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

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Charleston Noble ◽  
Ben Adlam ◽  
George M Church ◽  
Kevin M Esvelt ◽  
Martin A Nowak
Keyword(s):  
Gene Flow ◽  
Empirical Data ◽  
Local Population ◽  
Malaria Prevention ◽  
Field Trials ◽  
Gene Drive ◽  
Wild Populations ◽  
Target Species ◽  
Large Populations ◽  
Drive Systems

Recent reports have suggested that self-propagating CRISPR-based gene drive systems are unlikely to efficiently 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 for population alteration drives. Our models show that although resistance prevents spread to fixation in large populations, even the least effective drive systems reported to date are likely to be highly invasive. Releasing a small number of organisms will often cause invasion of the local population, followed by invasion of additional populations connected by very low rates of gene flow. Hence, initiating contained field trials as tentatively endorsed by the National Academies report on gene drive could potentially result in unintended spread to additional populations. Our mathematical results suggest that self-propagating gene drive is best suited to applications such as malaria prevention that seek to affect all wild populations of the target species.

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 Daisy quorum drives for the genetic restoration of wild populations

2017 ◽  
Author(s):  
John Min ◽  
Charleston Noble ◽  
Devora Najjar ◽  
Kevin M. Esvelt
Keyword(s):  
Local Population ◽  
Ecological Engineering ◽  
Local Area ◽  
Drive System ◽  
Shared Environment ◽  
Gene Drive ◽  
Wild Type ◽  
Wild Populations ◽  
Quorum Systems ◽  
Drive Systems

AbstractAn ideal gene drive system to alter wild populations would 1) exclusively affect organisms within the political boundaries of consenting communities, and 2) be capable of restoring any engineered population to its original genetic state. Here we describe ‘daisy quorum’ drive systems that meet these criteria by combining daisy drive with underdominance. A daisy quorum drive system is predicted to spread through a population until all of its daisy elements have been lost, at which point its fitness becomes frequency-dependent: mostly altered populations become fixed for the desired change, while engineered genes at low frequency are swiftly eliminated by natural selection. The result is an engineered population surrounded by wild-type organisms with limited mixing at the boundary. Releasing large numbers of wild-type organisms or a few bearing a population suppression element can reduce the engineered population below the quorum, triggering elimination of all engineered sequences. In principle, the technology can restore any drive-amenable population carrying engineered genes to wild-type genetics. Daisy quorum systems may enable efficient, community-supported, and genetically reversible ecological engineering.SummaryLocal communities should be able to control their own environments without forcing those choices on others. Ideally, each community could reversibly alter local wild organisms in ways that cannot spread beyond their own boundaries, and any engineered population could be restored to its original genetic state. We've invented a 'daisy quorum' drive system that appears to meet these criteria.“Daisy” refers to a daisy drive, which typically uses a daisy-chain of linked genes to spread a change through a local population while losing links every generation until it stops spreading. “Quorum” reflects the system's ability to “vote” on whether a local population should be altered or not: once all daisy elements are lost, it favors replication by the altered version or the original depending on which is more abundant in the local area. Put together, they result in a change that first spreads through a local population, then either becomes locally prevalent is eliminating, inhibiting mixing at the boundary. All organisms in the target population are altered, but changes are unable to spread much beyond that area due to being greatly outnumbered by wild-type organisms and consequently less able to replicate.We haven't yet performed any experiments involving daisy quorum systems. Rather, we’re describing what we intend to do, including the safeguards we will use and our assessment of risks, in the hope that others will evaluate our plans and tell us if there's anything wrong that we missed. We hope that all researchers working on gene drive systems - and other technologies that could impact the shared environment - will similarly pre-register their plans. Sharing plans can reduce needless duplication, accelerate progress, and make the proposed work safer for everyone.

scholarly journals Field selectivity of a spinosad-poisoned bait toward target tephritids and non-target insects

2014 ◽  
pp. 11-15 ◽  
Author(s):  
Marco Infusino ◽  
Nino Iannotta ◽  
Stefano Scalercio
Keyword(s):  
Pest Control ◽  
Ceratitis Capitata ◽  
Negative Impact ◽  
Control Strategies ◽  
Field Trials ◽  
Pest Species ◽  
Wild Populations ◽  
Target Species ◽  
Key Points ◽  
Insect Monitoring

One of the key-points in sustainable agriculture is to minimize the amount of pesticides inputs in agro-ecosystems increasing selectivity of active agents on target pests mainly. According to this perspective, control strategies utilising baits receive a growing interest. a spinosad-poisoned sugar-based bait, the so called GF-120 bait, utilised against diptera Tephritidae, recently appeared on the market. The toxicity of spinosad for non-target insects is demonstrated by several authors. However, the amount of pesticide applied is strongly reduced by using it with an attractive food-bait, even if field evidences on the selective attraction of this bait are missing. The aim of this paper is to evaluate the selectivity of GF-120 bait toward target and non-target insects under field conditions, focussing our attention on pollinators. Field trials were performed in a 20 years old olive orchard, where 12 baited and 12 unbaited traps were positioned for insect monitoring. The abundance of the most common orders of insects and target pest species Bactrocera oleae and Ceratitis capitata has been assessed. The main finding of this research is that many pollinators are not attracted by the bait, while target and non-target diptera are significantly attracted by the bait with the exception of Muscidae. The attraction toward a part of non-target diptera should be better explored in order to avoid negative impact on beneficial and non-target species. The need of pest control strategies safer for the environment and the wild populations of non-target organisms seems to be satisfied by the use of this bait.

scholarly journals Evolutionary dynamics of CRISPR gene drives

2016 ◽  
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.

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

2018 ◽  
Author(s):  
Charleston Noble ◽  
Ben Adlam ◽  
George M Church ◽  
Kevin M Esvelt ◽  
Martin A Nowak
Keyword(s):  
Author Response ◽  
Gene Drive ◽  
Wild Populations ◽  
Drive Systems ◽  
Response Current

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

2019 ◽  
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.

scholarly journals Weakly deleterious natural genetic variation amplifies probability of resistance in multiplexed gene drive systems

2021 ◽  
Author(s):  
Bhavin S Khatri ◽  
Austin Burt
Keyword(s):  
De Novo ◽  
Large Population ◽  
Stochastic Simulations ◽  
Gene Drive ◽  
End Joining ◽  
Single Nucleotide ◽  
Major Barrier ◽  
Standing Variation ◽  
Large Populations ◽  
Drive Systems

Evolution of resistance is a major barrier to successful deployment of gene drive systems to suppress natural populations. Multiplexed guide RNAs that require resistance mutations in all target cut sites is a promising strategy to overcome resistance. Using novel stochastic simulations that accurately model evolution at very large population sizes, we explore the probability of resistance due to three important mechanisms: 1) non-homologous end-joining mutations, 2) single nucleotide mutants arising de novo or, 3) single nucleotide polymorphisms pre-existing as standing variation. If the fraction of functional end-joining mutants is rare, we show that standing variation dominates, via a qualitatively new phenomenon where weakly deleterious variants significantly amplify the probability of multi-site resistance. This means resistance can be probable even with many target sites in not very large populations. This result has broad application to resistance arising in multi-site evolutionary scenarios including the evolution of vaccine escape mutations in large populations.

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 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 The effect of mating complexity on gene drive dynamics

2021 ◽  
Author(s):  
Prateek Verma ◽  
R. Guy Reeves ◽  
Samson Simon ◽  
Mathias Otto ◽  
Chaitanya S. Gokhale
Keyword(s):  
Mate Choice ◽  
Mating Systems ◽  
Population Level ◽  
Gene Drive ◽  
Wild Populations ◽  
Transgenic Organisms ◽  
Drive Systems ◽  
The Impact ◽  
Gene Drives ◽  
Drive Dynamics

AbstractGene drive technology is being presented as a means to deliver on some of the global challenges humanity faces today in healthcare, agriculture and conservation. However, there is a limited understanding of the consequences of releasing self-perpetuating transgenic organisms into the wild populations under complex ecological conditions. In this study, we analyze the impact of three factors, mate-choice, mating systems and spatial mating network, on the population dynamics for two distinct classes of modification gene drive systems; distortion and viability-based ones. All three factors had a high impact on the modelling outcome. First, we demonstrate that distortion based gene drives appear to be more robust against the mate-choice than viability-based gene drives. Second, we find that gene drive spread is much faster for higher degrees of polygamy. With fitness cost, speed is the highest for intermediate levels of polygamy. Finally, the spread of gene drive is faster and more effective when the individuals have fewer connections in a spatial mating network. Our results highlight the need to include mating complexities while modelling the population-level spread of gene drives. This will enable a more confident prediction of release thresholds, timescales and consequences of gene drive in populations.

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