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

2018 ◽  
Author(s):  
Héctor M. Sánchez C. ◽  
Sean L. Wu ◽  
Jared B. Bennett ◽  
John M. Marshall
Keyword(s):  
Spatial Dynamics ◽  
Population Level ◽  
Spatially Explicit ◽  
Pest Species ◽  
Gene Drive ◽  
Simulation Framework ◽  
Population Replacement ◽  
Wide Range ◽  
Drive Systems ◽  
Genetic Simulation

AbstractMalaria, dengue, Zika, and other mosquito-borne diseases continue to pose a major global health burden through much of the world, despite the widespread distribution of insecticide-based tools and antimalarial drugs. The advent of CRISPR/Cas9-based gene editing and its demonstrated ability to streamline the development of gene drive systems has reignited interest in the application of this technology to the control of mosquitoes and the diseases they transmit. The versatility of this technology has also enabled a wide range of gene drive architectures to be realized, creating a need for their population-level and spatial dynamics to be explored. To this end, we present MGDrivE (Mosquito Gene Drive Explorer): a simulation framework designed to investigate the population dynamics of a variety of gene drive architectures and their spread through spatially-explicit mosquito populations. A key strength of the MGDrivE framework is its modularity: a) a genetic inheritance module accommodates the dynamics of gene drive systems displaying user-defined inheritance patterns, b) a population dynamic module accommodates the life history of a variety of mosquito disease vectors and insect agricultural pest species, and c) a landscape module accommodates the distribution of insect metapopulations connected by migration in space. Example MGDrivE simulations are presented to demonstrate the application of the framework to CRISPR/Cas9-based homing gene drive for: a) driving a disease-refractory gene into a population (i.e. population replacement), and b) disrupting a gene required for female fertility (i.e. population suppression), incorporating homing-resistant alleles in both cases. We compare MGDrivE with other genetic simulation packages, and conclude with a discussion of future directions in gene drive modeling.

scholarly journals Genomic insertion locus and Cas9 expression in the germline affect CRISPR/Cas9-based gene drive performance in the yellow fever mosquito Aedes aegypti

2021 ◽  
Author(s):  
William R Reid ◽  
Jingyi Lin ◽  
Adeline E Williams ◽  
Rucsanda Juncu ◽  
Ken E Olson ◽  
...  
Keyword(s):  
Aedes Aegypti ◽  
Yellow Fever ◽  
Drive System ◽  
Gene Drive ◽  
Yellow Fever Mosquito ◽  
Genomic Locus ◽  
Population Replacement ◽  
Novel Approach ◽  
Drive Systems ◽  
Insertion Locus

The yellow fever mosquito Aedes aegypti is a major vector of arthropod-borne viruses, including dengue, chikungunya, and Zika. A novel approach to mitigate arboviral infections is to generate mosquitoes refractory to infection by overexpressing antiviral effector molecules. Such an approach requires a mechanism to spread these antiviral effectors through a population, for example, by using CRISPR/Cas9-based gene drive systems. Here we report an autonomous single-component gene drive system in Ae. aegypti that is designed for persistent population replacement. Critical to the design of a single-locus autonomous gene drive is that the selected genomic locus be amenable to both gene drive and the appropriate expression of the antiviral effector. In our study, we took a reverse engineering approach to target two genomic loci ideal for the expression of antiviral effectors and further investigated the use of three promoters for Cas9 expression (nanos, β2-tubulin, or zpg) for the gene drive. We found that both promoter selection and genomic target site strongly influenced the efficiency of the drive, resulting in 100% inheritance in some crosses. We also observed the formation of inheritable gene drive blocking indels (GDBI) in the genomic locus with the highest levels of gene drive. Overall, our drive system forms a platform for the further testing of driving antipathogen effector genes through Ae. aegypti populations.

scholarly journals Double drives and private alleles for localised population genetic control

PLoS Genetics ◽  
2021 ◽  
Vol 17 (3) ◽  
pp. e1009333
Author(s):  
Katie Willis ◽  
Austin Burt
Keyword(s):  
Genetic Control ◽  
Population Genetic ◽  
Genomic Analysis ◽  
Target Population ◽  
Pest Species ◽  
Gene Drive ◽  
Population Replacement ◽  
Target Populations ◽  
Control Disease ◽  
Alternative Designs

Synthetic gene drive constructs could, in principle, provide the basis for highly efficient interventions to control disease vectors and other pest species. This efficiency derives in part from leveraging natural processes of dispersal and gene flow to spread the construct and its impacts from one population to another. However, sometimes (for example, with invasive species) only specific populations are in need of control, and impacts on non-target populations would be undesirable. Many gene drive designs use nucleases that recognise and cleave specific genomic sequences, and one way to restrict their spread would be to exploit sequence differences between target and non-target populations. 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 CRISPR PAM sites in island and mainland populations of the malaria mosquitoAnopheles gambiaeindicates 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.

scholarly journals Locally Fixed Alleles: A method to localize gene drive to island populations

2019 ◽  
Author(s):  
Jaye Sudweeks ◽  
Brandon Hollingsworth ◽  
Dimitri V. Blondel ◽  
Karl J. Campbell ◽  
Sumit Dhole ◽  
...  
Keyword(s):  
Target Population ◽  
Small Island ◽  
Island Population ◽  
Threshold Condition ◽  
Gene Drive ◽  
Population Replacement ◽  
Multiple Alleles ◽  
Island Populations ◽  
Wide Range ◽  
Parameter Values

AbstractInvasive species pose a major threat to biodiversity on islands. While successes have been achieved using traditional removal methods, such as toxicants aimed at rodents, these approaches have limitations and various off-target effects on island ecosystems. Gene drive technologies designed to eliminate a population provide an alternative approach, but the potential for drive-bearing individuals to escape from the target release area and impact populations elsewhere is a major concern. Here we propose the “Locally Fixed Alleles” approach as a novel means for localizing elimination by a drive to an island population that exhibits significant genetic isolation from neighboring populations. Our approach is based on the assumption that in small island populations of rodents, genetic drift will lead to multiple genomic alleles becoming fixed. In contrast, multiple alleles are likely to be maintained in larger populations on mainlands. Utilizing the high degree of genetic specificity achievable using homing drives, for example based on the CRISPR/Cas9 system, our approach aims at employing one or more locally fixed alleles as the target for a gene drive on a particular island. Using mathematical modeling, we explore the feasibility of this approach and the degree of localization that can be achieved. We show that across a wide range of parameter values, escape of the drive to a neighboring population in which the target allele is not fixed will at most lead to modest transient suppression of the non-target population. While the main focus of this paper is on elimination of a rodent pest from an island, we also discuss the utility of the locally fixed allele approach for the goals of population suppression or population replacement. Our analysis also provides a threshold condition for the ability of a gene drive to invade a partially resistant population.

scholarly journals Gene Drives Across Engineered Fitness Valleys: Modeling a Design to Prevent Drive Spillover

2020 ◽  
Author(s):  
Frederik J.H. de Haas ◽  
Sarah P. Otto
Keyword(s):  
Local Population ◽  
Target Population ◽  
Drive System ◽  
High Threshold ◽  
Gene Drive ◽  
Time Model ◽  
Population Replacement ◽  
Low Threshold ◽  
Drive Systems ◽  
Gene Drives

1AbstractEngineered gene drive techniques for population replacement and/or suppression have potential for tackling complex challenges, including reducing the spread of diseases and invasive species. Unfortunately, the self-propelled behavior of drives can lead to the spread of transgenic elements beyond the target population, which is concerning. Gene drive systems with a low threshold frequency for invasion, such as homing-based gene drive systems, require initially few transgenic individuals to spread and are therefore easy to implement. However their ease of spread presents a double-edged sword; their low threshold makes these drives much more susceptible to spread outside of the target population (spillover). 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. We develop and analyze a discrete-time model as proof of concept and find that this technique effectively generates stable local population suppression, while preventing the spread of transgenic elements beyond the target population under biologically realistic parameters.

scholarly journals The effect of mating complexity on gene drive dynamics

2021 ◽  
Author(s):  
Prateek Verma ◽  
R. Guy Reeves ◽  
Samson Simon ◽  
Mathias Otto ◽  
Chaitanya S. Gokhale
Keyword(s):  
Mate Choice ◽  
Mating Systems ◽  
Population Level ◽  
Gene Drive ◽  
Wild Populations ◽  
Transgenic Organisms ◽  
Drive Systems ◽  
The Impact ◽  
Gene Drives ◽  
Drive Dynamics

AbstractGene drive technology is being presented as a means to deliver on some of the global challenges humanity faces today in healthcare, agriculture and conservation. However, there is a limited understanding of the consequences of releasing self-perpetuating transgenic organisms into the wild populations under complex ecological conditions. In this study, we analyze the impact of three factors, mate-choice, mating systems and spatial mating network, on the population dynamics for two distinct classes of modification gene drive systems; distortion and viability-based ones. All three factors had a high impact on the modelling outcome. First, we demonstrate that distortion based gene drives appear to be more robust against the mate-choice than viability-based gene drives. Second, we find that gene drive spread is much faster for higher degrees of polygamy. With fitness cost, speed is the highest for intermediate levels of polygamy. Finally, the spread of 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 while modelling the population-level spread of gene drives. This will enable a more confident prediction of release thresholds, timescales and consequences of gene drive in populations.

scholarly journals Daisy-chain gene drives for the alteration of local populations

2019 ◽  
Vol 116 (17) ◽  
pp. 8275-8282 ◽  
Author(s):  
Charleston Noble ◽  
John Min ◽  
Jason Olejarz ◽  
Joanna Buchthal ◽  
Alejandro Chavez ◽  
...  
Keyword(s):  
Drive System ◽  
Chain Gene ◽  
Gene Drive ◽  
Rna Sequences ◽  
Guide Rna ◽  
Highly Active ◽  
Wide Range ◽  
Fitness Parameters ◽  
Drive Systems ◽  
Gene Drives

If they are able to spread in wild populations, CRISPR-based gene-drive elements would provide new ways to address ecological problems by altering the traits of wild organisms, but the potential for uncontrolled spread tremendously complicates ethical development and use. Here, we detail a self-exhausting form of CRISPR-based drive system comprising genetic elements arranged in a daisy chain such that each drives the next. “Daisy-drive” systems can locally duplicate any effect achievable by using an equivalent self-propagating drive system, but their capacity to spread is limited by the successive loss of nondriving elements from one end of the chain. Releasing daisy-drive organisms constituting a small fraction of the local wild population can drive a useful genetic element nearly to local fixation for a wide range of fitness parameters without self-propagating spread. We additionally report numerous highly active guide RNA sequences sharing minimal homology that may enable evolutionarily stable daisy drive as well as self-propagating CRISPR-based gene drive. Especially when combined with threshold dependence, daisy drives could simplify decision-making and promote ethical use by enabling local communities to decide whether, when, and how to alter local ecosystems.

scholarly journals Locally Fixed Alleles: A method to localize gene drive to island populations

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Jaye Sudweeks ◽  
Brandon Hollingsworth ◽  
Dimitri V. Blondel ◽  
Karl J. Campbell ◽  
Sumit Dhole ◽  
...  
Keyword(s):  
Target Population ◽  
Small Island ◽  
Island Population ◽  
Threshold Condition ◽  
Gene Drive ◽  
Population Replacement ◽  
Multiple Alleles ◽  
Island Populations ◽  
Wide Range ◽  
Parameter Values

Abstract Invasive species pose a major threat to biodiversity on islands. While successes have been achieved using traditional removal methods, such as toxicants aimed at rodents, these approaches have limitations and various off-target effects on island ecosystems. Gene drive technologies designed to eliminate a population provide an alternative approach, but the potential for drive-bearing individuals to escape from the target release area and impact populations elsewhere is a major concern. Here we propose the “Locally Fixed Alleles” approach as a novel means for localizing elimination by a drive to an island population that exhibits significant genetic isolation from neighboring populations. Our approach is based on the assumption that in small island populations of rodents, genetic drift will lead to alleles at multiple genomic loci becoming fixed. In contrast, multiple alleles are likely to be maintained in larger populations on mainlands. Utilizing the high degree of genetic specificity achievable using homing drives, for example based on the CRISPR/Cas9 system, our approach aims at employing one or more locally fixed alleles as the target for a gene drive on a particular island. Using mathematical modeling, we explore the feasibility of this approach and the degree of localization that can be achieved. We show that across a wide range of parameter values, escape of the drive to a neighboring population in which the target allele is not fixed will at most lead to modest transient suppression of the non-target population. While the main focus of this paper is on elimination of a rodent pest from an island, we also discuss the utility of the locally fixed allele approach for the goals of population suppression or population replacement. Our analysis also provides a threshold condition for the ability of a gene drive to invade a partially resistant population.

scholarly journals Daisy-chain gene drives for the alteration of local populations

2016 ◽  
Author(s):  
Charleston Noble ◽  
John Min ◽  
Jason Olejarz ◽  
Joanna Buchthal ◽  
Alejandro Chavez ◽  
...  
Keyword(s):  
Local Level ◽  
Field Trials ◽  
Local Communities ◽  
Chain Gene ◽  
Gene Drive ◽  
Guide Rna ◽  
Local Populations ◽  
Wide Range ◽  
Global Spread ◽  
Drive Systems

AbstractRNA-guided gene drive elements could address many ecological problems by altering the traits of wild organisms, but the likelihood of global spread tremendously complicates ethical development and use. Here we detail a localized form of CRISPR-based gene drive composed of genetic elements arranged in a daisy-chain such that each element drives the next. “Daisy drive” systems can duplicate any effect achievable using an equivalent global drive system, but their capacity to spread is limited by the successive loss of non-driving elements from the base of the chain. Releasing daisy drive organisms constituting a small fraction of the local wild population can drive a useful genetic element to local fixation for a wide range of fitness parameters without resulting in global spread. We additionally report numerous highly active guide RNA sequences sharing minimal homology that may enable evolutionary stable daisy drive as well as global CRISPR-based gene drive. Daisy drives could simplify decision-making and promote ethical use by enabling local communities to decide whether, when, and how to alter local ecosystems.Author’s Summary‘Global’ gene drive systems based on CRISPR are likely to spread to every population of the target species, hampering safe and ethical use. ‘Daisy drive’ systems offer a way to alter the traits of only local populations in a temporary manner. Because they can exactly duplicate the activity of any global CRISPR-based drive at a local level, daisy drives may enable safe field trials and empower local communities to make decisions concerning their own shared environments.For more details and an animation intended for a general audience, see the summary at Sculpting Evolution.

scholarly journals Double drives and private alleles for localised population genetic control

2021 ◽  
Author(s):  
Katie Willis ◽  
Austin Burt
Keyword(s):  
Genetic Control ◽  
Population Genetic ◽  
Genomic Analysis ◽  
Target Population ◽  
Pest Species ◽  
Gene Drive ◽  
Population Replacement ◽  
Target Populations ◽  
Mosquito Anopheles Gambiae ◽  
Control Disease

Synthetic gene drive constructs could, in principle, provide the basis for highly efficient interventions to control disease vectors and other pest species. This efficiency derives in part from leveraging natural processes of dispersal and gene flow to spread the construct and its impacts from one population to another. However, sometimes (for example, with invasive species) only specific populations are in need of control, and impacts on non-target populations would be undesirable. Many gene drive designs use nucleases that recognise and cleave specific genomic sequences, and one way to restrict their spread would be to exploit sequence differences between target and non-target populations. 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.

scholarly journals Modeling CRISPR gene drives for suppression of invasive rodents

2020 ◽  
Author(s):  
Samuel E. Champer ◽  
Nathan Oakes ◽  
Ronin Sharma ◽  
Pablo García-Díaz ◽  
Jackson Champer ◽  
...  
Keyword(s):  
Machine Learning ◽  
Population Model ◽  
Supervised Machine Learning ◽  
Sensitivity Analyses ◽  
Island Population ◽  
Gene Drive ◽  
Wide Range ◽  
Outcome Space ◽  
Drive Systems ◽  
Invasive Rodents

ABSTRACTInvasive rodent populations pose a threat to biodiversity across the globe. When confronted with these new 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. Such systems might 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 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. 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, but only if resistance can be kept to a minimal level. This study highlights the power of supervised machine learning for identifying the key parameters and processes that determine the population dynamics of a complex evolutionary system.

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