Modeling the mutation and reversal of engineered underdominance gene drives

Edgington, Matthew P.; Alphey, Luke

doi:10.1016/j.jtbi.2019.06.024

Cited by 13 publications

(7 citation statements)

References 37 publications

(71 reference statements)

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“…Therefore, DrMxR is currently only appropriate for studying gene drives that can only bring about population replacement without affecting population density. Suppression drives—intended to eradicate or reduce the target population or ‘reversal drives’—intended to reverse the genetic alteration introduced by the first gene drive [ 21 , 26 , 97 , 98 ] are not included in the app. Some newly proposed gene drive systems that are mainly intended for suppression but can also be used for replacement, such as CleavR, TARE, TADE, double-drives and Y-linked editors, cannot be currently modelled in this study [ 49 , 50 , 54 , 56 , 99 , 100 ].…”

Section: Discussionmentioning

confidence: 99%

A common gene drive language eases regulatory process and eco-evolutionary extensions

2021

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Background Synthetic gene drive technologies aim to spread transgenic constructs into wild populations even when they impose organismal fitness disadvantages. The extraordinary diversity of plausible drive mechanisms and the range of selective parameters they may encounter makes it very difficult to convey their relative predicted properties, particularly where multiple approaches are combined. The sheer number of published manuscripts in this field, experimental and theoretical, the numerous techniques resulting in an explosion in the gene drive vocabulary hinder the regulators’ point of view. We address this concern by defining a simplified parameter based language of synthetic drives. Results Employing the classical population dynamics approach, we show that different drive construct (replacement) mechanisms can be condensed and evaluated on an equal footing even where they incorporate multiple replacement drives approaches. Using a common language, it is then possible to compare various model properties, a task desired by regulators and policymakers. The generalization allows us to extend the study of the invasion dynamics of replacement drives analytically and, in a spatial setting, the resilience of the released drive constructs. The derived framework is available as a standalone tool. Conclusion Besides comparing available drive constructs, our tool is also useful for educational purpose. Users can also explore the evolutionary dynamics of future hypothetical combination drive scenarios. Thus, our results appraise the properties and robustness of drives and provide an intuitive and objective way for risk assessment, informing policies, and enhancing public engagement with proposed and future gene drive approaches.

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Section: Discussionmentioning

confidence: 99%

A common gene drive language eases regulatory process and eco-evolutionary extensions

2021

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“…Models fitted to data from UD MEL drive experiments also suggested dynamic fitness costs that depended on the frequency of transgenic organisms in the population [15]. Another recent modeling study highlights the possibility of toxin and antidote mutational breakdown for underdominance constructs; however, this is expected to be impactful over a larger timescale than considered here (hundreds of generations) [53]. At the ecological level, our model of Ae.…”

Section: Discussionmentioning

confidence: 60%

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

Bennett

et al. 2020

BMC Biol

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Background: The 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 thresholddependent 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 UD MEL-to explore their ability to be confined and remediated. Results: We 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 nondisease-transmitting male mosquitoes with release sizes on the scale of what has been previously implemented. UD MEL 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. Conclusions: Our 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.

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“…Daisy-chain systems can provide local spread of a drive element but they cannot propagate at the same scale as traditional drives; the goal is limited spread of drives, rather than targeted removal of active drives 36 . Finally, in the case of UD systems, proposals for population reversal requires the introduction of either wild-type individuals 40 or “free suppressor” individuals 38 . Therefore, we focused on novel drive systems that might provide a variable level of population control and ultimately allow for reversion to the original WT species without the need for a secondary release of modified (or wild-type) individuals.…”

Section: Discussionmentioning

confidence: 99%

Mathematical modeling of self-contained CRISPR gene drive reversal systems

Heffel

Finnigan

2019

Sci Rep

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There is a critical need for further research into methods to control biological populations. Numerous challenges to agriculture, ecological systems, and human health could be mitigated by the targeted reduction and management of key species (e.g. pests, parasites, and vectors for pathogens). The discovery and adaptation of the CRISPR/Cas editing platform co-opted from bacteria has provided a mechanism for a means to alter an entire population. A CRISPR-based gene drive system can allow for the forced propagation of a genetic element that bypasses Mendelian inheritance which can be used to bias sex determination, install exogenous information, or remove endogenous DNA within an entire species. Laboratory studies have demonstrated the potency by which gene drives can operate within insects and other organisms. However, continued research and eventual application face serious opposition regarding issues of policy, biosafety, effectiveness, and reversal. Previous mathematical work has suggested the use of modified gene drive designs that are limited in spread such as daisy chain or underdominance drives. However, no system has yet been proposed that allows for an inducible reversal mechanism without requiring the introduction of additional individuals. Here, we study gene drive effectiveness, fitness, and inducible drive systems that could respond to external stimuli expanding from a previous frequency-based population model. We find that programmed modification during gene drive propagation could serve as a potent safeguard to either slow or completely reverse drive systems and allow for a return to the original wild-type population.

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Modeling the mutation and reversal of engineered underdominance gene drives

Cited by 13 publications

References 37 publications

A common gene drive language eases regulatory process and eco-evolutionary extensions

A common gene drive language eases regulatory process and eco-evolutionary extensions

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

Mathematical modeling of self-contained CRISPR gene drive reversal systems

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