Novel SyntheticMedeaSelfish Genetic Elements Drive Population Replacement inDrosophila; a Theoretical Exploration ofMedea-Dependent Population Suppression

Akbari, Omar S.; Chen, Chun Hong; Marshall, John M.; Huang, Huifang; Antoshechkin, Igor; Hay, Bruce A.

doi:10.1021/sb300079h

Cited by 102 publications

(129 citation statements)

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“…Ongoing efforts to transfer the Medea system from flour beetles to other insects have, thus far, fallen short (Chen et al 2007;Akbari et al 2014). Underdominance systems have also been developed (Altrock et al 2010;Akbari et al 2013;Reeves et al 2014), but these are slow-spreading systems that require multiple releases of large numbers of male transgenic insects.…”

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confidence: 99%

Evolution of Resistance Against CRISPR/Cas9 Gene Drive

2017

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CRISPR/Cas9 gene drive (CGD) promises to be a highly adaptable approach for spreading genetically engineered alleles throughout a species, even if those alleles impair reproductive success. CGD has been shown to be effective in laboratory crosses of insects, yet it remains unclear to what extent potential resistance mechanisms will affect the dynamics of this process in large natural populations. Here we develop a comprehensive population genetic framework for modeling CGD dynamics, which incorporates potential resistance mechanisms as well as random genetic drift. Using this framework, we calculate the probability that resistance against CGD evolves from standing genetic variation, de novo mutation of wild-type alleles, or cleavage repair by nonhomologous end joining (NHEJ)-a likely by-product of CGD itself. We show that resistance to standard CGD approaches should evolve almost inevitably in most natural populations, unless repair of CGD-induced cleavage via NHEJ can be effectively suppressed, or resistance costs are on par with those of the driver. The key factor determining the probability that resistance evolves is the overall rate at which resistance alleles arise at the population level by mutation or NHEJ. By contrast, the conversion efficiency of the driver, its fitness cost, and its introduction frequency have only minor impact. Our results shed light on strategies that could facilitate the engineering of drivers with lower resistance potential, and motivate the possibility to embrace resistance as a possible mechanism for controlling a CGD approach. This study highlights the need for careful modeling of the population dynamics of CGD prior to the actual release of a driver construct into the wild.KEYWORDS CRISPR/Cas9; gene drive; homing drive; mutagenic chain reaction; whole population replacement T HE prospect of driving genetically modified alleles to fixation in a population has enticed scientists for .40 years (Curtis 1968;Foster et al. 1972). Potential applications are broad and ambitious, including the eradication of vectorborne diseases such as malaria, dengue, and Zika (Burt 2003;Esvelt et al. 2014;Champer et al. 2016). For example, mosquitoes could be genetically altered such that they can no longer transmit Plasmodium parasites. If these altered alleles could then be spread in a wild population, we could effectively eradicate malaria in humans. Similarly, a gene drive could be used to reverse insecticide resistance in an agricultural pest, or to spread a deleterious allele in an invasive species to drive it toward extinction.While various strategies for implementing a gene drive have been discussed since the 1970s, all previously proposed mechanisms have faced significant obstacles. Ongoing efforts to transfer the Medea system from flour beetles to other insects have, thus far, fallen short (Chen et al. 2007;Akbari et al. 2014). Underdominance systems have also been developed (Altrock et al. 2010;Akbari et al. 2013;Reeves et al. 2014), but these are slow-spreading systems that requi...

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confidence: 99%

Evolution of Resistance Against CRISPR/Cas9 Gene Drive

2017

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“…The Medea strain which was developed by Chen et al in Drosophila used microRNA-mediated silencing of a maternally expressed embryonic development gene, my88, as its toxin and early zygotic expression of a rescuing transgene as the antidote. A more complex Medea system employing additional mechanisms such as targeting signaling pathways like the Notch pathway has since been also demonstrated in D. melanogaster [25]. …”

Section: Transgenic Biotechnologymentioning

confidence: 99%

Developing the Arsenal Against Pest and Vector Dipterans: Inputs of Transgenic and Paratransgenic Biotechnologies

Ogaugwu¹,

Durvasula²

2017

Biological Control of Pest and Vector Insects

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Insects are the most numerous of all animals and are found in almost every inhabitable place on earth. The order Diptera (true flies) contains many members that are notorious agricultural pests, nuisance or vectors of diseases. The list is long: mosquitoes, tsetse flies, screw worms, fruit flies, sand flies, blow flies, house flies, gall and biting midges, black flies, leaf miners, horse flies, and so on. Efforts to combat some of these pests and vectors have resulted in control measures such as the chemical, physical, and cultural control methods. These methods, though largely beneficial, have disadvantages and limitations, which sometimes seem to outweigh the problems initially sought to be controlled. The chemical method, for example, is not environment-friendly since it negatively affects many nontarget organisms and disrupts ecosystem balance. Development of insecticide resistance by pests/vectors is another concern. Molecular biotechnology has introduced vast arrays of novel ways to tackle pests and disease vectors, as well as improve the potency of existing control methods. This chapter looks at transgenic and paratransgenic biotechnologies and how they have been applied so far to develop and expand the arsenal against dipteran pests and disease vectors. Further, we discuss the advantages, disadvantages, and limitations of these technologies.

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“…In Tribolium, Medea dynamics are attributed to an insertion of a composite Tc1 transposon inserted between two genes both having maternal and zygotic components [13]. Remarkably, this system was reverseengineered using entirely synthetic components in laboratory populations of D. melanogaster and was shown to rapidly drive population replacement [14,64]. These synthetic elements were constructed using two unique, tightly linked components-a maternal toxin consisting of maternally deposited microRNA designed to target an essential embryonic gene; and a zygotic antidote consisting of a tightly linked, zygotically expressed, microRNAresistant version of the embryonic essential gene.…”

Section: Medeamentioning

confidence: 99%