scholarly journals Population dynamics of underdominance gene drive systems in continuous space

2018 ◽  
Author(s):  
Jackson Champer ◽  
Joanna Zhao ◽  
Joanna Zhao ◽  
Samuel E. Champer ◽  
Jingxian Liu ◽  
...  
Keyword(s):  
Decision Making ◽  
Population Dynamics ◽  
Local Population ◽  
Spatial Context ◽  
Decision Making Process ◽  
Gene Drive ◽  
Continuous Space ◽  
Vector Borne Diseases ◽  
Vector Borne ◽  
Drive Systems

ABSTRACTUnderdominance gene drive systems promise a mechanism for rapidly spreading payload alleles through a local population while otherwise remaining confined, unable to spread into neighboring populations due to their frequency-dependent dynamics. Such systems could provide a new tool in the fight against vector-borne diseases by disseminating transgenic payloads through vector populations. If local confinement can indeed be achieved, the decision-making process for the release of such constructs would likely be considerably simpler compared to other gene drive mechanisms such as CRISPR homing drives. So far, the confinement ability of underdominance systems has only been demonstrated in models of panmictic populations linked by migration. How such systems would behave in realistic populations where individuals move over continuous space remains largely unknown. Here, we study several underdominance systems in continuous-space population models and show that their dynamics are drastically altered from those in panmictic populations. Specifically, we find that all underdominance systems we studied can fail to persist in such environments, even after successful local establishment. At the same time, we find that a two-locus two-toxin-antitoxin system can still successfully invade neighboring populations in many scenarios even under weak migration. This suggests that the parameter space for underdominance systems to both establish in a given region and remain confined to that region would likely be highly limited. Overall, these results indicate that spatial context must be considered when assessing strategies for the deployment of underdominance systems.

scholarly journals Population Dynamics of Underdominance Gene Drive Systems in Continuous Space

2020 ◽  
Vol 9 (4) ◽  
pp. 779-792 ◽  
Author(s):  
Jackson Champer ◽  
Joanna Zhao ◽  
Samuel E. Champer ◽  
Jingxian Liu ◽  
Philipp W. Messer
Keyword(s):  
Population Dynamics ◽  
Gene Drive ◽  
Continuous Space ◽  
Drive Systems

scholarly journals A CRISPR homing gene drive targeting a haplolethal gene removes resistance alleles and successfully spreads through a cage population

2020 ◽  
Vol 117 (39) ◽  
pp. 24377-24383 ◽  
Author(s):  
Jackson Champer ◽  
Emily Yang ◽  
Esther Lee ◽  
Jingxian Liu ◽  
Andrew G. Clark ◽  
...  
Keyword(s):  
Gene Drive ◽  
End Joining ◽  
Large Cage ◽  
Vector Borne Diseases ◽  
Guide Rnas ◽  
Genetic Modifications ◽  
New Strategy ◽  
Cage Population ◽  
Vector Borne ◽  
Gene Drives

Engineered gene drives are being explored as a new strategy in the fight against vector-borne diseases due to their potential for rapidly spreading genetic modifications through a population. However, CRISPR-based homing gene drives proposed for this purpose have faced a major obstacle in the formation of resistance alleles that prevent Cas9 cleavage. Here, we present a homing drive in Drosophila melanogaster that reduces the prevalence of resistance alleles below detectable levels by targeting a haplolethal gene with two guide RNAs (gRNAs) while also providing a rescue allele. Resistance alleles that form by end-joining repair typically disrupt the haplolethal target gene and are thus removed from the population because individuals that carry them are nonviable. We demonstrate that our drive is highly efficient, with 91% of the progeny of drive heterozygotes inheriting the drive allele and with no functional resistance alleles observed in the remainder. In a large cage experiment, the drive allele successfully spread to all individuals within a few generations. These results show that a haplolethal homing drive can provide an effective tool for targeted genetic modification of entire populations.

scholarly journals Efficient population modification gene-drive rescue system in the malaria mosquito Anopheles stephensi

2020 ◽  
Author(s):  
Adriana Adolfi ◽  
Valentino M. Gantz ◽  
Nijole Jasinskiene ◽  
Hsu-Feng Lee ◽  
Kristy Hwang ◽  
...  
Keyword(s):  
Anopheles Stephensi ◽  
Pathogen Transmission ◽  
Gene Drive ◽  
Initial Release ◽  
Genetic Technologies ◽  
Rescue System ◽  
Vector Borne ◽  
Kynurenine Hydroxylase ◽  
Drive Systems ◽  
Population Suppression

ABSTRACTThe development of Cas9/gRNA-mediated gene-drive systems has bolstered the advancement of genetic technologies for controlling vector-borne pathogen transmission. These include population suppression approaches, genetic analogs of insecticidal techniques that reduce the number of vector insects, and population modification (replacement/alteration) approaches, which interfere with competence to transmit pathogens. We developed a recoded gene-drive rescue system for population modification in the malaria vector, Anopheles stephensi, that relieves the load in females caused by integration of the drive into the kynurenine hydroxylase gene by rescuing its function. Non-functional resistant alleles are eliminated via a dominantly-acting maternal effect combined with slower-acting standard negative selection, and a functional resistant allele does not prevent drive invasion. Small cage trials show that single releases of gene-drive males robustly result in efficient population modification with ≥95% of mosquitoes carrying the drive within 5-11 generations over a range of initial release ratios.

scholarly journals Modulating CRISPR gene drive activity through nucleocytoplasmic localization of Cas9 in S. cerevisiae

2018 ◽  
Author(s):  
Megan E. Goeckel ◽  
Erianna M. Basgall ◽  
Isabel C. Lewis ◽  
Samantha C. Goetting ◽  
Yao Yan ◽  
...  
Keyword(s):  
Nuclease Activity ◽  
Gene Drive ◽  
Wild Populations ◽  
Vector Borne Diseases ◽  
Vector Borne ◽  
Mendelian Laws ◽  
Artificial Gene ◽  
Nuclear Localization Sequences ◽  
Gene Drives

ABSTRACTThe bacterial CRISPR/Cas genome editing system has provided a major breakthrough in molecular biology. One use of this technology is within a nuclease-based gene drive. This type of system can install a genetic element within a population at unnatural rates. Combatting of vector-borne diseases carried by metazoans could benefit from a delivery system that bypasses traditional Mendelian laws of segregation. Recently, laboratory studies in fungi, insects, and even mice, have demonstrated successful propagation of CRISPR gene drives and the potential utility of this type of mechanism. However, current gene drives still face challenges including evolved resistance, containment, and the consequences of application in wild populations. In this study, we use an artificial gene drive system in budding yeast to explore mechanisms to modulate nuclease activity of Cas9 through its nucleocytoplasmic localization. We examine non-native nuclear localization sequences on Cas9 fusion proteins in vivo and demonstrate that appended signals can titrate gene drive activity and serve as a potential molecular safeguard.

scholarly journals Computational Efficiency in Multivariate Adversarial Risk Analysis Models

2019 ◽  
Vol 16 (4) ◽  
pp. 314-332 ◽  
Author(s):  
Michael Perry ◽  
Hadi El-Amine
Keyword(s):  
Decision Making ◽  
Decision Problem ◽  
Computational Algorithm ◽  
Optimal Solution ◽  
Decision Making Process ◽  
Decision Space ◽  
Continuous Space ◽  
Strategic Objectives ◽  
Simulation Based ◽  
Analysis Models

In this paper, we address the computational feasibility of the class of decision theoretic models referred to as adversarial risk analyses (ARAs). These are models where a decision must be made with consideration for how an intelligent adversary may behave and where the decision-making process of the adversary is unknown and is elicited by analyzing the adversary's decision problem using priors on his utility function and beliefs. The motivation of this research was to develop a computational algorithm that can be applied across a broad range of ARA models; to the best of our knowledge, no such algorithm currently exists. Using a two-person sequential model, we incrementally increase the size of the model and develop a simulation-based approximation of the true optimum where an exact solution is computationally impractical. In particular, we begin with a relatively large decision space by considering a theoretically continuous space that must be discretized. Then, we incrementally increase the number of strategic objectives, which causes the decision space to grow exponentially. The problem is exacerbated by the presence of an intelligent adversary who also must solve an exponentially large decision problem according to some unknown decision-making process. Nevertheless, using a stylized example that can be solved analytically, we show that our algorithm not only solves large ARA models quickly but also accurately selects to the true optimal solution. Furthermore, the algorithm is sufficiently general that it can be applied to any ARA model with a large, yet finite, decision space.

scholarly journals A genetically encoded anti-CRISPR protein constrains gene drive spread and prevents population suppression

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chrysanthi Taxiarchi ◽  
Andrea Beaghton ◽  
Nayomi Illansinhage Don ◽  
Kyros Kyrou ◽  
Matthew Gribble ◽  
...  
Keyword(s):  
Genetically Modified Organisms ◽  
Reproductive Capacity ◽  
Gene Drive ◽  
Vector Borne Diseases ◽  
Pathogen Effectors ◽  
Germline Expression ◽  
Vector Borne ◽  
Malaria Mosquitoes ◽  
Gene Drives ◽  
Population Suppression

AbstractCRISPR-based gene drives offer promising means to reduce the burden of pests and vector-borne diseases. These techniques consist of releasing genetically modified organisms carrying CRISPR-Cas nucleases designed to bias their inheritance and rapidly propagate desired modifications. Gene drives can be intended to reduce reproductive capacity of harmful insects or spread anti-pathogen effectors through wild populations, even when these confer fitness disadvantages. Technologies capable of halting the spread of gene drives may prove highly valuable in controlling, counteracting, and even reverting their effect on individual organisms as well as entire populations. Here we show engineering and testing of a genetic approach, based on the germline expression of a phage-derived anti-CRISPR protein (AcrIIA4), able to inactivate CRISPR-based gene drives and restore their inheritance to Mendelian rates in the malaria vector Anopheles gambiae. Modeling predictions and cage testing show that a single release of male mosquitoes carrying the AcrIIA4 protein can block the spread of a highly effective suppressive gene drive preventing population collapse of caged malaria mosquitoes.

scholarly journals Small-molecule control of super-Mendelian inheritance in gene drives

2019 ◽  
Author(s):  
Víctor López Del Amo ◽  
Brittany S. Leger ◽  
Kurt J. Cox ◽  
Shubhroz Gill ◽  
Alena L. Bishop ◽  
...  
Keyword(s):  
Small Molecule ◽  
Chemical Control ◽  
Control Strategies ◽  
Mendelian Inheritance ◽  
Drive System ◽  
Gene Drive ◽  
Crop Pests ◽  
Vector Borne Diseases ◽  
Vector Borne ◽  
Gene Drives

ABSTRACTBy surpassing the 50% inheritance limit of Mendel’s law of independent assortment, CRISPR-based gene drives have the potential to fight vector-borne diseases or suppress crop pests. However, contemporary gene drives could spread unchecked, posing safety concerns that limit their use in both laboratory and field settings. Current technologies also lack chemical control strategies, which could be applied in the field for dose, spatial and temporal control of gene drives. We describe in Drosophila the first gene-drive system controlled by an engineered Cas9 and a synthetic, orally-available small molecule.Graphical Abstract

scholarly journals Current CRISPR gene drive systems are likely to be highly invasive in wild populations

2017 ◽  
Author(s):  
Charleston Noble ◽  
Ben Adlam ◽  
George M. Church ◽  
Kevin M. Esvelt ◽  
Martin A. Nowak
Keyword(s):  
Local Population ◽  
Gene Drive ◽  
Host Organism ◽  
Wild Populations ◽  
Flow Rates ◽  
Standing Variation ◽  
Large Populations ◽  
Mitigating Factors ◽  
Drive Systems ◽  
Gene Drives

AbstractRecent reports have suggested that CRISPR-based gene drives are unlikely to invade wild populations due to drive-resistant alleles that prevent cutting. Here we develop mathematical models based on existing empirical data to explicitly test this assumption. We show that although resistance prevents drive systems from spreading to fixation in large populations, even the least effective systems reported to date are highly invasive. Releasing a small number of organisms often causes invasion of the local population, followed by invasion of additional populations connected by very low gene flow rates. Examining the effects of mitigating factors including standing variation, inbreeding, and family size revealed that none of these prevent invasion in realistic scenarios. Highly effective drive systems are predicted to be even more invasive. Contrary to the National Academies report on gene drive, our results suggest that standard drive systems should not be developed nor field-tested in regions harboring the host organism.

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 Diagnosis of Vector-Borne Diseases Using MCDM Techniques

2019 ◽  
Vol 8 (6) ◽  
pp. 1367-1375
Keyword(s):  
Decision Making ◽  
Fuzzy Set ◽  
Diagnostic Tool ◽  
Medical Diagnosis ◽  
Intuitionistic Fuzzy Set ◽  
Vector Borne Diseases ◽  
Intuitionistic Fuzzy ◽  
The World ◽  
Vector Borne ◽  
Vikor Technique

Vector -borne diseases (VBDs) are one of the major problems of human are affecting adversely to people each year in every part of the world. In this work multiple decision-making technique is used to provide a better diagnosis for VBDs. It evaluates alternative diseases having contradictory symptoms. It is very tough to exactly determine crsiteria weight as well as rating of alternatives (diseases) on each criterion. Here VIKOR approach is applied for medical diagnosis of VBDs such as malaria, chikungunya, and dengue, and also used the notion of intuitionistic fuzzy set (IFS) theory to explain this concept. Furthermore, criteria selected according to relevant disease and weights assigned to them by medical experts. In order to accomplish the objective, patients’ data has been acquired using a questionnaire from three medical experts of Delhi region. The study shows that final outcomes are same as diagnosed by doctors regarding actual diseases as that by employing VIKOR technique based on questionnaire information. Thus, MCDM methodology can help in correct and timely diagnosis of VBDs and provides doctors a scientific diagnostic tool.

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