.12.464047. 2021-10-13 14:35:58.
Gene drives have shown great promise for suppression of pest populations. These engineered alleles can function by a variety of mechanisms, but the most common is the CRISPR homing drive, which converts wild-type alleles to drive alleles in the germline of heterozygotes. Some potential target species are haplodiploid, in which males develop from unfertilized eggs and thus have only one copy of each chromosome. This prevents drive conversion, a substantial disadvantage compared to diploids where drive conversion can take place in both sexes. Here, we study the characteristics of homing suppression gene drives in haplodiploids and find that a drive targeting a female fertility gene could still be successful. However, such drives are less powerful than in diploids. They are substantially more vulnerable to high resistance allele formation in the embryo due to maternally deposited Cas9 and gRNA and also to somatic cleavage activity. Examining models of continuous space where organisms move over a landscape, we find that haplodiploid suppression drives surprisingly perform nearly as well as in diploids, possibly due to their ability to spread further before inducing strong suppression. Together, these results indicate that gene drive can potentially be used to effectively suppress haplodiploid populations.
Spatial modelling for population replacement of mosquito vectors at continental scale
18861N. J. Beeton, A. Wilkins, A. Ickowicz, K. R. Hayes and G. R. Hosack, bioRxiv, 2021.10.06.463299. 2021-10-06 18:41:08.
We explore transmission of the gene drive between the subspecies, different hybridisation mechanisms, the effects of both local dispersal and potential wind-aided migration to the spread, and the development of resistance to the gene drive. We find that given best current available knowledge on the subspecies’ life histories, an introduced gene drive system with typical characteristics can plausibly spread from even distant offshore islands to the African mainland with the aid of wind-driven migration, with resistance taking over within a decade. Our model demonstrates a range of realistic dynamics including the effect of prevailing wind on spread and spatio-temporally varying carrying capacities for subspecies. We thus show both the plausibility and importance of accounting for a wide range of mechanisms from regional to continental scales
Discrete dynamical models on Wolbachia infection frequency in mosquito populations with biased release ratios
18717Y. Shi and B. Zheng, Journal of Biological Dynamics, 2021-09-18 14:11:29.
We develop two discrete models to study how supplemental releases affect the Wolbachia spreading dynamics in cage mosquito populations. The first model focuses on the case when only infected males are released at each generation. This release strategy has been proved to be capable of speeding up the Wolbachia persistence by suppressing the compatible matings between uninfected individuals. The second model targets the case when only infected females are released at each generation. For both models, detailed model formulation, enumeration of the positive equilibria and their stability analysis are provided. Theoretical results show that the two models can generate bistable dynamics when there are three positive equilibrium points, semi-stable dynamics for the case of two positive equilibrium points. And when the positive equilibrium point is unique, it is globally asymptotically stable. Some numerical simulations are offered to get helpful implications on the design of the release strategy.
Predicting the spread and persistence of genetically modified dominant sterile male mosquitoes
18680A. Ickowicz, S. D. Foster, G. R. Hosack and K. R. Hayes, Parasites and Vectors, 14:480. 2021-09-16 13:03:47.
Reproductive containment provides an opportunity to implement a staged-release strategy for genetic control of malaria vectors, in particular allowing predictions about the spread and persistence of (self-limiting) sterile and male-biased strains to be compared to outcomes before moving to (self-sustaining) gene-drive strains. In this study, we: (i) describe a diffusion–advection–reaction model of the spread and persistence of a single cohort of male mosquitoes; (ii) elicit informative prior distributions for model parameters, for wild-type (WT) and genetically modified dominant sterile strains (DSM); (iii) estimate posterior distributions for WT strains using data from published mark-recapture-release (MRR) experiments, with inference performed through the Delayed-Rejection Adaptive Metropolis algorithm; and (iv) weight prior distributions, in order to make predictions about genetically modified strains using Bayes factors calculated for the WT strains. If a single cohort of 5000 genetically modified dominant sterile male mosquitoes are released at the same location as previous MRR experiments with their WT counterparts, there is a 90% probability that the expected number of released mosquitoes will fall to < 1 in 10 days, and that by 12 days there will be a 99% probability that no mosquitoes will be found more than 150 m from the release location. Spread and persistence models should form a key component of risk assessments of novel genetic control strategies for malaria vectors. Our predictions, used in an independent risk assessment, suggest that genetically modified sterile male mosquitoes will remain within the locality of the release site, and that they will persist for a very limited amount of time. Data gathered following the release of these mosquitoes will enable us to test the accuracy of these predictions and also provide a means to update parameter distributions for genetic strains in a coherent (Bayesian) framework. We anticipate this will provide additional insights about how to conduct probabilistic risk assessments of stage-released genetically modified mosquitoes.
Evolutionary robustness of killer meiotic drives
18676P. G. Madgwick and J. B. Wolf, Evolution Letters, 2021-09-12 12:53:08.
A meiotic driver is a selfish genetic element that interferes with the process of meiosis to promote its own transmission. The most common mechanism of interference is gamete killing, where the meiotic driver kills gametes that do not contain it. A killer meiotic driver is predicted to spread rapidly through a population at the expense of other genes in the rest of the genome. The rapid spread of a killer meiotic driver is expected to be chased by the rapid spread of a suppressor that returns fair meiosis. Paradoxically, while this might imply that meiotic drivers should be evolutionarily transient, numerous ancient killer meiotic drivers have been discovered that have persisted for millions of years. To understand the rationale that could potentially explain such evolutionary robustness, we explore different possible mechanisms of killer meiotic drive and the different possible associated mechanisms of suppression. We use a framework that considers how the different stages of meiosis result in different structured interactions among cells with different genotypes in various combinations. Across possible interactions, we show that there are three genotypically distinct drive mechanisms that create alternative selective conditions for the spread of different types of suppressors. We show that killer meiotic drivers are more evolutionarily robust if they operate among sister cells (after meiosis I and before meiosis II) than at any other point during meiosis. The different drive mechanisms we identify make testable predictions that could explain why some killer meiotic drivers are transient while others are ancient.
Gene drive escape from resistance depends on mechanism and ecology
18261F. Cook, J. J. Bull and R. Gomulkiewicz, bioRxiv, 2021.08.30.458221. 2021-08-31 13:20:26.
Gene drives can potentially be used to suppress pest populations, and the advent of CRISPR technology has made it feasible to engineer them in many species, especially insects. What remains largely unknown for implementations is whether anti-drive resistance will evolve to block the population suppression. An especially serious threat to some kinds of drive is mutations in the CRISPR cleavage sequence that block the action of CRISPR, but designs have been proposed to avoid this type of resistance. Various types of resistance at loci away from the cleavage site remain a possibility, which is the focus here. It is known that modest-effect suppression drives can essentially `outrun' unlinked resistance even when that resistance is present from the start. We demonstrate here how the risk of evolving (unlinked) resistance can be further reduced without compromising overall suppression by introducing multiple suppression drives or by designing drives with specific ecological effects. However, we show that even modest-effect suppression drives remain vulnerable to the evolution of extreme levels of inbreeding, which halt the spread of the drive without actually interfering with its mechanism. The landscape of resistance evolution against suppression drives is therefore complex, but avenues exist for enhancing gene drive success.Competing Interest StatementThe authors have declared no competing interest.
Sterile males and females can synergistically suppress wild pests targeted by sterile insect technique
18837Y. Ikegawa, K. Ito, C. Himuro and A. Honma, Journal of Theoretical Biology, 530. 2021-08-23 11:21:38.
We constructed a mathematical model to examine the contribution of sterile males and females to the pest-control effect and the synergy between them. We consider that males seek out and court females in accord with their own female searching ability and preference, and that females subsequently choose one male from among males courting them in accordance with their own preference. Using this model, we compared the pest-control effect of bisexual and unisexual release, focusing on the difference in mating systems of the targeted insects. We showed that for swarm-type mating systems (with few courtship chances with higher encounter rates), bisexual release was the most effective, irrespective of the relative female searching ability between wild and sterile males. In this case, sterile females indirectly reduce wild females mating with either male by absorbing courtship from both wild and sterile males. By contrast, bisexual release is the most effective for scramble-type mating systems (more courtship chances with lower encounter rates) only when the female searching ability of sterile males is lower than that of wild males. In this case, sterile females absorb courtship from males with higher searching abilities. Therefore, the net impact of sterile females depends on the difference in sexual performance between wild and sterile males. Because the sexual performance of sterile insects is often degraded during the process of sterilization, we suggest that bisexual release can be a compatible measure to efficiently suppress wild pest populations.
A common gene drive language eases regulatory process and eco-evolutionary extensions
18022P. Verma, R. G. Reeves and C. S. Gokhale, BMC Ecology and Evolution, 21:156. 2021-08-09 14:36:22.
Synthetic gene drive technologies aim to spread transgenic constructs into wild populations even when they impose organismal fitness disadvantages. The extraordinary diversity of plausible drive mechanisms and the range of selective parameters they may encounter makes it very difficult to convey their relative predicted properties, particularly where multiple approaches are combined. The sheer number of published manuscripts in this field, experimental and theoretical, the numerous techniques resulting in an explosion in the gene drive vocabulary hinder the regulators’ point of view. We address this concern by defining a simplified parameter based language of synthetic drives. Employing the classical population dynamics approach, we show that different drive construct (replacement) mechanisms can be condensed and evaluated on an equal footing even where they incorporate multiple replacement drives approaches. Using a common language, it is then possible to compare various model properties, a task desired by regulators and policymakers. The generalization allows us to extend the study of the invasion dynamics of replacement drives analytically and, in a spatial setting, the resilience of the released drive constructs. The derived framework is available as a standalone tool. Besides comparing available drive constructs, our tool is also useful for educational purpose. Users can also explore the evolutionary dynamics of future hypothetical combination drive scenarios. Thus, our results appraise the properties and robustness of drives and provide an intuitive and objective way for risk assessment, informing policies, and enhancing public engagement with proposed and future gene drive approaches.
Risk management recommendations for environmental releases of gene drive modified insects
17829Y. Devos, J. D. Mumford, M. B. Bonsall, D. C. M. Glandorf and H. D. Quemada, Biotechnology Advances, 2021-07-25 13:02:06.
The ability to engineer gene drives (genetic elements that bias their own inheritance) has sparked enthusiasm and concerns. Engineered gene drives could potentially be used to address long-standing challenges in the control of insect disease vectors, agricultural pests and invasive species, or help to rescue endangered species. However, risk concerns and uncertainty associated with potential environmental release of gene drive modified insects (GDMIs) have led some stakeholders to call for a global moratorium on such releases or the application of other strict precautionary measures to mitigate perceived risk assessment and risk management challenges. Instead, we provide recommendations that may help to improve the relevance of risk assessment and risk management frameworks for environmental releases of GDMIs. These recommendations include: (1) developing additional and more practical risk assessment guidance to ensure appropriate levels of safety; (2) making policy goals and regulatory decision-making criteria operational for use in risk assessment so that what constitutes harm is clearly defined; (3) ensuring a more dynamic interplay between risk assessment and risk management to manage uncertainty through closely interlinked pre-release modelling and post-release monitoring; (4) considering potential risks against potential benefits, and comparing them with those of alternative actions to account for a wider (management) context; and (5) implementing a modular, phased approach to authorisations for incremental acceptance and management of risks and uncertainty. Along with providing stakeholder engagement opportunities in the risk analysis process, the recommendations proposed may enable risk managers to make choices that are more proportionate and adaptive to potential risks, uncertainty and benefits of GDMI applications, and socially robust.
Autocatalytic-protection for an unknown locus CRISPR-Cas countermeasure for undesired mutagenic chain reactions
17969E. Schonfeld, E. Schonfeld and D. Schonfeld, Journal of Theoretical Biology, 528:110831. 2021-07-11 13:41:33.
The mutagenic chain reaction (MCR) is a genetic tool to use a CRISPR–Cas construct to introduce a homing endonuclease, allowing gene drive to influence whole populations in a minimal number of generations (Esvelt et al., 2014, Gantz and Bier, 2015, Gantz and Bier, 2016). The question arises: if an active genetic terror event is released into a population, could we prevent the total spread of the undesired allele (Gantz, et al., 2015, Webber et al., 2015)? Thus far, effective protection methods require knowledge of the terror locus (Grunwald et al., 2019). Here we introduce a novel approach, an autocatalytic-Protection for an Unknown Locus (a-PUL), whose aim is to spread through a population and arrest and decrease an active terror event’s spread without any prior knowledge of the terror-modified locus, thus allowing later natural selection and ERACR drives to restore the normal locus (Hammond et al., 2017). a-PUL, using a mutagenic chain reaction, includes (i) a segment encoding a non-Cas9 endonuclease capable of homology-directed repair suggested as Type II endonuclease Cpf1 (Cas12a), (ii) a ubiquitously-expressed gene encoding a gRNA (gRNA1) with a U4AU4 3′-overhang specific to Cpf1 and with crRNA specific to some desired genomic sequence of non-coding DNA, (iii) a ubiquitously-expressed gene encoding two gRNAs (gRNA2/gRNA3) both with tracrRNA specific to Cas9 and crRNA specific to two distinct sites of the Cas9 locus, and (iv) homology arms flanking the Cpf1/gRNA1/gRNA2/gRNA3 cassette that are identical to the region surrounding the target cut directed by gRNA1 (Khan, 2016, Zetsche et al., 2015). We demonstrate the proof-of-concept and efficacy of our protection construct through a Graphical Markov model and computer simulation.
Part of ‘master plan’: Researchers receive grant to fund research on malaria
17748L. Huang, The Daily Californian, 2021-07-11 13:33:25.
Early this month, The Marshall Lab at UC Berkeley received an $800,000 grant from the Bill and Melinda Gates Foundation to fund its research on genetics-based malaria mosquito control. The Marshall Lab is one of many teams playing a part in the Gates Foundation’s decades-long “master plan” to eradicate malaria, according to associate professor John Marshall, the project’s principal investigator. Based on data from the World Health Organization, malaria kills hundreds of thousands of people a year. The lab has focused on malaria prevention ever since it opened its doors in 2015, publishing work about mosquito intervention and control mechanisms related to genetic mathematical modeling. “If you have a drug to control malaria or a mosquito net, then how that is implemented on a continental scale is more than a problem of having the intervention itself — you need to think about the numbers involved,” Marshall said. Marshall compared mosquitoes to humans in that they have similar genetic makeups. He said some mosquito genes can be altered to either prevent disease transmission to humans or reduce rates of mosquito reproduction. Marshall’s team plans to apply its Mosquito Gene Drive Explorer, which simulates releases of genetically modified mosquitoes into habitats, to aid fellow researchers funded by the Gates Foundation. With the system, researchers can identify the efficacy of systems for reducing cases of malaria in order to pinpoint which characteristics of gene constructs can be prioritized to most efficiently suppress the disease.
Marshall Lab receives Gates grant for genetics-based malaria mosquito control
17654Berkeley Public Health, Berkeley Public Health, 2021-07-08 19:33:19.
Berkeley Public Health Associate Professor John Marshall, PhD, and Assistant Project Scientist Héctor Sánchez, PhD, have received an $800,000 grant from the Bill & Melinda Gates Foundation to support their lab’s work in genetics-based malaria mosquito control. Malaria, the most devastating mosquito-borne disease, poses a major public health burden throughout much of the world. Novel genetics-based tools that can be shown to be safe and effective would be transformative in eliminating the disease and the suffering it causes. “Malaria continues to be exceptionally difficult to eliminate with currently-available tools,” said Marshall. “Insecticide-treated nets and antimalarial drugs have succeeded in reducing the African malaria burden by about a half, but their impact has stagnated in recent years and new tools are needed. There is now growing recognition that the most promising new tools for malaria elimination are vaccines and gene-edited mosquitoes.”
Fine-scale estimation of key life-history parameters of malaria vectors: implications for next-generation vector control technologies
17329A. L. Morris, A. Ghani and N. Ferguson, Parasites and Vectors, 14:311. 2021-06-08 14:48:41.
Mosquito control has the potential to significantly reduce malaria burden on a region, but to influence public health policy must also show cost-effectiveness. Gaps in our knowledge of mosquito population dynamics mean that mathematical modelling of vector control interventions have typically made simplifying assumptions about key aspects of mosquito ecology. Often, these assumptions can distort the predicted efficacy of vector control, particularly next-generation tools such as gene drive, which are highly sensitive to local mosquito dynamics.
Invasion and maintenance of meiotic drivers in populations of ascomycete fungi
17071I. Martinossi-Allibert, C. Veller, S. L. Ament-Velasquez, A. A. Vogan, C. Rueffler and H. Johannesson, Evolution, 20. 2021-03-25 14:37:42.
Meiotic drivers (MDs) are selfish genetic elements that are able to become overrepresented among the products of meiosis. This transmission advantage makes it possible for them to spread in a population even when they impose fitness costs on their host organisms. Whether an MD can invade a population, and subsequently reach fixation or coexist in a stable polymorphism, depends on the one hand on the biology of the host organism, including its life cycle, mating system, and population structure, and on the other hand on the specific fitness effects of the driving allele on the host. Here, we present a population genetic model for spore killing, a type of drive specific to fungi. We show how ploidy level, rate of selfing, and efficiency of spore killing affect the invasion probability of a driving allele and the conditions for its stable coexistence with a nondriving allele. Our model can be adapted to different fungal life cycles, and is applied here to two well-studied genera of filamentous ascomycetes known to harbor spore-killing elements, Neurospora and Podospora. We discuss our results in the light of recent empirical findings for these two systems.
A confinable home and rescue gene drive for population modification
16579N. P. Kandul, J. Liu, J. B. Bennett, J. M. Marshall and O. S. Akbari, eLife, 10:e65939. 2021-03-05 16:30:16.
Homing based gene drives, engineered using CRISPR/Cas9, have been proposed to spread desirable genes throughout populations. However, invasion of such drives can be hindered by the accumulation of resistant alleles. To limit this obstacle, we engineer a confinable population modification Home-and-Rescue (HomeR) drive in Drosophila targeting an essential gene. In our experiments, resistant alleles that disrupt the target gene function were recessive lethal, and therefore disadvantaged. We demonstrate that HomeR can achieve an increase in frequency in population cage experiments, but that fitness costs due to the Cas9 insertion limit drive efficacy.
Quantifying the risk of vector-borne disease transmission attributable to genetically modified vectors
16530G. R. Hosack, A. Ickowicz and K. R. Hayes, Royal Society Open Science, 8:201525. 2021-03-03 18:28:51.
The relative risk of disease transmission caused by the potential release of transgenic vectors, such as through sterile insect technique or gene drive systems, is assessed with comparison with wild-type vectors. The probabilistic risk framework is demonstrated with an assessment of the relative risk of lymphatic filariasis, malaria and o'nyong'nyong arbovirus transmission by mosquito vectors to human hosts given a released transgenic strain of Anopheles coluzzii carrying a dominant sterile male gene construct. Harm is quantified by a logarithmic loss function that depends on the causal risk ratio, which is a quotient of basic reproduction numbers derived from mathematical models of disease transmission. The basic reproduction numbers are predicted to depend on the number of generations in an insectary colony and the number of backcrosses between the transgenic and wild-type lineages. Analogous causal risk ratios for short-term exposure to a single cohort release are also derived. These causal risk ratios were parametrized by probabilistic elicitations, and updated with experimental data for adult vector mortality. For the wild-type, high numbers of insectary generations were predicted to reduce the number of infectious human cases compared with uncolonized wild-type. Transgenic strains were predicted to produce fewer infectious cases compared with the uncolonized wild-type.
Designing gene drives to limit spillover to non-target populations
16516G. Greenbaum, M. W. Feldman, N. A. Rosenberg and J. Kim, PLOS Genetics, 17:e1009278. 2021-02-25 15:02:27.
We develop mathematical models of gene-drive dynamics that incorporate migration between a target and non-target populations to investigate the possibility of effectively applying a gene drive in the target population while limiting its spillovers to the non-target population (‘differential targeting’). We observe that the feasibility of differential targeting depends on the gene-drive design specification, as well as on the migration rates between the populations. Even when differential targeting is possible, as migration increases, the possibility for differential targeting disappears. We find that differential targeting can be effective for low migration rates, and that it is sensitive to the design of the gene drive under high migration rates. We suggest that differential targeting could be used, in combination with other mitigation measures, as an additional safeguard to limit gene drive spillovers.
GeneConvene Global Collaborative Webinar Series | Ecological Modeling in Risk Assessment of Gene Drives
16445Hector Quemada and David O'Brochta, 2021-02-23 18:20:53.
Unlike non-gene drive organisms, which can be limited in time and space and therefore provide data in small scale tests that can be relevant to large scale releases, the potential for large-scale spread from a limited release, even in well-isolated trials, means that reliance on models will be a more important tool for risk assessors. To date, this work has only started to receive attention. This series of four presentations deals with the development and use of models in ecology generally. Some of these presentations will also deal with the use of models specifically to assess the ecological impacts of gene drive organisms.
GeneConvene Webinar Series on: Ecological Modeling in Risk Assessment of Gene Drives
16435Hector Quemada and David O'Brochta, 2021-02-23 16:59:25.
Unlike non-gene drive organisms, which can be limited in time and space and therefore provide data in small scale tests that can be relevant to large scale releases, the potential for large-scale spread from a limited release, even in well-isolated trials, means that reliance on models will be a more important tool for risk assessors. To date, this work has only started to receive attention. This series of four presentations deals with the development and use of models in ecology generally. Some of these presentations will also deal with the use of models specifically to assess the ecological impacts of gene drive organisms.
Demographic feedbacks can hamper the spatial spread of a gene drive
16203L. Girardin and F. Débarre, arXiv, 2021-01-27 15:32:53.
Our results indicate that taking into account the interplay between population dynamics and population genetics might actually be crucial, as it can effectively reverse the direction of the invasion and lead to failure. Our findings can be extended to other bistable systems, such as the spread of cytoplasmic incompatibilities caused by Wolbachia.
Double drives and private alleles for localised population genetic control
15945K. Willis and A. Burt, bioRxiv, 2021.01.08.425856. 2021-01-09 16:30:16.
In this paper we propose and model a series of low threshold double drive designs for population suppression, each consisting of two constructs, one imposing a reproductive load on the population and the other inserted into a differentiated locus and controlling the drive of the first. Simple deterministic, discrete-generation computer simulations are used to assess the alternative designs. We find that the simplest double drive designs are significantly more robust to pre-existing cleavage resistance at the differentiated locus than single drive designs, and that more complex designs incorporating sex ratio distortion can be more efficient still, even allowing for successful control when the differentiated locus is neutral and there is up to 50% pre-existing resistance in the target population. Similar designs can also be used for population replacement, with similar benefits. A population genomic analysis of PAM sites in island and mainland populations of the malaria mosquito Anopheles gambiae indicates that the differentiation needed for our methods to work can exist in nature. Double drives should be considered when efficient but localised population genetic control is needed and there is some genetic differentiation between target and non-target populations.
Self-Deleting Genes Project To Tackle Mosquito-Borne Diseases
15923D. Ozdemir, INTERESTING ENGINEERING, 2021-01-08 18:58:57.
Did you know that mosquitoes kill at least 725,000 persons every year? They truly are one of the world's deadliest animals which is the reason why scientists from all around are trying to find new ways of dealing with them. Controlling mosquito populations and preventing them from transmitting disease at times through genetic engineering is one way of doing that. Now, a new Texas A&M AgriLife Research project has plans of enabling "test runs" of the proposed changes in mosquitoes that are automatically deleted from their genetic code. Researchers have used genetic engineering in the past to modify mosquitoes in a way that they pass on infertility, don't grow wings, can't spread malaria, or have impaired smell. However, as New Atlas reports, this sort of modification can have harmful consequences that may be impossible to reverse when released into the wild.
Suppression gene drive in continuous space can result in unstable persistence of both drive and wild-type alleles
15938J. Champer, I. K. Kim, S. E. Champer, A. G. Clark and P. W. Messer, Mol Ecol, 2021-01-07 19:32:54.
Using spatially explicit simulations, we show that the release of a suppression drive can result in what we term "chasing" dynamics, in which wild-type individuals recolonize areas where the drive locally eliminated the population. Despite the drive subsequently reconquering these areas, complete population suppression often fails to occur or is substantially delayed. This increases the likelihood that the drive is lost or that resistance evolves. We analyze how chasing dynamics are influenced by the type of drive, its efficiency, fitness costs, and ecological factors such as the maximal growth rate of the population and levels of dispersal and inbreeding. We find that chasing is more common for lower efficiency drives when dispersal is low and that some drive mechanisms are substantially more prone to chasing behavior than others. Our results demonstrate that the population dynamics of suppression gene drives are determined by a complex interplay of genetic and ecological factors, highlighting the need for realistic spatial modeling to predict the outcome of drive releases in natural populations.
Self-deleting genes promise risk-free genetic engineering of mosquitoes
15852D. Quick, New Atlas, 2020-12-29 18:53:49.
A new project by Texas A&M AgriLife Research is looking to enable "test runs" of genetic changes to mosquitoes that are automatically deleted. Various angles of attack using genetic engineering to combat mosquitoes have been pursued in recent years, including modifying them so they pass on infertility, don't grow wings, can't spread malaria or have impaired smell. But making genetic modifications to an organism and then releasing them into the wild runs the risk of unintended and harmful consequences that may be difficult to reverse. That's where the new Texas A&M AgriLife Research project comes in. It is looking to enable "test runs" of genetic modifications that would then automatically be deleted from the mosquitoes' genetic code after a period of time.
Self-deleting genes to be tested as part of mosquito population control concept
15926B. Hays, UPI, 2020-12-28 18:59:14.
Scientists at Texas A&M have developed a new technique for altering the genes of mosquitoes -- the new technology will cause genetic changes to self-delete from the mosquitoes' genome. Thanks to the breakthrough, described Monday in the Philosophical Transactions of the Royal Society B, researchers can now test-run experimental gene edits without permanently altering a mosquito's genome."People are wary of transgenes spreading in the environment in an uncontrolled manner. We feel that ours is a strategy to potentially prevent that from happening," Zach Adelman, professor of entomology at the Texas A&M College of Agriculture, said in a news release. "The idea is, can we program a transgene to remove itself? Then, the gene won't persist in the environment."
$3.9M project on self-deleting genes takes aim at mosquito-borne diseases
15847O. Kuchment, AGRILIFE Today, 2020-12-28 18:52:03.
To control mosquito populations and prevent them from transmitting diseases such as malaria, many researchers are pursuing strategies in mosquito genetic engineering. A new Texas A&M AgriLife Research project aims to enable temporary “test runs” of proposed genetic changes in mosquitoes, after which the changes remove themselves from the mosquitoes’ genetic code. The project’s first results were published on Dec. 28 in Philosophical Transactions of the Royal Society B, titled “Making gene drive biodegradable.”
Self-deleting genes tested as part of the concept of mosquito population control
15844charlottelarson, NEWYORK NEWS TIMES, 2020-12-28 18:49:28.
Most genetic engineering strategies designed to control mosquito populations, and their ability to spread diseases such as malaria, require gene editing to be combined with gene drives. Gene drives allow altered DNA to spread rapidly throughout the population.
Making gene drive biodegradable
15687J. Zapletal, N. Najmitabrizi, M. Erraguntla, M. A. Lawley, K. M. Myles and Z. N. Adelman, Philosophical Transactions of the Royal Society B: Biological Sciences, 376:20190804. 2020-12-28 15:02:10.
Here, we consider the inclusion of self-elimination mechanisms into the design of homing-based gene drive transgenes. This approach not only caused the excision of the gene drive transgene, but also generates a transgene-free allele resistant to further action by the gene drive. Strikingly, our models suggest that this mechanism, acting at a modest rate (10%) as part of a single-component system, would be sufficient to cause the rapid reversion of even the most robust homing-based gene drive transgenes, without the need for further remediation.
Evading resistance to gene drives
15422R. Gomulkiewicz, M. L. Thies and J. J. Bull, bioRxiv, 2020.08.27.270611. 2020-12-12 15:44:15.
Our analyses suggest that among gene drives that cause moderate suppression, toxin-antidote systems are less apt to select for resistance than homing drives. Single drives of moderate effect might cause only moderate population suppression, but multiple drives (perhaps delivered sequentially) would allow arbitrary levels of suppression. The most favorable case for evolution of resistance appears to be with suppression homing drives in which resistance is dominant and fully suppresses transmission distortion; partial suppression by resistance heterozygotes or recessive resistance are less prone to resistance evolution. Given that it is now possible to engineer CRISPR-based gene drives capable of circumventing allelic resistance, this design may allow for the engineering of suppression gene drives that are effectively resistance-proof.
Modelling the Wolbachia incompatible insect technique: strategies for effective mosquito population elimination
15281D. E. Pagendam, B. J. Trewin, N. Snoad, S. A. Ritchie, A. A. Hoffmann, K. M. Staunton, C. Paton and N. Beebe, BMC Biology, 18:13. 2020-12-02 16:29:23.
We introduce a simple Markov population process model for studying mosquito populations subjected to a Wolbachia-IIT programme which exhibit an unstable equilibrium threshold. The model is used to study, in silico, scenarios that are likely to yield a successful elimination result. Our results suggest that elimination is best achieved by releasing males at rates that adapt to the ever-decreasing wild population, thus reducing the risk of releasing Wolbachia-infected females while reducing costs.
Split drive killer-rescue provides a novel threshold-dependent gene drive
15254M. P. Edgington, T. Harvey-Samuel and L. Alphey, Scientific Reports, 10. 2020-11-25 18:32:01.
Population genetics mathematical models are developed here to demonstrate the threshold-dependent nature of the proposed system and its robustness to imperfect homing, incomplete penetrance of toxins and transgene fitness costs, each of which are of practical significance given that real-world components inevitably have such imperfections. We show that although end-joining repair mechanisms may cause the system to break down, under certain conditions, it should persist over time scales relevant for genetic control programs. The potential of such a system to provide localised population suppression via sex ratio distortion or female-specific lethality is also explored. Additionally, we investigate the effect on introduction thresholds of adding an extra CRISPR base element, showing that this may either increase or decrease dependent on parameter context
Further guidance required for assessment of gene drive technology, says EFSA
15137Euractiv, The World News Monitor, 2020-11-16 16:25:26.
Existing guidelines are adequate for evaluating risks associated with gene-drive modified insects, but further guidance is needed for some areas, most notably for environmental risk assessments. The evaluation was requested to explore the issue ahead of the consideration of any possible applications of the technology and is also designed to support the EU in discussions on the biosafety of GMOs in international fora such as the United Nations. It found that while existing guidelines are sufficient for evaluating risks associated with technology, further guidance is needed for some areas, such as molecular characterisation, environmental risk assessment and post-market environmental monitoring.
Adequacy and sufficiency evaluation of existing EFSA guidelines for the molecular characterisation, environmental risk assessment and post-market environmental monitoring of genetically modified insects containing engineered gene drives
15043E. Panel o. G. M. Organisms, H. Naegeli, J.-L. Bresson, T. Dalmay, I. C. Dewhurst, M. M. Epstein, P. Guerche, J. Hejatko, F. J. Moreno, E. Mullins, F. Nogué, N. Rostoks, J. J. Sánchez Serrano, G. Savoini, E. Veromann, F. Veronesi, M. B. Bonsall, J. Mumfor, EFSA Journal, 18:e06297. 2020-11-12 19:24:46.
As a proactive measure, the European Food Safety Authority (EFSA) has been requested by the European Commission to review whether its previously published guidelines for the risk assessment of genetically modified animals (EFSA, 2012 and 2013), including insects (GMIs), are adequate and sufficient for GDMIs, primarily disease vectors, agricultural pests and invasive species, for deliberate release into the environment. Under this mandate, EFSA was not requested to develop risk assessment guidelines for GDMIs. In this Scientific Opinion, the Panel on Genetically Modified Organisms (GMO) concludes that EFSA's guidelines are adequate, but insufficient for the molecular characterisation (MC), environmental risk assessment (ERA) and post-market environmental monitoring (PMEM) of GDMIs. While the MC,ERA and PMEM of GDMIs can build on the existing risk assessment framework for GMIs that do not contain engineered gene drives, there are specific areas where further guidance is needed for GDMIs.
EFSA advises on risk assessment of engineered gene drives
15069EFSA, European Food and Safety Authority, 2020-11-12 18:15:34.
EFSA’s existing guidelines for the risk assessment of genetically modified animals are adequate for evaluating risks associated with gene drive modified insects. However, further guidance is needed for some areas, such as molecular characterisation, environmental risk assessment and post-market environmental monitoring, say EFSA’s experts on Genetically Modified Organisms.
Modeling CRISPR gene drives for suppression of invasive rodents
15003S. E. Champer, N. Oakes, R. Sharma, P. García-Díaz, J. Champer and P. W. Messer, bioRxiv, 2020.11.05.369942. 2020-11-05 15:27:54.
Here, we develop a high-fidelity model of an island population of invasive rodents that includes three types of suppression gene drive systems. The individual-based model is spatially explicit and allows for overlapping generations and a fluctuating population size. Our model includes variables for drive fitness, efficiency, resistance allele formation rate, as well as a variety of ecological parameters.
Gene Drives across engineered fitness valleys: Modeling a design to prevent drive spillover.
14880F. J. H. de Haas and S. Otto, bioRxiv, 2020.10.29.360404. 2020-10-29 15:44:22.
We model a proposed drive system that transitions in time from a low threshold drive system (homing-based gene drive) to a high threshold drive system (underdominance) using daisy chain technology. This combination leads to a spatially restricted drive strategy while maintaining an attainable release threshold.
MGDrivE 2: A simulation framework for gene drive systems incorporating seasonality and epidemiological dynamics
14733S. L. Wu, J. B. Bennett, H. M. Sanchez C, A. J. Dolgert, T. M. Leon and J. M. Marshall, bioRxiv, 2020.10.16.343376. 2020-10-17 15:42:27.
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.
Dynamics of Wild and Sterile Mosquito Population Models with Delayed Releasing
14817L. M. Cai, International Journal of Bifurcation and Chaos, 30:15. 2020-09-15 17:16:03.
We extend the previous ODE models to the delayed releasing models in two different ways of releasing sterile mosquitos, where both constant and exponentially distributed delays are considered, respectively. By applying the theory and methods of delay differential equations, the effect of time delays on the stability of equilibria in the system is rigorously analyzed.
Suppressing evolution in genetically engineered systems through repeated supplementation
15188N. C. Layman, B. M. Tuschhoff, A. J. Basinski, C. H. Remien, J. J. Bull and S. L. Nuismer, Evolutionary Applications, 12. 2020-09-05 15:21:40.
Genetically engineered organisms are prone to evolve in response to the engineering. This evolution is often undesirable and can negatively affect the purpose of the engineering. Methods that maintain the stability of engineered genomes are therefore critical to the successful design and use of genetically engineered organisms. One potential method to limit unwanted evolution is by taking advantage of the ability of gene flow to counter local adaption, a process of supplementation. Here, we investigate the feasibility of supplementation as a mechanism to offset the evolutionary degradation of a transgene in three model systems: a bioreactor, a gene drive, and a transmissible vaccine.
Modelling the suppression of a malaria vector using a CRISPR-Cas9 gene drive to reduce female fertility
13724A. R. North, A. Burt and H. C. J. Godfray, BMC Biology, 18:98. 2020-08-11 12:23:41.
Gene drives based on CRISPR-Cas9 technology are increasingly being considered as tools for reducing the capacity of mosquito populations to transmit malaria, and one of the most promising options is driving endonuclease genes that reduce the fertility of female mosquitoes. Here, we use simulation modelling to understand the factors affecting the spread of this type of gene drive over a one million-square kilometre area of West Africa containing substantial environmental and social heterogeneity.
Incorporating Characteristics of Gene Drive Engineered Ae. aegypti as Methods to Reduce Dengue and Zika Virus into the Bayesian Network – Relative Risk Model, Using Ponce, Puerto Rico as a Case Study
16097S. R. Eikenbary, WWU Graduate School Collection, 2020-08-10 19:24:02.
The Bayesian network relative risk model can perform the risk assessment of gene drive engineered Ae. aegypti for vector control and as part of an adaptive management strategy to reduce dengue and Zika transmission. This study illustrates how the BN-RRM can integrate gene drive related information within a risk assessment framework suitable for adaptive management of these novel stressors.
Modeling the suppression dynamics of Aedes mosquitoes with mating inhomogeneity
13847M. Huang and L. Hu, Journal of Biological Dynamics, 14:656-678. 2020-08-04 13:51:41.
In this work, we introduce a delay differential equation model with mating inhomogeneity to discuss mosquito population suppression based on Wolbachia. Our analyses show that the wild mosquitoes could be eliminated if either the adult mortality rate exceeds the threshold δ∗A or the release amount exceeds the threshold r∗ uniformly. Our simulations suggest that the releasing should be started at least 5 weeks before the peak dengue season, taking into account both the release amount and the suppression speed.
A One-Sided Competition Mathematical Model for the Sterile Insect Technique
14287A. Ben Dhahbi, Y. Chargui, S. M. Boulaaras and S. Ben Khalifa, Complexity, 2020:12. 2020-07-30 13:59:01.
We study a simple mathematical model describing the dynamics of a wild-type pest insects population experiencing competition from sterile insects (one-sided competition).
On Nonlinear Pest/Vector Control via the Sterile Insect Technique: Impact of Residual Fertility
14291M. S. Aronna and Y. Dumont, Bulletin of Mathematical Biology, 82:29. 2020-07-09 14:09:49.
We consider a minimalist model for the Sterile Insect Technique (SIT), assuming that residual fertility can occur in the sterile male population.
Invasion and maintenance of spore killers in populations of ascomycete fungi
15129I. Martinossi-Allibert, C. Veller, S. L. Ament-Velásquez, A. A. Vogan, C. Rueffler and H. Johannesson, bioRxiv, 2020.04.06.026989. 2020-06-30 16:08:48.
We show how ploidy level, rate of selfing, and efficiency of spore killing affect the invasion probability of a driving allele and the conditions for its stable coexistence with the non-driving allele. Our model can be adapted to different fungal life-cycles, and is applied here to two well-studied genera of filamentous ascomycetes known to harbor spore killing elements, Podospora and Neurospora. We discuss our results in the light of recent empirical findings for these two systems.Competing Interest StatementThe authors have declared no competing interest.
Field performance of sterile male mosquitoes released from an uncrewed aerial vehicle
12708J. Bouyer, N. J. Culbert, A. H. Dicko, M. G. Pacheco, J. Virginio, M. C. Pedrosa, L. Garziera, A. T. M. Pinto, A. Klaptocz, J. Germann, T. Wallner, G. Salvador-Herranz, R. A. Herrero, H. Yamada, F. Balestrino and M. J. B. Vreysen, Science Robotics, 5:10. 2020-06-15 20:48:48.
Genetic control methods of mosquito vectors of malaria, dengue, yellow fever, and Zika are becoming increasingly popular due to the limitations of other techniques such as the use of insecticides. The sterile insect technique is an effective genetic control method to manage insect populations. However, it is crucial to release sterile mosquitoes by air to ensure homogeneous coverage, especially in large areas. Here, we report a fully automated adult mosquito release system operated from an uncrewed aerial vehicle or drone. Our system, developed and tested in Brazil, enabled a homogeneous dispersal of sterile male Aedes aegypti while maintaining their quality, leading to a homogeneous sterile-to-wild male ratio due to their aggregation in the same sites. Our results indicate that the released sterile males were able to compete with the wild males in mating with the wild females; thus, the sterile males were able to induce sterility in the native female population. The use of drones to implement the sterile insect technique will lead to improvements in areal coverage and savings in operational costs due to the requirement of fewer release sites and field staff.
Simulation models from: Can CRISPER-mediated gene drive work in pest and beneficial haplodiploid species?
11968J. Li and B. Tabashnik, Dryad, 2020-05-26 18:17:03.
Gene drives based on CRISPR/Cas9 have the potential to reduce the enormous harm inflicted by crop pests and insect vectors of human disease, as well as to bolster valued species. In contrast with extensive empirical and theoretical studies in diploid organisms, little is known about CRISPR gene drive in haplodiploids, despite their immense global impacts as pollinators, pests, natural enemies of pests, and invasive species in native habitats. Here we analyze mathematical models demonstrating that, in principle, CRISPR homing gene drive can work in haplodiploids, as well as at sex-linked loci in diploids. However, relative to diploids, conditions favoring the spread of alleles deleterious to haplodiploid pests by CRISPR gene drive are narrower, the spread is slower, and resistance to the drive evolves faster. By contrast, the spread of alleles that impose little fitness cost or boost fitness was not greatly hindered in haplodiploids relative to diploids. Therefore, altering traits to minimize damage caused by harmful haplodiploids, such as interfering with transmission of plant pathogens, may be more likely to succeed than control efforts based on introducing traits that reduce pest fitness. Enhancing fitness of beneficial haplodiploids with CRISPR gene drive is also promising.
Simulating effects of fitness and dispersal on the use of Trojan sex chromosomes for the management of invasive species
11488C. C. Day, E. L. Landguth, R. K. Simmons, W. P. Baker, A. R. Whiteley, P. M. Lukacs and A. Bearlin, Journal of Applied Ecology, 2020-03-19 20:15:27.
The use of Trojan Y chromosomes (TYC) for controlling invasive species involves manipulating the sex chromosomes of captive-raised individuals. Following release, the offspring of these individuals consist of only one sex, thereby skewing the sex ratio of the invasive population and potentially leading to eradication. Simulation models are needed that can inform managers about how to maximize the likelihood of invasive species eradication, since implementation of this novel management approach in the field is still rare. Here, we present the first spatially explicit, mechanistic simulation model of a real-world TYC program for invasive species eradication. Using a brook trout Salvelinus fontinalis system model, we investigated the effects of competitive and reproductive fitness of the captive-raised YY males, dispersal behaviour upon their release and landscape heterogeneity on eradication success. Likelihood of eradication was dependent on both the competitive and reproductive fitness of the Trojan individuals. Competitive fitness (i.e. survival) had a higher threshold for eradication, below which the invasive populations were not eradicated. Movement ecology of both the wild and YY male populations was important for eradication. Under a restricted dispersal scenario for YY males following their release, the wild population was not extirpated but maintained a stable, yet reduced, population size. Analysis of landscape configuration indicated that time to eradication of local patches increased with greater connectivity within the stream network. In addition to sex ratio distortion, density-dependent mortality resulting from outplantings made an important contribution to population decline and therefore may also affect native competitors. Synthesis and applications. The use of Trojan sex chromosomes to skew population sex ratios is a novel method for the suppression and eradication of aquatic invasive species. Results from our modelling work indicate that while eradication is possible, maximizing its likelihood requires an understanding of the fitness and movement ecology of both the wild and YY male populations of the invasive species. Both our model and the principles derived from this study related to fitness and behavioural landscape ecology can be broadly applied to other invaded species and systems.
Vector genetics, insecticide resistance and gene drives: an agent-based modeling approach to evaluate malaria transmission and elimination
7941P. Selvaraj, E. A. Wenger, D. Bridenbecker, N. Windbichler, J. R. Russell, J. Gerardin, C. A. Bever and M. Nikolov, bioRxiv, 2020.01.27.920421. 2020-02-06 20:32:18.
Vector control has been a key component in the fight against malaria for decades, and chemical insecticides are critical to the success of vector control programs worldwide. However, increasing resistance to insecticides threatens to undermine these efforts. Understanding the evolution and propagation of resistance is thus imperative to mitigating loss of intervention effectiveness. Additionally, accelerated research and development of new tools that can be deployed alongside existing vector control strategies is key to eradicating malaria in the near future. Methods such as gene drives that aim to genetically modify large mosquito populations in the wild to either render them refractory to malaria or impair their reproduction may prove invaluable tools. Mathematical models of gene flow in populations can offer invaluable insight into the behavior and potential impact of gene drives as well as the spread of insecticide resistance in the wild. Here, we present the first multi-locus, agent-based model of vector genetics that accounts for mutations and many-to-many mappings of genotypes to phenotypes to investigate gene flow and the propagation of gene drives in Anopheline populations. This model is embedded within a large scale individual-based model of malaria transmission representative of a high burden, high transmission setting characteristic of the Sahel. Results are presented for the selection of insecticide-resistant vectors and the spread of resistance through repeated deployment of insecticide treated nets (ITNs), in addition to scenarios where gene drives act in concert with existing vector control tools such as ITNs. The roles of seasonality, spatial distribution of vector habitat and feed sites, and existing vector control in propagating alleles that confer phenotypic traits via gene drives that result in reduced transmission are explored. The ability to model a spectrum of vector species with different genotypes and phenotypes in the context of malaria transmission allows us to test deployment strategies for existing interventions that reduce the deleterious effects of resistance and allows exploration of the impact of new tools being proposed or developed.Author summary Vector control interventions are essential to the success of global malaria control and elimination efforts but increasing insecticide resistance worldwide threatens to derail these efforts. Releasing genetically modified mosquitoes that use gene drives to pass on desired genes and their associated phenotypic traits to the entire population within a few generations has been proposed to address resistance and other issues such as transmission heterogeneity that can sustain malaria transmission indefinitely. While the ethics and safety of these methods are being debated, mathematical models offer an efficient way of predicting the behavior and estimating the efficacy of these interventions if deployed to specific regions facing challenges to reaching elimination. We have developed a detailed mathematical model of vector genetics where specific genomes code for physical attributes that influence transmission and are affected by the surrounding environment. This is the first model to incorporate an individual-based multi locus genetic model into a detailed individual-based model of malaria transmission. This model opens the door to investigate a number of subtle but important questions such as the effects of small numbers of mosquitoes in a region sustaining malaria transmission during the low transmission season, and the success of gene drives in regions where extant vector control interventions could kill off gene drive mosquitoes before establishment. Here, we investigate the reduced efficacy of current vector control measures in the presence of insecticide resistance and evaluate the likelihood of achieving local malaria elimination using gene drive mosquitoes released into a high transmission setting alongside other vector control measures.
Optimal control and analysis of a modified trojan Y-Chromosome strategy
11491M. A. Beauregard, R. D. Parshad, S. Boon, H. Conaway, T. Griffin and J. J. Lyu, Ecological Modelling, 416. 2020-01-15 20:19:52.
The Trojan Y Chromosome (TYC) strategy is a promising eradication method that attempts to manipulate the female to male ratio to promote the reduction of the population of an invasive species. The manipulation stems from an introduction of sex-reversed males, called supermales, into an ecosystem. The offspring of the supermales is guaranteed to be male. Mathematical models have shown that the population can be driven to extinction with a continuous supply of supermales. In this paper, a new model of the TYC strategy is introduced and analyzed that includes two important modeling characteristics, that are neglected in all previous models. First, the new model includes intraspecies competition for mates. Second, a strong Allee effect is included. Several conclusions about the strategy via optimal control are established. These results have large scale implications for the biological control of invasive species.
Design and analysis of CRISPR-based underdominance toxin-antidote gene drives
5626Champer, J., S. E. Champer, I. Kim, A. G. Clark and P. W. Messer, bioRxiv, 861435:861435. 2019-12-17 16:38:34.
CRISPR gene drive systems offer a mechanism for transmitting a desirable transgene throughout a population for purposes ranging from vector-borne disease control to invasive species suppression. In this simulation study, we model and assess the performance of several CRISPR-based underdominance gene drive constructs employing toxin-antidote principles. These drives disrupt the wild-type version of an essential gene using a CRISPR nuclease (the toxin) while simultaneously carrying a recoded version of the gene (the antidote). Drives of this nature allow for releases that could be potentially confined to a desired geographic location. This is because such drives have a nonzero invasion threshold frequency, referring to the critical frequency required for the drive to spread through the population. We model drives which target essential genes that are either haplosufficient or haplolethal, using nuclease promoters with expression restricted to the germline, promoters that additionally result in cleavage activity in the early embryo from maternal deposition, and promoters that have ubiquitous somatic expression. We also study several possible drive architectures, considering both “same-site” and “distant-site” systems, as well as several reciprocally targeting drives. Together, these drive variants provide a wide range of invasion threshold frequencies and options for both population modification and suppression. Our results suggest that CRISPR toxin-antidote underdominance drive systems could allow for the design of highly flexible and potentially confinable gene drive strategies.
Gene Drives: Dynamics and Regulatory Matters-A Report from the Workshop “Evaluation of Spatial and Temporal Control of Gene Drives,” April 4-5, 2019, Vienna
12396B. Giese, J. L. Friess, N. H. Barton, P. W. Messer, F. Debarre, M. F. Schetelig, N. Windbichler, H. Meimberg and C. Boete, Bioessays, 41:3. 2019-10-07 18:26:19.
Gene Drives are regarded as future tools with a high potential for population control. Due to their inherent ability to overcome the rules of Mendelian inheritance, gene drives (GD) may spread genes rapidly through populations of sexually reproducing organisms. A release of organisms carrying a GD would constitute a paradigm shift in the handling of genetically modified organisms because gene drive organisms (GDO) are designed to drive their transgenes into wild populations and thereby increase the number of GDOs. The rapid development in this field and its focus on wild populations demand a prospective risk assessment with a focus on exposure related aspects. Presently, it is unclear how adequate risk management could be guaranteed to limit the spread of GDs in time and space, in order to avoid potential adverse effects in socio‐ecological systems. The recent workshop on the “Evaluation of Spatial and Temporal Control of Gene Drives” hosted by the Institute of Safety/Security and Risk Sciences (ISR) in Vienna aimed at gaining some insight into the potential population dynamic behavior of GDs and appropriate measures of control. Scientists from France, Germany, England, and the USA discussed both topics in this meeting on April 4–5, 2019. This article summarizes results of the workshop.
Ecological effects on underdominance threshold drives for vector control
16267D. Khamis, C. El Mouden, K. Kura and M. B. Bonsall, Journal of Theoretical Biology, 456:1-15. 2018-11-07 16:39:27.
Here, ecological and epidemiological dynamics are coupled to a model of mosquito genetics to investigate theoretically the impact of different types of underdominance gene drive on disease prevalence. We model systems with two engineered alleles carried either on the same pair of chromosomes at the same locus or homozygously on different pairs at different loci, genetic lethality that affects both sexes or only females, and bi-sex or male-only releases.
Population Consequences of Releasing Sex-Reversed Fish: Applications and Concerns
11500C. Wederkind, Sex Control in Aquaculture, Chp 8:179-188. 2018-11-02 20:38:44.
Sex differentiation is generally more labile in gonochoristic fish than it is, for example, in birds and mammals. Environmentally induced sex reversal is, therefore, often possible, and creates genotype‐phenotype mismatches that can be useful in population management. Interestingly, sex chromosomes of fish are typically not significantly decayed (i.e., all types of offspring of sex‐reversed individuals may be viable, including YY and WW individuals that can then often be sex reversed again). Releasing sex‐reversed fish, or releasing untreated YY and WW offspring of sex‐reversed fish, into natural populations can, therefore, affect the sex ratio of the population in the following generations and, hence, affect population growth.
A spatially discrete, integral projection model and its application to invasive carp
11503R. A. Erickson, E. A. Eager, P. M. Kocovsky, D. C. Glover, J. L. Kallis and K. R. Long, Ecological Modelling, 387:163-171. 2018-09-21 20:46:26.
Natural resource managers and ecologists often desire an understanding of spatial dynamics such as migration, dispersion, and meta-population dynamics. Network-node models can capture these salient features. Additionally, the state-variable used with many species may be appropriately modeled as a continuous variable (e.g., length) and management activities sometimes can only target individuals of certain sizes. Integral projection models (IPMs) can capture this life history characteristic and allow for the examination of size-specific management. We combined an IPM with a network-node model to capture both of these salient features. We then demonstrated how this model could be used to understand and manage populations of invasive species focusing on grass carp as an example. Grass carp disrupt ecosystems outside of their native range and have spread around much of the world, including North America. The impacts of grass carp include adversely changing aquatic plant communities, which in turn affect a wide range of endpoints ranging from water quality to waterfowl recruitment. We specifically examined two theoretical systems using parameters from the literature. First, we modeled a lake with two tributaries and examined how modified sterile males could be used as a control tool. We found that modified sterile males may be a feasible control tool to limit population growth. Second, we modeled a series of river pools and examined how harvest and deterrents could be used to decrease the risk of expanding grass carp's range within a river system. Within this system, we also compared the impacts of size specific harvest and uniform harvest across all sizes. We found that targeting the largest, spawning populations may be more important than targeting the populations close to the invasion front for reducing the risk of spreading grass carp. We also demonstrate that size of harvested fish was important for controlling populations.
Pest demography critically determines the viability of synthetic gene drives for population control
11505K. E. Wilkins, T. A. A. Prowse, P. Cassey, P. Q. Thomas and J. V. Ross, Mathematical Biosciences, 305:160-169. 2018-09-13 20:48:39.
Synthetic gene drives offer a novel solution for the control of invasive alien species. CRISPR-based gene drives can positively bias their own inheritance, and comprise a DNA sequence that is replicated by homologous recombination. Since gene drives can be positioned to silence fertility or developmental genes, they could be used for population suppression. However, the production of resistant alleles following self-replication errors threatens the technology's viability for pest eradication in real-world applications. Further, a robust assessment of how pest demography impacts the expected progression of gene drives through populations is currently lacking. We used a deterministic, two-sex, birth-death model to investigate how demographic assumptions affect the efficiency of suppression drives for controlling invasive rodents on islands, for two different gene-drive strategies. We show that mass-action reproduction results in overly optimistic eradication outcomes when compared to the more realistic assumption of polygynous breeding. When polygyny was assumed, both gene-strategies failed due to the evolution of resistance unless a reproductive Allee effect (reduced reproductive rates at low population density) was also included; although model outcomes were highly sensitive to the strength of this effect. Increasing the size of the initial gene-drive introduction (up to 10% of carrying capacity) had little impact on population outcomes. Understanding the demography of a population targeted for eradication is critical before the viability of gene-drive suppression can be adequately assessed.
Genetics-based methods for agricultural insect pest management
18687N. Alphey and M. B. Bonsall, Agricultural and Forest Entomology, 20:131-140. 2018-05-01 13:30:37.
Abstract The sterile insect technique is an area-wide pest control method that reduces agricultural pest populations by releasing mass-reared sterile insects, which then compete for mates with wild insects. Contemporary genetics-based technologies use insects that are homozygous for a repressible dominant lethal genetic construct rather than being sterilized by irradiation. Engineered strains of agricultural pest species, including moths such as the diamondback moth Plutella xylostella and fruit flies such as the Mediterranean fruit fly Ceratitis capitata, have been developed with lethality that only operates on females. Transgenic crops expressing insecticidal toxins are widely used; the economic benefits of these crops would be lost if toxin resistance spread through the pest population. The primary resistance management method is a high-dose/refuge strategy, requiring toxin-free crops as refuges near the insecticidal crops, as well as toxin doses sufficiently high to kill wild-type insects and insects heterozygous for a resistance allele. Mass-release of toxin-sensitive engineered males (carrying female-lethal genes), as well as suppressing populations, could substantially delay or reverse the spread of resistance. These transgenic insect technologies could form an effective resistance management strategy. We outline some policy considerations for taking genetic insect control systems through to field implementation.
The optimal implementation of the Trojan Y chromosome eradication strategy of invasive species
11510M. R. Kelly and X. Y. Wang, Journal of Biological Systems, 25:399-418. 2017-08-02 15:25:17.
Invasive aquatic species continue to be a persistent problem around the world. The Trojan Y Chromosome (TYC) eradication strategy has recently been developed to help fight the problem in aquatic systems by targeting only the invasive species, sparing native marine stock. It involves rearing genetically modified samples of the invasive species and introducing them into the environment to alter the sex ratio of the invasive population. The paper is devoted to finding the optimal implementation of the TYC eradication strategy of an invasive species as well as a modified, potentially more cost-effective strategy. The modified TYC strategy (MTYC) eliminates one round of exposure to sex hormones compared to the TYC strategy. After introducing both strategies, the optimal control problems for each are formulated. The two strategies are compared through numerical simulations. Our results illustrate that the MTYC strategy, with lower implementation costs, is a better strategy option when trying to minimize the overall effective cost in most scenarios.
Daisyfield gene drive systems harness repeated genomic elements as a generational clock to limit spread
13623J. Min, C. Noble, D. Najjar and K. M. Esvelt, bioRxiv, 104877. 2017-02-06 13:30:21.
Here we describe a novel form of gene drive based on the introduction of multiple copies of an engineered ‘daisy’ sequence into repeated elements of the genome. Each introduced copy encodes guide RNAs that target one or more engineered loci carrying the CRISPR nuclease gene and the desired traits. When organisms encoding a drive system are released into the environment, each generation of mating with wild-type organisms will reduce the average number of the guide RNA elements per ‘daisyfield’ organism by half, serving as a generational clock
Lethal Gene Drive Selects Inbreeding
13627J. J. Bull, bioRxiv, 046847. 2016-06-03 13:55:41.
ere, population genetic models are used to consider the evolution of inbreeding (specifically selfing) as a possible response to a recessively lethal HEG with complete segregation distortion. Numerical analyses indicate a rich set of outcomes, but selfing often evolves in response to the HEG, with a corresponding partial restoration of mean fitness. Whether selfing does indeed evolve and its effect in restoring fitness depends heavily on the magnitude of inbreeding depression. Overall, these results point toward an underappreciated evolutionary response to block the harmful effects of a selfish gene.
Stochastic models for the Trojan Y-Chromosome eradication strategy of an invasive species
11514X. Y. Wang, J. R. Walton and R. D. Parshad, Journal of Biological Dynamics, 10:179-199. 2015-12-16 15:32:37.
The Trojan Y-Chromosome (TYC) strategy, an autocidal genetic bio-control method, has been proposed to eliminate invasive alien species. In this work, we develop a Markov jump process model for this strategy, and we verify that there is a positive probability for wild-type females going extinct within a finite time. Moreover, when sex-reversed Trojan females are introduced at a constant population size, we formulate a stochastic differential equation (SDE) model as an approximation to the proposed Markov jump process model. Using the SDE model, we investigate the probability distribution and expectation of the extinction time of wild-type females by solving Kolmogorov equations associated with these statistics. The results indicate how the probability distribution and expectation of the extinction time are shaped by the initial conditions and the model parameters.
Global existence and asymptotic behavior of a model for biological control of invasive species via supermale introduction
11530R. D. Parshad, S. Kouachi and J. B. Gutierrez, Communications in Mathematical Sciences, 11:971-992. 2013-06-15 16:00:28.
The purpose of this manuscript is to propose a model for the biological control of invasive species, via introduction of phenotypically modified organisms into a target population. We are inspired by the earlier Trojan Y Chromosome model [J.B. Gutierrez, J.L. Teem, J. Theo. Bio., 241(22), 333-341, 2006]. However, in the current work, we remove the assumption of logistic growth rate, and do not consider the addition of sex-reversed supermales. Also the constant birth and death coefficients, considered earlier, are replaced by functionally dependent ones. In this case the nonlinearities present serious difficulties since they change sign, and the components of the solution are not a priori bounded, in some LP-space for p large, to permit the application of the well known regularizing effect principle. Thus functional methods to deduce the global existence in time, for the system in question, are not applicable. Our techniques are based on the Lyapunov functional method. We prove global existence of solutions, as well as existence of a finite dimensional global attractor, that supports states of extinction. Our analytical finding are in accordance with numerical simulations, which we also present.
Demographic effects on the use of genetic options for the control of mosquitofish, Gambusia holbrooki
11528R. E. Thresher, M. Canning and N. J. Bax, Ecological Applications, 23:801-814. 2013-06-01 15:57:26.
This study tests the sensitivity of genetically based pest control options based on sex ratio distortion to intra-and intersexual aggressive interactions that affect male and female survival and fitness. Data on these interactions and their impacts were gathered for the mosquitofish Gambusia holbrooki (Poeciliidae), a promiscuous species with a strongly male-biased operational sex ratio and well-documented male harassment of females. The experimental design consisted of an orthogonal combination of two population densities and three sex ratios, ranging from strongly male-biased to strongly female-biased, and long-term observations of laboratory populations. Contrary to expectations, the number of males in a population had little evident effect on population demographics. Rather, the density of adult females determined population fecundity (as a result of a stock-recruitment relationship involving females, but not males), constrained male densities (apparently as a result of cannibalism or intersexual aggression), and regulated itself (most likely through effects of intrasexual aggression on female recruitment). The principal effect of males was to constrain their own densities via effects of male-male aggression on adult male mortality rates. Through use of a realistically parameterized genetic/demographic model, we show that of three different genetic options applied to control G. holbrooki, one based on recombinant sex ratio distortion (release of Female Lethal carriers) is marginally more efficient than a sterile male release program, and both outperform an option based on chromosomal sex ratio distortion (Trojan W). Nonlinear dependence of reproductive rate on female density reduces the efficacy of all three approaches. The major effect of intra-and intersexual aggression is mediated through females, whose interactions reduce female numbers and increase the efficacy of a control program based on sex ratio. Socially mediated male mortality has a small impact on control programs due to operational sex ratios that are heavily male-biased. The sensitivity of sex ratio-based control options to social factors will depend on the mating system of the targeted pest, but evidence of widespread density-dependent population regulation suggests that, for most species, the effects of elevated adult mortality (due to intra-and intersexual aggression) on control programs are likely to be slight.
Analysis of the Trojan Y-Chromosome eradication strategy for an invasive species
11524X. Y. Wang, J. R. Walton, R. D. Parshad, K. Storey and M. Boggess, Journal of Mathematical Biology, 68:1731-1756. 2013-05-24 15:52:53.
The Trojan Y-Chromosome (TYC) strategy, an autocidal genetic biocontrol method, has been proposed to eliminate invasive alien species. In this work, we analyze the dynamical system model of the TYC strategy, with the aim of studying the viability of the TYC eradication and control strategy of an invasive species. In particular, because the constant introduction of sex-reversed trojan females for all time is not possible in practice, there arises the question: What happens if this injection is stopped after some time? Can the invasive species recover? To answer that question, we perform a rigorous bifurcation analysis and study the basin of attraction of the recovery state and the extinction state in both the full model and a certain reduced model. In particular, we find a theoretical condition for the eradication strategy to work. Additionally, the consideration of an Allee effect and the possibility of a Turing instability are also studied in this work. Our results show that: (1) with the inclusion of an Allee effect, the number of the invasive females is not required to be very low when the introduction of the sex-reversed trojan females is stopped, and the remaining Trojan Y-Chromosome population is sufficient to induce extinction of the invasive females; (2) incorporating diffusive spatial spread does not produce a Turing instability, which would have suggested that the TYC eradication strategy might be only partially effective, leaving a patchy distribution of the invasive species.
Existence of global attractor for the Trojan Y Chromosome model
11534X. P. Zhao, B. Liu and N. Duan, Electronic Journal of Qualitative Theory of Differential Equations, 2011-07-11 17:09:12.
This paper is concerned with the long time behavior of solution for the equation derived by the Trojan Y Chromosome (TYC) model with spatial spread. Based on the regularity estimates for the semigroups and the classical existence theorem of global attractors, we prove that this equations possesses a global attractor in H-k(Omega)(4) (k >= 0) space.
Analysis of the Trojan Y chromosome model for eradication of invasive species in a dendritic riverine system
11532J. B. Gutierrez, M. K. Hurdal, R. D. Parshad and J. L. Teem, Journal of Mathematical Biology, 64:319-340. 2011-03-04 17:07:15.
The use of Trojan Y chromosomes has been proposed as a genetic strategy for the eradication of invasive species. The strategy is particularly relevant to invasive fish species that have XY sex determination system and are amenable to sex-reversal. In this paper we study the dynamics of an invasive fish population occupying a dendritic domain in which Trojan individuals bearing multiple Y chromosomes have been released as a means of eradication. We demonstrate the existence of a bounded absorbing set that represents extinction of the invasive species irrespective of the dendritic configuration. The method of analysis used to obtain global estimates could be applied to other population problems and other geometries.
The Impact of Dissociation on Transposon-Mediated Disease Control Strategies
23831J. M. Marshall, Genetics, 178:1673-1682. 2008-03-01 23:54:22.
Vector-borne diseases such as malaria and dengue fever continue to be a major health concern through much of the world. The emergence of chloroquine-resistant strains of malaria and insecticide-resistant mosquitoes emphasize the need for novel methods of disease control. Recently, there has been much interest in the use of transposable elements to drive resistance genes into vector populations as a means of disease control. One concern that must be addressed before a release is performed is the potential loss of linkage between a transposable element and a resistance gene. Transposable elements such as P and hobo have been shown to produce internal deletion derivatives at a significant rate, and there is concern that a similar process could lead to loss of the resistance gene from the drive system following a transgenic release. Additionally, transposable elements such as Himar1 have been shown to transpose significantly more frequently when free of exogenous DNA. Here, we show that any transposon-mediated gene drive strategy must have an exceptionally low rate of dissociation if it is to be effective. Additionally, the resistance gene must confer a large selective advantage to the vector to surmount the effects of a moderate dissociation rate and transpositional handicap.
Can transposable elements be used to drive disease refractoriness genes into vector populations?
6271M. G. Kidwell and J. M. C. Ribeiro, Parasitology Today, 8:325-329. 1992-01-08 16:40:55.
A number of biological procedures are currently being considered as alternatives to insecticide-based methods for the control of insect vectors of disease. Among these are the adaptation of various genetic mechanisms to drive genes of interest, such as refractoriness to malaria in mosquitoes, into natural populations, for vector control purposes. Here, Margaret Kidwell and Jose Ribeiro develop a rationale for the possible use of transposable genetic elements, one of these potential drive mechanisms, and some of the problems being faced in seeking to determine the feasibility of such a strategy are described.
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