A toxin-antidote CRISPR gene drive system for regional population modification

Champer, Jackson; Lee, Yoo Lim; Yang, Eun Kyung; Liu, Chen; Clark, Andrew G.; Messer, Philipp W.

doi:10.1101/628354

Cited by 21 publications

(59 citation statements)

References 47 publications

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“…Overall, our study shows that TA systems can provide flexible and effective mechanisms for a variety of potential gene drive applications. Their feasibility has already been demonstrated for TARE in D. melanogaster for same-site 29 and distant-site 30 configurations. Future experiments should investigate the feasibility and dynamics of the other TA drives we have proposed here and how they can be brought to other species of interest such as mosquitoes.…”

Section: Discussionmentioning

confidence: 99%

“…The TARE drive can be "same-site" as in Figure 2A or a "distant-site" drive in which the drive allele is not located at the same genomic site as the target allele ( Figure S2A). Successful samesite 29 , and distant-site 30 systems have already been engineered with high germline and embryo cut rates and little to no observable fitness costs. These systems have nearly equivalent performance when cut rates are high ( Figure S2B), but the distant-site drive retains higher performance when both the germline and embryo cut rates are low ( Figure S3C) since it often has two wild-type alleles available to cleave rather than just one as for the same-site drive.…”

Section: Figure 1 Overview Of Ta Systems and Comparison To Other Drimentioning

confidence: 99%

“…There are several potential variants of TA systems, including those based on recessive lethal genes (TARE, Toxin-Antidote Recessive Embryo), haplolethal genes (TADE, Toxin-Antidote Dominant Embryo), and genes with expression after meiosis I that is required for sperm development (TADS, Toxin-Antidote Dominant Sperm). Recently, we developed a "same-site" TARE drive capable of spreading through population cages 29 , and others constructed a "distantsite" TARE drive termed ClvR that was similarly successful 30 . Thus, such systems are highly promising for further development.…”

Section: Introductionmentioning

confidence: 99%

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Performance analysis of novel toxin-antidote CRISPR gene drive systems

Champer

Kim

Clark

et al. 2019

Preprint

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117

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Gene drives can potentially fixate in a population by biasing inheritance in their favor, opening up a variety of potential applications in areas such as disease-vector control and conservation. CRISPR homing gene drives have shown much promise for providing an effective drive mechanism, but they typically suffer from the rapid formation of resistance alleles. Even if the problem of resistance can be overcome, the utility of such drives would still be limited by their tendency to spread into all areas of a population. To provide additional options for gene drive applications that are substantially less prone to the formation of resistance alleles and could potentially remain confined to a target area, we developed several designs for CRISPR-based gene drives utilizing toxin-antidote (TA) principles. These drives target and disrupt an essential gene with the drive providing rescue. Here, we assess the performance of several types of TA gene drive systems using modeling and individual-based simulations. We show that Toxin-Antidote Recessive Embryo (TARE) drive should allow for the design of robust, regionally confined, population modification strategies with high flexibility in choosing drive promoters and recessive lethal targets. Toxin-Antidote Dominant Embryo (TADE) drive requires a haplolethal target gene and a germline-restricted promoter but should enable the design of both faster regional population modification drives and even regionally-confined population suppression drives. Toxin-antidote dominant sperm (TADS) drive can be used for population modification or suppression. It spreads nearly as quickly as a homing drive and can flexibly use a variety of promoters, but unlike the other TA systems, it is not regionally confined and requires highly specific target genes. Overall, our results suggest that CRISPR-based TA gene drives provide promising candidates for further development in a variety of organisms and may allow for flexible ecological engineering strategies. METHODSDeterministic model. To analyze the dynamics of TA systems, we developed a deterministic, discrete-generation modeling approach. These models were used to demonstrate frequency trajectories and to calculate parameters such as introduction thresholds. Initially, drive/wild-type heterozygotes are added to a population of wild-type individuals at a specified introduction frequency. In each generation, frequencies were tracked for each genotype. Females select a mate randomly, with each male's chance of being selected being proportional to his fitness value. Females then generate a number of potential offspring equal to twice their fitness value.

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Section: Discussionmentioning

confidence: 99%

Section: Figure 1 Overview Of Ta Systems and Comparison To Other Drimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Performance analysis of novel toxin-antidote CRISPR gene drive systems

Champer

Kim

Clark

et al. 2019

Preprint

Self Cite

117

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“…Drives targeting haplolethal genes could also be redesigned to operate without homologydirected repair for population modification or suppression, though such drives would likely have substantially different dynamics 27 . Similar drives targeting recessive lethal genes have already been constructed 28,29 .…”

Section: Discussionmentioning

confidence: 99%

Resistance is futile: A CRISPR homing gene drive targeting a haplolethal gene

Champer

Yang

Lee

et al. 2019

Preprint

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Engineered gene drives are being explored as a potential strategy for the control of vector-borne diseases due to their ability to rapidly spread genetic modifications through a population. While an effective CRISPR homing gene drive for population suppression has recently been demonstrated in mosquitoes, formation of resistance alleles that prevent Cas9 cleavage remains the major obstacle for drive strategies aiming at population modification, rather than elimination. Here, we present a homing drive in Drosophila melanogaster that reduces resistance allele formation below detectable levels by targeting a haplolethal gene with two gRNAs while also providing a rescue allele. This is because any resistance alleles that form by end-joining repair will typically disrupt the haplolethal target gene, rendering the individuals carrying them nonviable. We demonstrate that our drive is highly efficient, with 91% of the progeny of drive heterozygotes inheriting the drive allele and with no resistance alleles observed in the remainder. In a large cage experiment, the drive allele successfully spread to all individuals. These results show that a haplolethal homing drive can be a highly effective tool for population modification.

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“…homing‐based drives using homing endonuclease genes; sex‐linked meiotic drives; Medea, the maternal effect dominant embryonic arrest system; underdominance or heterozygote inferiority drives; heritable microorganisms as illustrated by Wolbachia ; Frieß et al., )] with diverse characteristics are possible [e.g. conventional vs. integral gene drives (Nash et al., ); toxin‐antidote recessive embryo gene drives (Champer et al., ); allelic gene drives (Guichard et al., )].…”

Section: Problem Formulation In Practice: Case Studiesmentioning

confidence: 99%

Using problem formulation for fit‐for‐purpose pre‐market environmental risk assessments of regulated stressors

Devos

Devlin

Ippolito

et al. 2019

EFS2

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Pre-market/prospective environmental risk assessments (ERAs) contribute to risk analyses performed to facilitate decisions about the market introduction of regulated stressors. Robust ERAs begin with an explicit problem formulation, which involves among other steps: (1) formally devising plausible pathways to harm that describe how the deployment of a regulated stressor could be harmful; (2) formulating risk hypotheses about the likelihood and severity of such events; (3) identifying the information that will be useful to test the risk hypotheses; and (4) developing a plan to acquire new data for hypothesis testing should tests with existing information be insufficient for decision-making. Here, we apply problem formulation to the assessment of possible adverse effects of RNA interference-based insecticidal genetically modified (GM) plants, GM growth hormone coho salmon, gene drive-modified mosquitoes and classical biological weed control agents on non-target organisms in a prospective manner, and of neonicotinoid insecticides on bees in a retrospective manner. In addition, specific considerations for the problem formulation for the ERA of nanomaterials and for landscape-scale population-level ERAs are given. We argue that applying problem formulation to ERA maximises the usefulness of ERA studies for decision-making, through an iterative process, because: (1) harm is defined explicitly from the start; (2) the construction of risk hypotheses is guided by policy rather than an exhaustive attempt to address any possible differences; (3) existing information is used effectively; (4) new data are collected with a clear purpose; (5) risk is characterised against well-defined criteria of hypothesis corroboration or falsification; and (6) risk assessment conclusions can be communicated clearly. However, problem formulation is still often hindered by the absence of clear policy goals and decision-making criteria (e.g. definition of protection goals and what constitutes harm) that are needed to guide the interpretation of scientific information. We therefore advocate further dialogue between risk assessors and risk managers to clarify how ERAs can address policy goals and decision-making criteria. Ideally, this dialogue should take place for all classes of regulated stressors, as this can promote alignment and consistency on the desired level of protection and maximum tolerable impacts across regulated stressors.

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A toxin-antidote CRISPR gene drive system for regional population modification

Cited by 21 publications

References 47 publications

Performance analysis of novel toxin-antidote CRISPR gene drive systems

Performance analysis of novel toxin-antidote CRISPR gene drive systems

Resistance is futile: A CRISPR homing gene drive targeting a haplolethal gene

Using problem formulation for fit‐for‐purpose pre‐market environmental risk assessments of regulated stressors

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