Novel combination of CRISPR-based gene drives eliminates resistance and localises spread

Abstract

Invasive species are among the major driving forces behind biodiversity loss. Gene drive technology may offer a humane, efficient and cost-effective method of control. For safe and effective deployment it is vital that a gene drive is both self-limiting and can overcome evolutionary resistance. We present HD-ClvR, a novel combination of CRISPR-based gene drives that eliminates resistance and localises spread. As a case study, we model HD-ClvR in the grey squirrel (Sciurus carolinensis), which is an invasive pest in the UK and responsible for both biodiversity and economic losses. HD-ClvR combats resistance allele formation by combining a homing gene drive with a cleave-and-rescue gene drive. The inclusion of a self-limiting daisyfield gene drive allows for controllable localisation based on animal supplementation. We use both randomly mating and spatial models to simulate this strategy. Our findings show that HD-ClvR can effectively control a targeted grey squirrel population, with little risk to other populations. HD-ClvR offers an efficient, self-limiting and controllable gene drive for managing invasive pests.

A confinable home-and-rescue gene drive for population modification

“…autonomous, linked-Cas9) and two-locus (i.e. split-drive) versions of ClvR ( Faber et al, 2020 ; Oberhofer et al, 2020a , Oberhofer et al, 2020b , Oberhofer et al, 2019 ), the one-locus TARE system from Champer et al, 2020a , as well as a two-locus TARE configuration based on their design, an HGD targeting a non-essential gene ( Gantz et al, 2015 ; Hammond et al, 2016 ), and HomeR (for mechanistic comparisons of these systems, see Figure 3—figure supplement 1 ). In each case, we first simulated population spread of each gene drive system for an ideal parameterization (see 'Materials and methods' for more details) and included additional simulations for HomeR under current experimentally derived parameters (HomeR-exp; Figure 3A and C , parameters consistent with Figure 2C ).…”

“…Two-locus designs showed significantly reduced ability to reach 95% carrier frequency in females, often requiring more and larger (20% of the total population size) releases to be effective ( Figure 4C ). For split-drive designs, only the first release was homozygous Cas9 and gene drive, while supplementary releases were homozygous Cas9 only ( Faber et al, 2020 ; Oberhofer et al, 2020a , Oberhofer et al, 2020b , Oberhofer et al, 2019 ). A similar pattern of efficacy is seen for ClvR, TARE, and HomeR, but by splitting the HGD and maintaining the fitness effects on the Cas9 allele, it is now able to reach 95% introgression over a small parameter range.…”

Adequacy and sufficiency evaluation of existing EFSA guidelines for the molecular characterisation, environmental risk assessment and post‐market environmental monitoring of genetically modified insects containing engineered gene drives

“…Following discussions with the European Commission (Directorate-General for Health and Food Safety), it was agreed to limit the scope of the mandate (see Section 1.1) to insects, as they represent the most likely cases of GDMOs moving to practical applications for deliberate release into the environment. Although the use of engineered gene drive systems is under consideration in mammals (Leitschuh et al, 2018;Conklin, 2019;Godwin et al, 2019;Grunwald et al, 2019;Manser et al, 2019;Faber et al, 2020) and plants (Neve, 2018;Barrett et al, 2019;Gardiner et al, 2020), basic technical challenges need to be overcome before an engineered gene drive will be possible in these taxa (NASEM, 2016;Godwin et al, 2019;Pixley et al, 2019;Scudellari, 2019). In the future, however, EFSA could be mandated by the European Commission to evaluate whether its guidelines for the risk assessment of genetically modified (GM) mammals and plants are adequate and sufficient for the risk assessment of GM mammals and plants containing engineered gene drives.…”

A gene drive does not spread easily in populations of the honey bee parasite Varroa destructor

“…However, we do not yet know if a gene drive can spread in a varroa population. Prior to any gene drive system being implemented, it is essential to develop a species-specific genetic and demographic model to predict the effectiveness of a drive spreading successfully (James, 2005;Sinkins & Gould, 2006;Prowse et al, 2017;Unckless et al, 2017;Noble et al, 2018;KaramiNejadRanjbar et al, 2018;Lester et al, 2020;Faber et al, 2021). This is especially important in non-model species where mating biology and sex-determination systems can limit the spread of gene drives.…”