Alternative Techniques and Options for Risk Reduction of Gene Drives

Giese, Bernd; Gleich, Arnim von; Frieß, Johannes L.

doi:10.1007/978-3-030-38934-5_7

Cited by 3 publications

(4 citation statements)

References 45 publications

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“…Altogether, our experiments show that the use of a Cas12a nuclease can add a temperature-dependent layer of containment over gene-drive propagation. In addition to providing some level of inactivity when desired, unlike to the always-on Cas9 nuclease, gene-drive containment is an important feature demanded by the gene drive community and regulators [23][24][25][26] . Also, these Cas12a-based gene-drive systems displayed super-Mendelian inheritance rates comparable to previous Cas9-based systems (80-90%) that efficiently spread in a target population under laboratory conditions 27 , though future investigations are needed to explore the propagation dynamics of Cas12a-based systems and the formation of resistant alleles that are also a concern for gene-drive propagation 28,29 .…”

Section: Discussionmentioning

confidence: 99%

Next-generation CRISPR gene-drive systems using Cas12a nuclease

Juste¹,

Okamoto

Feng

et al. 2023

Preprint

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One method for reducing the impact of vector-borne diseases is through the use of CRISPR-based gene drives, which manipulate insect populations due to their ability to rapidly propagate desired genetic traits into a target population. However, all current gene drives employ a Cas9 nuclease that is constitutively active, impeding our control over their propagation abilities and limiting the generation of novel gene drive arrangements. Yet, other nucleases such as the temperature-sensitive Cas12a have not been explored for gene drive designs. To address this, we herein present a proof-of-concept gene-drive system driven by Cas12a that can be regulated via temperature modulation. Furthermore, we combined Cas9 and Cas12a to build double gene drives capable of simultaneously spreading two independent engineered alleles. The development of Cas12a-mediated gene drives provides an innovative option for designing next-generation vector control strategies to combat disease vectors and agricultural pests.

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Section: Discussionmentioning

confidence: 99%

Next-generation CRISPR gene-drive systems using Cas12a nuclease

Juste¹,

Okamoto

Feng

et al. 2023

Preprint

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“…The most commonly envisioned means to achieve self-limitation for a gene drive relies on geographic isolation, which requires the presence of reproductive barriers between target and non-target populations (Dhole et al 2018;Greenbaum et al 2021;Harris and Greenbaum 2023). Such spatial containment would rely on active monitoring and strict biosecurity measures that are difficult to enforce and costly (Giese et al 2020).…”

Section: Introductionmentioning

confidence: 99%

“…2021; Harris and Greenbaum 2023). Such spatial containment would rely on active monitoring and strict biosecurity measures that are difficult to enforce and costly (Giese et al . 2020).…”

Section: Introductionmentioning

confidence: 99%

Controlling the frequency dynamics of homing gene drives for intermediate outcomes

Camm,

Fournier-Level

2024

Preprint

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Gene drives have enormous potential for solving biological issues by forcing the spread of desired alleles through populations. However, to safeguard from the potentially irreversible consequences on natural populations, gene drives with intermediate outcomes that neither fixate nor get removed from the population are of outstanding interest. To elucidate the conditions leading to intermediate gene drive frequency, a stochastic, individual allele-focused gene drive model accessible was developed to simulate the diffusion of a homing gene drive in a population. The frequencies of multiple alleles at a locus targeted by a gene drive were tracked under various scenarios. These explored the effect of gene drive conversion efficiency, strength and frequency of resistance alleles, presence and strength of a fitness cost for the gene drive, its dominance and the level of inbreeding. Four outcomes were consistently observed: Fixation, Loss, Temporary and Equilibrium. The latter two are defined by the frequency of the gene drive peaking then crashing or plateauing, respectively. No single variable determined the outcome of a drive, instead requiring a combination of variables. The difference between the conversion efficiency and resistance level differentiated the Temporary and Equilibrium outcomes. The frequency dynamics of the gene drive within outcomes varied extensively, with different variables driving this dynamics between outcomes. These simulation results highlight the possibility of fine-tuning gene drive outcomes and compensating through biotechnological design constraint imposed by population features. To that end, we provide a web application implementing our model which will guide the safer design of gene drives able to achieve a range of controllable outcome tailored to population management needs.

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“…Gene drives can be inherently self-limiting, but this is generally due to low inheritance biasing efficiency, high fitness costs, or frequency-dependent effects, all of which can reduce their practical use. Some self-limiting systems have been proposed that are restricted in specific ways that maintain efficient but local transgene invasion [2]. These include targeting specific DNA sequences found only in subpopulations [3], dependence on supplementation with a synthetic inducer molecule [4,5], and split drive systems.…”

Section: Introductionmentioning

confidence: 99%

Daisy-chain gene drives: The role of low cut-rate, resistance mutations, and maternal deposition

et al. 2022

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The introgression of genetic traits through gene drive may serve as a powerful and widely applicable method of biological control. However, for many applications, a self-perpetuating gene drive that can spread beyond the specific target population may be undesirable and preclude use. Daisy-chain gene drives have been proposed as a means of tuning the invasiveness of a gene drive, allowing it to spread efficiently into the target population, but be self-limiting beyond that. Daisy-chain gene drives are made up of multiple independent drive elements, where each element, except one, biases the inheritance of another, forming a chain. Under ideal inheritance biasing conditions, the released drive elements remain linked in the same configuration, generating copies of most of their elements except for the last remaining link in the chain. Through mathematical modelling of populations connected by migration, we have evaluated the effect of resistance alleles, different fitness costs, reduction in the cut-rate, and maternal deposition on two alternative daisy-chain gene drive designs. We find that the self-limiting nature of daisy-chain gene drives makes their spread highly dependent on the efficiency and fidelity of the inheritance biasing mechanism. In particular, reductions in the cut-rate and the formation of non-lethal resistance alleles can cause drive elements to lose their linked configuration. This severely reduces the invasiveness of the drives and allows for phantom cutting, where an upstream drive element cuts a downstream target locus despite the corresponding drive element being absent, creating and biasing the inheritance of additional resistance alleles. This phantom cutting can be mitigated by an alternative indirect daisy-chain design. We further find that while dominant fitness costs and maternal deposition reduce daisy-chain invasiveness, if overcome with an increased release frequency, they can reduce the spread of the drive into a neighbouring population.

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Alternative Techniques and Options for Risk Reduction of Gene Drives

Cited by 3 publications

References 45 publications

Next-generation CRISPR gene-drive systems using Cas12a nuclease

Next-generation CRISPR gene-drive systems using Cas12a nuclease

Controlling the frequency dynamics of homing gene drives for intermediate outcomes

Daisy-chain gene drives: The role of low cut-rate, resistance mutations, and maternal deposition

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