Population Dynamics of Underdominance Gene Drive Systems in Continuous Space

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.

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

10.1101/769810 ◽

2019 ◽

Cited By ~ 7

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.

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MGDrivE 2: A simulation framework for gene drive systems incorporating seasonality and epidemiological dynamics

10.1101/2020.10.16.343376 ◽

2020 ◽

Author(s):

Sean L. Wu ◽

Jared B. Bennett ◽

Héctor M. Sánchez C. ◽

Andrew J. Dolgert ◽

Tomás M. León ◽

...

Keyword(s):

Population Dynamics ◽

Disease Transmission ◽

Field Trials ◽

Pathogen Transmission ◽

Environmental Data ◽

List Type ◽

Gene Drive ◽

Simulation Framework ◽

Implementation Framework ◽

Drive Systems

AbstractInterest in gene drive technology has continued to grow as promising new drive systems have been developed in the lab and discussions are moving towards implementing field trials. The prospect of field trials requires models that incorporate a significant degree of ecological detail, including parameters that change over time in response to environmental data such as temperature and rainfall, leading to seasonal patterns in mosquito population density. Epidemiological outcomes are also of growing importance, as: i) the suitability of a gene drive construct for release will depend on its expected impact on disease transmission, and ii) initial field trials are expected to have a measured entomological outcome and a modeled epidemiological outcome.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. Key strengths and improvements of the MGDrivE 2 framework are: i) the ability of parameters to vary with time and induce seasonal population dynamics, ii) an epidemiological module accommodating reciprocal pathogen transmission between humans and mosquitoes, and iii) an implementation framework based on stochastic Petri nets that enables efficient model formulation and flexible implementation.Example MGDrivE 2 simulations are presented to demonstrate the application of the framework to a CRISPR-based homing gene drive system intended to drive a disease-refractory gene into a population, incorporating time-varying temperature and rainfall data, and predict impact on human disease incidence and prevalence. Further documentation and use examples are provided in vignettes at the project’s CRAN repository.MGDrivE 2 is an open-source R package freely available on CRAN. We intend the package to provide a flexible tool capable of modeling gene drive constructs as they move closer to field application and to infer their expected impact on disease transmission.

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Anticipatory governance of gene drive systems

10.1603/ice.2016.92368 ◽

2016 ◽

Author(s):

Jennifer Kuzma

Keyword(s):

Gene Drive ◽

Anticipatory Governance ◽

Drive Systems

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Optimized CRISPR tools and site-directed transgenesis in Culex quinquefasciatus mosquitoes for gene drive development

10.1101/2021.02.10.430702 ◽

2021 ◽

Author(s):

Xuechun Feng ◽

Víctor López Del Amo ◽

Enzo Mameli ◽

Megan Lee ◽

Alena L. Bishop ◽

...

Keyword(s):

Culex Quinquefasciatus ◽

Technology Development ◽

Companion Animals ◽

Fruit Fly ◽

Valuable Insight ◽

Gene Drive ◽

Future Technology ◽

Drive Systems ◽

Global Vector ◽

Human And Animal Diseases

ABSTRACTCulex mosquitoes are a global vector for multiple human and animal diseases, including West Nile virus, lymphatic filariasis, and avian malaria, posing a constant threat to public health, livestock, companion animals, and endangered birds. While rising insecticide resistance has threatened the control of Culex mosquitoes, advances in CRISPR genome-editing tools have fostered the development of alternative genetic strategies such as gene drive systems to fight disease vectors. However, though gene-drive technology has quickly progressed in other mosquitoes, advances have been lacking in Culex. Here, we developed a Culex-specific Cas9/gRNA expression toolkit and used site-directed homology-based transgenesis to generate and validate a Culex quinquefasciatus Cas9-expressing line. We showed that gRNA scaffold variants improve transgenesis efficiency in both Culex and Drosophila and boost gene-drive performance in the fruit fly. These findings support future technology development to control Culex mosquitoes and provide valuable insight for improving these tools in other species.

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Gene Therapy: A Promising Therapeutic Strategy for Malaria

University of Ottawa Journal of Medicine ◽

10.18192/uojm.v8i2.3651 ◽

2018 ◽

Vol 8 (2) ◽

pp. 40-44

Author(s):

Raafay Shehzad

Keyword(s):

Gene Therapy ◽

Therapeutic Strategy ◽

Homing Endonuclease ◽

Genetic Material ◽

Gene Drive ◽

Treatment And Prevention ◽

Preventative Measures ◽

Drive Systems ◽

Embryonic Arrest ◽

Diabetes And Obesity

Malaria is a serious illness caused by the Plasmodium parasite, which places approximately 3.5 billion people at risk. Currently, preventative measures are key in combatting this disease. However, gene therapy is an emerging field that shows promising results for the treatment of malaria, by modifying cells through the delivery of genetic material. Most notable was the discovery of CRISPR-Cas9, which not only allows deleterious mutations to be repaired, but does so with specificity, speed, and simplicity. There are numerous ongoing trials focusing on gene therapy in malaria treatment and prevention. They involve different approaches such as the genetic modification of vector mosquitoes to interfere with malaria transmission, use of CRISPR-Cas9, maternal-effect dominant embryonic arrest, homing endonuclease gene drive systems, and the design of specific Morpholino oligomers to interfere with the expression of parasitic characteristics. Overall, this emerging field shows promising results to treat and prevent not just malaria, but other diseases such as cancer, diabetes, and obesity.

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

10.1101/2020.08.02.233056 ◽

2020 ◽

Cited By ~ 6

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.

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Invasion and migration of spatially self-limiting gene drives: a comparative analysis

10.1101/159855 ◽

2017 ◽

Cited By ~ 2

Author(s):

Sumit Dhole ◽

Michael R. Vella ◽

Alun L. Loyd ◽

Fred Gould

Keyword(s):

Target Population ◽

Gene Drive ◽

Fitness Costs ◽

Invasion And Migration ◽

Migration Rates ◽

Chain System ◽

Drive Systems ◽

And Migration ◽

The One ◽

Gene Drives

AbstractRecent advances in research on gene drives have produced genetic constructs that could theoretically spread a desired gene (payload) into all populations of a species, with a single release in one place. This attribute has advantages, but also comes with risks and ethical concerns. There has been a call for research on gene drive systems that are spatially and/or temporally self-limiting. Here we use a population genetics model to compare the expected characteristics of three spatially self-limiting gene drive systems: one-locus underdominance, two-locus underdominance, and daisy-chain drives. We find large differences between these gene drives in the minimum release size required for successfully driving a payload into a population. The daisy-chain system is the most efficient, requiring the smallest release, followed by the two-locus underdominance system, and then the one-locus underdominance system. However, when the target population exchanges migrants with a non-target population, the gene drives requiring smaller releases suffer from higher risks of unintended spread. For payloads that incur relatively low fitness costs (up to 30%), a simple daisy-chain drive is practically incapable of remaining localized, even with migration rates as low as 0.5% per generation. The two-locus underdominance system can achieve localized spread under a broader range of migration rates and of payload fitness costs, while the one-locus underdominance system largely remains localized. We also find differences in the extent of population alteration and in the permanence of the alteration achieved by the three gene drives. The two-locus underdominance system does not always spread the payload to fixation, even after successful drive, while the daisy-chain system can, for a small set of parameter values, achieve a temporally-limited spread of the payload. These differences could affect the suitability of each gene drive for specific applications.Note:This manuscript has been accepted for publication in the journal Evolutionary Applications and is pending publication. We suggest that any reference to or quotation of this article should be made with this recognition.

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Experiments confirm a dispersive phenotype associated with a natural gene drive system

Royal Society Open Science ◽

10.1098/rsos.202050 ◽

2021 ◽

Vol 8 (5) ◽

Author(s):

Jan-Niklas Runge ◽

Anna K. Lindholm

Keyword(s):

Sperm Competition ◽

Local Density ◽

House Mice ◽

Gene Drive ◽

Wild Type ◽

Fitness Costs ◽

Oestrus Cycle ◽

Drive Systems ◽

Average Body ◽

Average Body Weight

Meiotic drivers are genetic entities that increase their own probability of being transmitted to offspring, usually to the detriment of the rest of the organism, thus ‘selfishly’ increasing their fitness. In many meiotic drive systems, driver-carrying males are less successful in sperm competition, which occurs when females mate with multiple males in one oestrus cycle (polyandry). How do drivers respond to this selection? An observational study found that house mice carrying the t haplotype, a meiotic driver, are more likely to disperse from dense populations. This could help the t avoid detrimental sperm competition, because density is associated with the frequency of polyandry. However, no controlled experiments have been conducted to test these findings. Here, we confirm that carriers of the t haplotype are more dispersive, but we do not find this to depend on the local density. t -carriers with above-average body weight were particularly more likely to disperse than wild-type mice. t -carrying mice were also more explorative but not more active than wild-type mice. These results add experimental support to the previous observational finding that the t haplotype affects the dispersal phenotype in house mice, which supports the hypothesis that dispersal reduces the fitness costs of the t .

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Evolutionary dynamics of CRISPR gene drives

10.1101/057281 ◽

2016 ◽

Cited By ~ 10

Author(s):

Charleston Noble ◽

Jason Olejarz ◽

Kevin M. Esvelt ◽

George M. Church ◽

Martin A. Nowak

Keyword(s):

Evolutionary Dynamics ◽

Evolutionary Stability ◽

Clear Understanding ◽

Gene Drive ◽

Host Organism ◽

Wild Populations ◽

Selfish Genetic Elements ◽

Real World Applications ◽

Drive Systems ◽

Gene Drives

AbstractThe alteration of wild populations has been discussed as a solution to a number of humanity’s most pressing ecological and public health concerns. Enabled by the recent revolution in genome editing, CRISPR gene drives, selfish genetic elements which can spread through populations even if they confer no advantage to their host organism, are rapidly emerging as the most promising approach. But before real-world applications are considered, it is imperative to develop a clear understanding of the outcomes of drive release in nature. Toward this aim, we mathematically study the evolutionary dynamics of CRISPR gene drives. We demonstrate that the emergence of drive-resistant alleles presents a major challenge to previously reported constructs, and we show that an alternative design which selects against resistant alleles greatly improves evolutionary stability. We discuss all results in the context of CRISPR technology and provide insights which inform the engineering of practical gene drive systems.

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