Active Genetic Neutralizing Elements for Halting or Deleting Gene Drives

Xu, Xiangru; Bulger, Emily A.; Gantz, Valentino M.; Klanseck, Carissa; Heimler, Stephanie; Auradkar, Ankush; Bennett, Jared B.; Miller, Lauren A.; Leahy, Sarah; Juste, Sara Sanz; Buchman, Anna; Akbari, Omar S.; Marshall, John M.; Bier, Ethan

doi:10.1016/j.molcel.2020.09.003

Cited by 58 publications

(94 citation statements)

References 41 publications

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“…Several approaches have been recently proposed for mitigating spillovers, involving complex gene drive architectures and deployment strategies [39,[62][63][64][65][66][67][68][69], as well as for countermeasures to halt an ongoing gene drive [10,[70][71][72]. A few of these gene drive architectures have been demonstrated in laboratory settings [10,38,53,60,73].…”

Section: Discussionmentioning

confidence: 99%

Designing gene drives to limit spillover to non-target populations

et al. 2021

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The prospect of utilizing CRISPR-based gene-drive technology for controlling populations has generated much excitement. However, the potential for spillovers of gene-drive alleles from the target population to non-target populations has raised concerns. Here, using mathematical models, we investigate the possibility of limiting spillovers to non-target populations by designing differential-targeting gene drives, in which the expected equilibrium gene-drive allele frequencies are high in the target population but low in the non-target population. We find that achieving differential targeting is possible with certain configurations of gene drive parameters, but, in most cases, only under relatively low migration rates between populations. Under high migration, differential targeting is possible only in a narrow region of the parameter space. Because fixation of the gene drive in the non-target population could severely disrupt ecosystems, we outline possible ways to avoid this outcome. We apply our model to two potential applications of gene drives—field trials for malaria-vector gene drives and control of invasive species on islands. We discuss theoretical predictions of key requirements for differential targeting and their practical implications.

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Section: Discussionmentioning

confidence: 99%

Designing gene drives to limit spillover to non-target populations

et al. 2021

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“…The inheritance module is unchanged, and inheritance “cubes,” describing the distribution of offspring genotypes given maternal and paternal genotypes for a given genetic element, are usable in both versions. Several new inheritance cubes have been made available, including: a) homing-based remediation systems, including ERACR (Element for Reversing the Autocatalytic Chain Reaction) and e-CHACR (Erasing Construct Hitchhiking on the Autocatalytic Chain Reaction) [ 25 , 26 ], and b) newly proposed drive systems capable of regional population replacement, including CleaveR (Cleave and Rescue) [ 27 ] and TARE (Toxin-Antidote Recessive Embryo) drive [ 28 ].…”

Section: Design and Implementationmentioning

confidence: 99%

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

Bennett

et al. 2021

PLoS Comput Biol

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Interest 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): a significant 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 fundamental 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 split gene drive system intended to drive a disease-refractory gene into a population in a confinable and reversible manner, incorporating time-varying temperature and rainfall data. The simulations also evaluate 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 freely available as an open-source R package on CRAN (https://CRAN.R-project.org/package=MGDrivE2). 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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“…They could be designed to mitigate potential unintended consequences of another engineered gene drive by removing or preventing the spread of the original organism. The development of reversal gene drives is proceeding in flies and mosquitoes, and their potential use in the environment is being explored with population genetic models (Gantz and Bier, 2016;Vella et al, 2017;Friedman et al, 2020;Xu et al, 2020). However, it has been noted that reversal gene drives may induce further changes that may undo a phenotypic alteration caused by the initial drive, so they may not restore the original modification to the wild type or redress fully ecological effects from the original engineered gene drive (e.g.…”

Section: Reversal Gene Drivesmentioning

confidence: 99%

“…Reversal gene drives may be designed to either turn on or turn off engineered gene drive activity in the presence or absence of small organic molecules (Heffel and Finnigan, 2019;L opez Del Amo et al, 2020b), or mitigate potential unintended consequences of another engineered gene drive by removing or preventing the spread of the original drive, or overwriting it (Friedman et al, 2020;Oberhofer et al, 2020a;Xu et al, 2020; see Section 3.3.5). However, it is noted that such engineered gene drive systems are highly theoretical at the time of writing, and may induce further changes that may undo a phenotypic alteration caused by the initial drive, so they may not restore the original modification to the wild type or redress fully ecological effects from the original engineered gene drive (Champer et al, 2016;Xu et al, 2020). It has therefore been recommended not to rely upon a reversal gene drive as the sole strategy for mitigating the effects of another engineered gene drive, and to carefully examine risks associated with each of the countermeasures' limitations prior to release (e.g.…”

Section: Strategies For the Environmental Risk Assessment Of Geneticamentioning

confidence: 99%

Adequacy and sufficiency evaluation of existing EFSA guidelines for the molecular characterisation, environmental risk assessment and post‐market environmental monitoring of genetically modified insects containing engineered gene drives

Naegeli¹,

Bresson²,

Dalmay³

et al. 2020

EFS2

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Advances in molecular and synthetic biology are enabling the engineering of gene drives in insects for disease vector/pest control. Engineered gene drives (that bias their own inheritance) can be designed either to suppress interbreeding target populations or modify them with a new genotype. Depending on the engineered gene drive system, theoretically, a genetic modification of interest could spread through target populations and persist indefinitely, or be restricted in its spread or persistence. While research on engineered gene drives and their applications in insects is advancing at a fast pace, it will take several years for technological developments to move to practical applications for deliberate release into the environment. Some gene drive modified insects (GDMIs) have been tested experimentally in the laboratory, but none has been assessed in small-scale confined field trials or in open release trials as yet. There is concern that the deliberate release of GDMIs in the environment may have possible irreversible and unintended consequences. As a proactive measure, the European Food Safety Authority (EFSA) has been requested by the European Commission to review whether its previously published guidelines for the risk assessment of genetically modified animals (EFSA, 2012 and 2013), including insects (GMIs), are adequate and sufficient for GDMIs, primarily disease vectors, agricultural pests and invasive species, for deliberate release into the environment. Under this mandate, EFSA was not requested to develop risk assessment guidelines for GDMIs. In this Scientific Opinion, the Panel on Genetically Modified Organisms (GMO) concludes that EFSA's guidelines are adequate, but insufficient for the molecular characterisation (MC), environmental risk assessment (ERA) and post-market environmental monitoring (PMEM) of GDMIs. While the MC, ERA and PMEM of GDMIs can build on the existing risk assessment framework for GMIs that do not contain engineered gene drives, there are specific areas where further guidance is needed for GDMIs.

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Active Genetic Neutralizing Elements for Halting or Deleting Gene Drives

Cited by 58 publications

References 41 publications

Designing gene drives to limit spillover to non-target populations

Designing gene drives to limit spillover to non-target populations

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

Adequacy and sufficiency evaluation of existing EFSA guidelines for the molecular characterisation, environmental risk assessment and post‐market environmental monitoring of genetically modified insects containing engineered gene drives

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