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

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.

Download Full-text

Modeling confinement and reversibility of threshold-dependent gene drive systems in spatially-explicit Aedes aegypti populations

10.1101/607267 ◽

2019 ◽

Cited By ~ 2

Author(s):

Héctor M. Sánchez C. ◽

Jared B. Bennett ◽

Sean L. Wu ◽

Gordana Rašić ◽

Omar S. Akbari ◽

...

Keyword(s):

Aedes Aegypti ◽

Disease Transmission ◽

Release Site ◽

Field Trials ◽

Mosquito Vector ◽

Gene Drive ◽

Isolated Populations ◽

Dependent Behavior ◽

Wide Scale ◽

Drive Systems

AbstractBackgroundThe discovery of CRISPR-based gene editing and its application to homing-based gene drive systems has been greeted with excitement, for its potential to control mosquito-borne diseases on a wide scale, and concern, for the invasiveness and potential irreversibility of a release. Gene drive systems that display threshold-dependent behavior could potentially be used during the trial phase of this technology, or when localized control is otherwise desired, as simple models predict them to spread into partially isolated populations in a confineable manner, and to be reversible through releases of wild-type organisms. Here, we model hypothetical releases of two recently-engineered threshold-dependent gene drive systems - reciprocal chromosomal translocations and a form of toxin-antidote-based underdominance known as UDMEL - to explore their ability to be confined and remediated.ResultsWe simulate releases of Aedes aegypti, the mosquito vector of dengue, Zika and other arboviruses, in Yorkeys Knob, a suburb of Cairns, Australia, where previous biological control interventions have been undertaken on this species. We monitor spread to the neighboring suburb of Trinity Park to assess confinement. Results suggest that translocations could be introduced on a suburban scale, and remediated through releases of non-disease-transmitting male mosquitoes with release sizes on the scale of what has been previously implemented. UDMEL requires fewer releases to introduce, but more releases to remediate, including of females capable of disease transmission. Both systems are expected to be confineable to the release site; however, spillover of translocations into neighboring populations is less likely.ConclusionsOur analysis supports the use of translocations as a threshold-dependent drive system capable of spreading disease-refractory genes into Ae. aegypti populations in a confineable and reversible manner. It also highlights increased release requirements when incorporating life history and population structure into models. As the technology nears implementation, further ecological work will be essential to enhance model predictions in preparation for field trials.

Download Full-text

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.

Download Full-text

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

G3 Genes|Genome|Genetics ◽

10.1534/g3.119.400985 ◽

2019 ◽

Vol 10 (2) ◽

pp. 827-837 ◽

Cited By ~ 13

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.

Download Full-text

Population Dynamics of Underdominance Gene Drive Systems in Continuous Space

ACS Synthetic Biology ◽

10.1021/acssynbio.9b00452 ◽

2020 ◽

Vol 9 (4) ◽

pp. 779-792 ◽

Cited By ~ 11

Author(s):

Jackson Champer ◽

Joanna Zhao ◽

Samuel E. Champer ◽

Jingxian Liu ◽

Philipp W. Messer

Keyword(s):

Population Dynamics ◽

Gene Drive ◽

Continuous Space ◽

Drive Systems

Download Full-text

Population dynamics of underdominance gene drive systems in continuous space

10.1101/449355 ◽

2018 ◽

Cited By ~ 7

Author(s):

Jackson Champer ◽

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.

Download Full-text

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

10.1101/350488 ◽

2018 ◽

Cited By ~ 10

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.

Download Full-text

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

Nature Communications ◽

10.1038/s41467-020-19426-0 ◽

2020 ◽

Vol 11 (1) ◽

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 ◽

Advanced Development

Abstract Cas9/gRNA-mediated gene-drive systems have advanced development of genetic technologies for controlling vector-borne pathogen transmission. These technologies include population suppression approaches, genetic analogs of insecticidal techniques that reduce the number of insect vectors, and population modification (replacement/alteration) approaches, which interfere with competence to transmit pathogens. Here, we develop a recoded gene-drive rescue system for population modification of 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 rare functional resistant alleles do 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.

Download Full-text

Daisy-chain gene drives for the alteration of local populations

10.1101/057307 ◽

2016 ◽

Cited By ~ 30

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.

Download Full-text

Development of a confinable gene drive system in the human disease vector Aedes aegypti

eLife ◽

10.7554/elife.51701 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 25

Author(s):

Ming Li ◽

Ting Yang ◽

Nikolay P Kandul ◽

Michelle Bui ◽

Stephanie Gamez ◽

...

Keyword(s):

Aedes Aegypti ◽

Field Trials ◽

Pathogen Transmission ◽

Control Measures ◽

Mosquito Vector ◽

Gene Drive ◽

Wild Populations ◽

Linked Gene ◽

Pathogen Effector ◽

Gene Drives

Aedes aegypti is the principal mosquito vector for many arboviruses that increasingly infect millions of people every year. With an escalating burden of infections and the relative failure of traditional control methods, the development of innovative control measures has become of paramount importance. The use of gene drives has sparked significant enthusiasm for genetic control of mosquitoes; however, no such system has been developed in Ae. aegypti. To fill this void, here we develop several CRISPR-based split gene drives for use in this vector. With cleavage rates up to 100% and transmission rates as high as 94%, mathematical models predict that these systems could spread anti-pathogen effector genes into wild populations in a safe, confinable and reversible manner appropriate for field trials and effective for controlling disease. These findings could expedite the development of effector-linked gene drives that could safely control wild populations of Ae. aegypti to combat local pathogen transmission.

Download Full-text

Mobility and infectiousness in the spatial spread of an emerging fungal pathogen

10.1101/2020.05.07.082651 ◽

2020 ◽

Author(s):

Kate E. Langwig ◽

J. Paul White ◽

Katy L. Parise ◽

Heather M. Kaarakka ◽

Jennifer A. Redell ◽

...

Keyword(s):

Population Dynamics ◽

Infectious Diseases ◽

Fungal Pathogen ◽

Host Population ◽

Pathogen Transmission ◽

Accurate Estimation ◽

List Type ◽

Pseudogymnoascus Destructans ◽

Arrival Times ◽

White Nose Syndrome

AbstractEmerging infectious diseases can have devastating effects on host communities, causing population collapse and species extinctions. The timing of novel pathogen arrival into naïve species communities can have consequential effects that shape the trajectory of epidemics through populations. Pathogen introductions are often presumed to occur when hosts are highly mobile. However, spread patterns can be influenced by a multitude of other factors including host body condition and infectiousness.White-nose syndrome (WNS) is a seasonal emerging infectious disease of bats, which is caused by the fungal pathogen Pseudogymnoascus destructans. Within-site transmission of P. destructans primarily occurs over winter, however the influence of bat mobility and infectiousness on the seasonal timing of pathogen spread to new populations is unknown. We combined data on host population dynamics and pathogen transmission from 22 bat communities to investigate the timing of pathogen arrival and the consequences of varying pathogen arrival times on disease impacts.We found that midwinter arrival of the fungus predominated spread patterns, suggesting that bats were most likely to spread P. destructans when they are highly infectious, but have reduced mobility. In communities where P. destructans was detected in early winter, one species suffered higher fungal burdens and experienced more severe declines than at sites where the pathogen was detected later in the winter, suggesting that the timing of pathogen introduction had consequential effects for some bat communities. We also found evidence of source-sink population dynamics over winter, suggesting some movement among sites occurs during hibernation, even though bats at northern latitudes were thought to be fairly immobile during this period. Winter emergence behavior symptomatic of white-nose syndrome may further exacerbate these winter bat movements to uninfected areas.Our results suggest that low infectiousness during host migration may have reduced the rate of expansion of this deadly pathogen, and that elevated infectiousness during winter plays a key role in seasonal transmission. Furthermore, our results highlight the importance of both accurate estimation of the timing of pathogen spread and the consequences of varying arrival times to prevent and mitigate the effects of infectious diseases.

Download Full-text