Abstract
Homing-based gene drives use a germline source of nuclease to copy themselves at specific target sites in a genome and bias their inheritance. Such gene drives can be designed to spread and deliberately suppress populations of malaria mosquitoes by impairing female fertility. However, strong unintended fitness costs of the drive and a propensity to generate resistant mutations can limit a gene drive's potential to spread. Alternative germline regulatory sequences in the drive element confer improved fecundity of carrier individuals and reduced propensity for target site resistance. This is explained by reduced rates of end-joining repair of DNA breaks from parentally deposited nuclease in the embryo, which can produce heritable mutations that reduce gene drive penetrance. We tracked the generation and selection of resistant mutations over the course of a gene drive invasion of a population. Improved gene drives show faster invasion dynamics, increased suppressive effect and later onset of target site resistance. Our results show that regulation of nuclease expression is as important as the choice of target site when developing a robust homing-based gene drive for population suppression.
Highlights
Gene drives and malaria controlGene drives are genetic elements that are capable of biasing their own inheritance, allowing their autonomous spread in a population, even from a very low initial frequency
Building suppression gene drives for mosquito control that are fit for purpose requires a combination of the following features: optimal target sites that show high functional constraint; the targeting of multiple sites by the same gene drive construct; fine tuning of the expression of the nuclease that serves as the gene drive’s ‘motor’ in order that the drive shows the most efficient invasion dynamics
Regulating gene drive expression mitigates resistance substantiated: multiplexing through the use of multiple guide RNAs in a single drive construct has been shown to improve robustness of a range of drive elements [13,21,37,38]; judicious choice of functionally constrained sites in essential genes has meant that gene drives targeting such sites do not generate resistant alleles that are selected, at least in the laboratory [8,37]
Summary
Gene drives are genetic elements that are capable of biasing their own inheritance, allowing their autonomous spread in a population, even from a very low initial frequency. Coupling a trait of interest to a drive element is a way of deliberately modifying a population, potentially in a very short timeframe. In the case of the mosquito vector of malaria, gene drives have been proposed to spread traits that either interfere with the mosquito’s capacity to reproduce, or its capacity to transmit the malaria parasite. We know that vector control is effective in controlling malaria–the malaria burden was halved in the period 2000–2015 and the vast majority of this gain was achieved through targeting the vector with conventional insecticide-based approaches (bednets and residual spraying) [1]. Gene drive is a technology with the potential to augment and complement existing control approaches in a self-sustaining way
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