Can CRISPR-based gene drive be confined in the wild? A question for molecular and population biology

Marshall, John M.; Akbari, Omar S.

doi:10.1101/173914

Cited by 22 publications

(35 citation statements)

References 49 publications

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“…One innovative technology, first articulated by Austin Burt in 2003 (19), utilizes homing-based gene-drive technologies to expedite the elimination and eradication of vector-borne diseases (20)(21)(22)(23)(24)(25). Conceptually, these drives function by exploiting the organism's innate DNA repair machinery to copy or "home" themselves into a target genomic location prior to meiosis in the germline.…”

Section: Introductionmentioning

confidence: 99%

Development of a Confinable Gene-Drive System in the Human Disease Vector,Aedes aegypti

Li¹,

Yang²,

Kandul³

et al. 2019

Preprint

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Aedes aegypti, the principal mosquito vector for many arboviruses that causes yellow fever, dengue, Zika, and chikungunya, increasingly infects 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 recently sparked significant enthusiasm for the genetic control of mosquito populations, however no such system has been developed in Ae. aegypti. To fill this void and demonstrate efficacy in Ae. aegypti, 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%, 2 mathematical models predict that these systems could spread anti-pathogen effector genes into wild Ae. aegypti populations in a safe, confinable and reversible manner appropriate for field trials and effective for controlling disease. These findings could expedite the development of effectorlinked gene drives that could safely control wild populations of Ae. aegypti to combat local pathogen transmission. Significance StatementAe. aegypti is a globally distributed arbovirus vector spreading deadly pathogens to millions of people annually. Current control methods are inadequate and therefore new technologies need to be innovated and implemented. With the aim of providing new tools for controlling this pest, here we engineered and tested several split gene drives in this species. These drives functioned at very high efficiency and may provide a tool to fill the void in controlling this vector. Taken together, our results provide compelling path forward for the feasibility of future effector-linked split-drive technologies that can contribute to the safe, sustained control and potentially the elimination of pathogens transmitted by this species.

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Section: Introductionmentioning

confidence: 99%

Development of a Confinable Gene-Drive System in the Human Disease Vector,Aedes aegypti

Li¹,

Yang²,

Kandul³

et al. 2019

Preprint

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“…RISPR gene-drive systems offer tremendous potential for engineering wild populations due to their ability to selfpropagate, biasing inheritance from Mendelian (50%) to super-Mendelian (>50%) [1][2][3][4][5][6][7] . This technology has important applications in fighting vector-borne diseases (e.g., malaria) by suppressing 3,7 or modifying 4 mosquito populations to decrease their burden on public health, managing crop pests 8,9 , and suppressing invasive rodents to support island restoration efforts 10,11 .…”

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confidence: 99%

A transcomplementing gene drive provides a flexible platform for laboratory investigation and potential field deployment

et al. 2020

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CRISPR-based gene drives can spread through wild populations by biasing their own transmission above the 50% value predicted by Mendelian inheritance. These technologies offer population-engineering solutions for combating vector-borne diseases, managing crop pests, and supporting ecosystem conservation efforts. Current technologies raise safety concerns for unintended gene propagation. Herein, we address such concerns by splitting the drive components, Cas9 and gRNAs, into separate alleles to form a trans-complementing split-gene-drive (tGD) and demonstrate its ability to promote super-Mendelian inheritance of the separate transgenes. This dual-component configuration allows for combinatorial transgene optimization and increases safety by restricting escape concerns to experimentation windows. We employ the tGD and a small-molecule-controlled version to investigate the biology of component inheritance and resistant allele formation, and to study the effects of maternal inheritance and impaired homology on efficiency. Lastly, mathematical modeling of tGD spread within populations reveals potential advantages for improving current gene-drive technologies for field population modification.

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“…A third problem is that we do not yet understand the consequences of more complex population structure, involving more than two populations or populations that are internally structured. Given these difficulties, to understand and mitigate the dangers of spillovers, it would be important to study more elaborate population structures in models of gene drives, as well as to explore additional biosafety mechanisms, such as daisy-chain gene drives [51] or other molecular safe-guarding techniques [37,[52][53][54][55][56].…”

Section: Discussionmentioning

confidence: 99%

Designing gene drives to limit spillover to non-target populations

Greenbaum

Feldman

Rosenberg

et al. 2019

Preprint

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The prospect of utilizing CRISPR-based gene drive technology for controlling populations, such as invasive and disease-vector species, has generated much excitement. However, the potential for spillovers of gene drive alleles from the target population to non-target populations -events that may be ecologically catastrophic -has raised concerns. Here, using two-population mathematical models, we investigate the possibility of limiting spillovers and impact on 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. Most of these configurations ensure differential targeting only under relatively low migration rates between target and non-target populations. Under high migration, differential targeting is possible only in a narrow region of the parameter space. When migration is increased, differential-targeting states can sharply transition to states of global fixation or global loss of the gene drive. Because fixation of the gene drive in the non-target population could severely disrupt ecosystems, we outline possible ways to avoid this outcome. Our results emphasize that, although gene drive technology is promising, understanding the potential consequences for populations other than the targets requires detailed analysis of gene drive spillovers, and that ways to limit the unintended effects of gene drives should be explored prior to the application of gene drives in natural settings.

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Can CRISPR-based gene drive be confined in the wild? A question for molecular and population biology

Cited by 22 publications

References 49 publications

Development of a Confinable Gene-Drive System in the Human Disease Vector,Aedes aegypti

Development of a Confinable Gene-Drive System in the Human Disease Vector,Aedes aegypti

A transcomplementing gene drive provides a flexible platform for laboratory investigation and potential field deployment

Designing gene drives to limit spillover to non-target populations

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