scholarly journals Gene Drive Dynamics in Natural Populations: The Importance of Density Dependence, Space, and Sex

2020 ◽  
Vol 51 (1) ◽  
pp. 505-531 ◽  
Author(s):  
Sumit Dhole ◽  
Alun L. Lloyd ◽  
Fred Gould
Keyword(s):  
Density Dependence ◽  
Natural Populations ◽  
Ecological Factors ◽  
Single Individual ◽  
Gene Drive ◽  
Deterministic Models ◽  
Realistic Assessment ◽  
Dependence Space ◽  
Gene Drives ◽  
Drive Dynamics

The spread of synthetic gene drives is often discussed in the context of panmictic populations connected by gene flow and described with simple deterministic models. Under such assumptions, an entire species could be altered by releasing a single individual carrying an invasive gene drive, such as a standard homing drive. While this remains a theoretical possibility, gene drive spread in natural populations is more complex and merits a more realistic assessment. The fate of any gene drive released in a population would be inextricably linked to the population's ecology. Given the uncertainty often involved in ecological assessment of natural populations, understanding the sensitivity of gene drive spread to important ecological factors is critical. Here we review how different forms of density dependence, spatial heterogeneity, and mating behaviors can impact the spread of self-sustaining gene drives. We highlight specific aspects of gene drive dynamics and the target populations that need further research.

scholarly journals Assessment of a Split Homing Based Gene Drive for Efficient Knockout of Multiple Genes

2019 ◽  
Vol 10 (2) ◽  
pp. 827-837 ◽  
Author(s):  
Nikolay P. Kandul ◽  
Junru Liu ◽  
Anna Buchman ◽  
Valentino M. Gantz ◽  
Ethan Bier ◽  
...  
Keyword(s):  
Disease Transmission ◽  
Target Genes ◽  
High Efficiency ◽  
Population Control ◽  
Natural Populations ◽  
Pathogen Transmission ◽  
Gene Drive ◽  
Guide Rnas ◽  
Cas9 Protein ◽  
Gene Drives

Homing based gene drives (HGD) possess the potential to spread linked cargo genes into natural populations and are poised to revolutionize population control of animals. Given that host encoded genes have been identified that are important for pathogen transmission, targeting these genes using guide RNAs as cargo genes linked to drives may provide a robust method to prevent disease transmission. However, effectiveness of the inclusion of additional guide RNAs that target separate genes has not been thoroughly explored. To test this approach, we generated a split-HGD in Drosophila melanogaster that encoded a drive linked effector consisting of a second gRNA engineered to target a separate host-encoded gene, which we term a gRNA-mediated effector (GME). This design enabled us to assess homing and knockout efficiencies of two target genes simultaneously, and also explore the timing and tissue specificity of Cas9 expression on cleavage/homing rates. We demonstrate that inclusion of a GME can result in high efficiency of disruption of both genes during super-Mendelian propagation of split-HGD. Furthermore, both genes were knocked out one generation earlier than expected indicating the robust somatic expression of Cas9 driven by Drosophila germline-limited promoters. We also assess the efficiency of ‘shadow drive’ generated by maternally deposited Cas9 protein and accumulation of drive-induced resistance alleles along multiple generations, and discuss design principles of HGD that could mitigate the accumulation of resistance alleles while incorporating a GME.

scholarly journals Assessment of a split homing based gene drive for efficient knockout of multiple genes

2019 ◽  
Author(s):  
Nikolay P. Kandul ◽  
Junru Liu ◽  
Anna Buchman ◽  
Valentino M. Gantz ◽  
Ethan Bier ◽  
...  
Keyword(s):  
Target Gene ◽  
Tissue Specificity ◽  
Target Genes ◽  
High Efficiency ◽  
Population Control ◽  
Natural Populations ◽  
Pathogen Transmission ◽  
Gene Drive ◽  
Guide Rnas ◽  
Gene Drives

AbstractHoming based gene drives (HGD) possess the potential to spread linked cargo genes into natural populations and are poised to revolutionize population control of animals. Given that host-encoded genes have been identified that are important for pathogen transmission, targeting these genes using guide RNAs as cargo genes linked to drives may provide a robust method to prevent transmission. However, effectiveness of the inclusion of additional guide RNAs that target separate host encoded genes has not been thoroughly explored. To test this approach, here we generated a split-HGD in Drosophila melanogaster that encoded a drive linked effector consisting of a second gRNA engineered to target a separate host encoded gene, which we term a gRNA-mediated effector (GME). This design enabled us to assess homing and knockout efficiencies of two target genes simultaneously, and also explore the timing and tissue specificity of Cas9 expression on cleavage/homing rates. We demonstrate that inclusion of a GME can result in high efficiency of disruption of its target gene during super-Mendelian propagation of split-HGD. However, maternal deposition and embryonic expression of Cas9 resulted in the generation of drive resistant alleles which can accumulate and limit the spread of such a drive. Alternative design principles are discussed that could mitigate the accumulation of resistance alleles while incorporating a GME.

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 Can a population targeted by a CRISPR-based homing gene drive be rescued?

2020 ◽  
Author(s):  
Nicolas O. Rode ◽  
Virginie Courtier-Orgogozo ◽  
Florence Débarre
Keyword(s):  
Genetic Control ◽  
Natural Populations ◽  
Genetically Engineered ◽  
Control Technique ◽  
Gene Drive ◽  
Wild Type ◽  
Safety Issues ◽  
Type Population ◽  
Variable Population ◽  
Gene Drives

AbstractCRISPR-based homing gene drive is a genetic control technique aiming to modify or eradicate natural populations. This technique is based on the release of individuals carrying an engineered piece of DNA that can be preferentially inherited by the progeny. Developing countermeasures is important to control the spread of gene drives, should they result in unanticipated damages. One proposed countermeasure is the introduction of individuals carrying a brake construct that targets and inactivates the drive allele but leaves the wild-type allele unaffected. Here we develop models to investigate the efficiency of such brakes. We consider a variable population size and use a combination of analytical and numerical methods to determine the conditions where a brake can prevent the extinction of a population targeted by an eradication drive. We find that a brake is not guaranteed to prevent eradication and that characteristics of both the brake and the drive affect the likelihood of recovering the wild-type population. In particular, brakes that restore fitness are more efficient than brakes that do not. Our model also indicates that threshold-dependent drives (drives that can spread only when introduced above a threshold) are more amenable to control with a brake than drives that can spread from an arbitrary low introduction frequency (threshold-independent drives). Based on our results, we provide practical recommendations and discuss safety issues.Article summary for Issue HighlightsHoming gene drive is a new genetic control technology that aims to spread a genetically engineered DNA construct within natural populations even when it impairs fitness. In case of unanticipated damages, it has been proposed to stop homing gene drives by releasing individuals carrying a genedrive brake; however, the efficiency of such brakes has been little studied. The authors develop a model to investigate the dynamics of a population targeted by a homing drive in absence or in presence of brake. The model provides insights for the design of more efficient brakes and safer gene drives.

scholarly journals Suppression gene drive in continuous space can result in unstable persistence of both drive and wild-type alleles

2019 ◽  
Author(s):  
Jackson Champer ◽  
Isabel Kim ◽  
Samuel E. Champer ◽  
Andrew G. Clark ◽  
Philipp W. Messer
Keyword(s):  
Natural Populations ◽  
Spatial Models ◽  
Ecological Factors ◽  
Natural Environments ◽  
Gene Drive ◽  
Wild Type ◽  
Lower Efficiency ◽  
Continuous Space ◽  
Selfish Genetic Elements ◽  
Drive Systems

ABSTRACTRapid evolutionary processes can produce drastically different outcomes when studied in panmictic population models versus spatial models where the rate of evolution is limited by dispersal. One such process is gene drive, which allows “selfish” genetic elements to quickly spread through a population. Engineered gene drive systems are being considered as a means for suppressing disease vector populations or invasive species. While laboratory experiments and modeling in panmictic populations have shown that such drives can rapidly eliminate a population, it is not yet clear how well these results translate to natural environments where individuals inhabit a continuous landscape. Using spatially explicit simulations, we show that instead of population elimination, release of a suppression drive can result in what we term “chasing” dynamics. This describes a condition in which wild-type individuals quickly recolonize areas where the drive has locally eliminated the population. Despite the drive subsequently chasing the wild-type allele into these newly re-colonized areas, complete population suppression often fails or is substantially delayed. This delay increases the likelihood that the drive becomes lost or that resistance evolves. We systematically analyze how chasing dynamics are influenced by the type of drive, its efficiency, fitness costs, as well as ecological and demographic factors such as the maximal growth rate of the population, the migration rate, and the level of inbreeding. We find that chasing is generally more common for lower efficiency drives and in populations with low dispersal. However, we further find 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.

scholarly journals Reducing resistance allele formation in CRISPR gene drive

2018 ◽  
Vol 115 (21) ◽  
pp. 5522-5527 ◽  
Author(s):  
Jackson Champer ◽  
Jingxian Liu ◽  
Suh Yeon Oh ◽  
Riona Reeves ◽  
Anisha Luthra ◽  
...  
Keyword(s):  
Natural Populations ◽  
Mendelian Inheritance ◽  
Gene Drive ◽  
Subsequent Formation ◽  
Vector Borne Diseases ◽  
Effective Strategies ◽  
Guide Rnas ◽  
Vector Borne ◽  
Resistance Rates ◽  
Gene Drives

CRISPR homing gene drives can convert heterozygous cells with one copy of the drive allele into homozygotes, thereby enabling super-Mendelian inheritance. Such a mechanism could be used, for example, to rapidly disseminate a genetic payload in a population, promising effective strategies for the control of vector-borne diseases. However, all CRISPR homing gene drives studied in insects thus far have produced significant quantities of resistance alleles that would limit their spread. In this study, we provide an experimental demonstration that multiplexing of guide RNAs can both significantly increase the drive conversion efficiency and reduce germline resistance rates of a CRISPR homing gene drive inDrosophila melanogaster. We further show that an autosomal drive can achieve drive conversion in the male germline, with no subsequent formation of resistance alleles in embryos through paternal carryover of Cas9. Finally, we find that thenanospromoter significantly lowers somatic Cas9 expression compared with thevasapromoter, suggesting thatnanosprovides a superior choice in drive strategies where gene disruption in somatic cells could have fitness costs. Comparison of drive parameters among the different constructs developed in this study and a previous study suggests that, while drive conversion and germline resistance rates are similar between different genomic targets, embryo resistance rates can vary significantly. Taken together, our results mark an important step toward developing effective gene drives capable of functioning in natural populations and provide several possible avenues for further control of resistance rates.

scholarly journals Experimental demonstration of tethered gene drive systems for confined population modification or suppression

2021 ◽  
Author(s):  
Matthew Metzloff ◽  
Emily Yang ◽  
Sumit Dhole ◽  
Andrew G. Clark ◽  
Philipp W. Messer ◽  
...  
Keyword(s):  
Population Control ◽  
Local Population ◽  
Natural Populations ◽  
Great Promise ◽  
Gene Drive ◽  
Native Range ◽  
Target Populations ◽  
Experimental Cage ◽  
Drive Systems ◽  
Gene Drives

Homing gene drives hold great promise for the genetic control of natural populations. However, current homing systems are capable of spreading uncontrollably between populations connected by even marginal levels of migration. This could represent a substantial sociopolitical barrier to the testing or deployment of such drives and may generally be undesirable when the objective is only local population control, such as suppression of an invasive species outside of its native range. Tethered drive systems, in which a locally confined gene drive provides the CRISPR nuclease needed for a homing drive, could provide a solution to this problem, offering the power of a homing drive and confinement of the supporting drive. Here, we demonstrate the engineering of a tethered drive system in Drosophila, using a TARE drive to support modification and suppression homing drives. Each drive was able to bias inheritance in its favor, and the TARE drive was shown to spread only when released above a threshold frequency in experimental cage populations. After the TARE drive had established in the population, it facilitated the spread of a subsequently released split homing modification drive (to all individuals in the cage) and of a homing suppression drive (to its equilibrium frequency). Our results show that the tethered drive strategy is a viable and easily engineered option for providing confinement of homing drives to target populations. 

scholarly journals Can a Population Targeted by a CRISPR-Based Homing Gene Drive Be Rescued?

2020 ◽  
Vol 10 (9) ◽  
pp. 3403-3415 ◽  
Author(s):  
Nicolas O Rode ◽  
Virginie Courtier-Orgogozo ◽  
Florence Débarre
Keyword(s):  
Natural Populations ◽  
Control Technique ◽  
Gene Drive ◽  
Wild Type ◽  
Safety Issues ◽  
Type Population ◽  
Variable Population ◽  
Gene Drives ◽  
Practical Recommendations ◽  
Variable Population Size

Abstract CRISPR-based homing gene drive is a genetic control technique aiming to modify or eradicate natural populations. This technique is based on the release of individuals carrying an engineered piece of DNA that can be preferentially inherited by the progeny. The development of countermeasures is important to control the spread of gene drives, should they result in unanticipated damages. One proposed countermeasure is the introduction of individuals carrying a brake construct that targets and inactivates the drive allele but leaves the wild-type allele unaffected. Here we develop models to investigate the efficiency of such brakes. We consider a variable population size and use a combination of analytical and numerical methods to determine the conditions where a brake can prevent the extinction of a population targeted by an eradication drive. We find that a brake is not guaranteed to prevent eradication and that characteristics of both the brake and the drive affect the likelihood of recovering the wild-type population. In particular, brakes that restore fitness are more efficient than brakes that do not. Our model also indicates that threshold-dependent drives (drives that can spread only when introduced above a threshold) are more amenable to control with a brake than drives that can spread from an arbitrary low introduction frequency (threshold-independent drives). Based on our results, we provide practical recommendations and discuss safety issues.

scholarly journals Modeling the efficacy of CRISPR gene drive for schistosomiasis control

2021 ◽  
Author(s):  
Richard E Grewelle ◽  
Javier Perez-Saez ◽  
Josh Tycko ◽  
Erica KO Namigai ◽  
Chloe G Rickards ◽  
...  
Keyword(s):  
Genetic Model ◽  
Ecological Factors ◽  
Model Organisms ◽  
Snail Population ◽  
Gene Drive ◽  
Intermediate Hosts ◽  
Multiple Alleles ◽  
Sexual And Asexual Reproduction ◽  
Models Of Disease ◽  
Gene Drives

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.

scholarly journals Novel combination of CRISPR-based gene drives eliminates resistance and localises spread

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nicky R. Faber ◽  
Gus R. McFarlane ◽  
R. Chris Gaynor ◽  
Ivan Pocrnic ◽  
C. Bruce A. Whitelaw ◽  
...  
Keyword(s):  
Driving Forces ◽  
Spatial Models ◽  
Cost Effective ◽  
Biodiversity Loss ◽  
Invasive Pest ◽  
Economic Losses ◽  
Sciurus Carolinensis ◽  
Gene Drive ◽  
Grey Squirrel ◽  
Gene Drives

AbstractInvasive species are among the major driving forces behind biodiversity loss. Gene drive technology may offer a humane, efficient and cost-effective method of control. For safe and effective deployment it is vital that a gene drive is both self-limiting and can overcome evolutionary resistance. We present HD-ClvR in this modelling study, a novel combination of CRISPR-based gene drives that eliminates resistance and localises spread. As a case study, we model HD-ClvR in the grey squirrel (Sciurus carolinensis), which is an invasive pest in the UK and responsible for both biodiversity and economic losses. HD-ClvR combats resistance allele formation by combining a homing gene drive with a cleave-and-rescue gene drive. The inclusion of a self-limiting daisyfield gene drive allows for controllable localisation based on animal supplementation. We use both randomly mating and spatial models to simulate this strategy. Our findings show that HD-ClvR could effectively control a targeted grey squirrel population, with little risk to other populations. HD-ClvR offers an efficient, self-limiting and controllable gene drive for managing invasive pests.

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