Gene drive for population genetic control: non-functional resistance and parental effects.

Andrea K Beaghton,Austin Burt,Andrea Crisanti,Tony Nolan,Andrew Hammond

doi:10.1098/rspb.2019.1586

Abstract

Gene drive is a natural process of biased inheritance that, in principle, could be used to control pest and vector populations. As with any form of pest control, attention should be paid to the possibility of resistance evolving. For nuclease-based gene drive aimed at suppressing a population, resistance could arise by changes in the target sequence that maintain function, and various strategies have been proposed to reduce the likelihood that such alleles arise. Even if these strategies are successful, it is almost inevitable that alleles will arise at the target site that are resistant to the drive but do not restore function, and the impact of such sequences on the dynamics of control has been little studied. We use population genetic modelling of a strategy targeting a female fertility gene to demonstrate that such alleles may be expected to accumulate, and thereby reduce the reproductive load on the population, if nuclease expression per se causes substantial heterozygote fitness effects or if parental (especially paternal) deposition of nuclease either reduces offspring fitness or affects the genotype of their germline. All these phenomena have been observed in synthetic drive constructs. It will, therefore, be important to allow for non-functional resistance alleles in predicting the dynamics of constructs in cage populations and the impacts of any field release.

Highlights

Some species—relatively few—cause substantial harm to human health or the environment, and are subject to significant control efforts
As with any form of pest control, due consideration should be given to the possibility that resistance will evolve, and for this approach, the most obvious form of resistance is a change in the sequence recognized by the nuclease such that it is no longer cleaved, but maintains its function in the organism
The possibility that a nuclease-based gene drive might select for functional target-site resistance is well acknowledged, and various possibilities are being explored to reduce the likelihood of this occurring [6,11,14,15]

Summary

Introduction

Some species—relatively few—cause substantial harm to human health or the environment, and are subject to significant control efforts. In the first attempts to engineer this type of suppression drive, the control sequences showed some unintended (leaky) expression in somatic cells, resulting in some of those cells (where the target gene is needed) being homozygous null, thereby reducing fitness [5] Because this fitness cost is due to expression of the nuclease, it is not borne by non-functional resistant genes, which can, have a relative advantage and accumulate to higher frequencies in the population than they otherwise would. As has been observed, nuclease expression causes strong fitness effects in drive heterozygotes, or if parental deposition of nuclease reduces offspring fitness or affects the genotype of their germline, we find that there can be reductions in the equilibrium frequency of the driving construct and the reproductive load imposed upon the population Under such conditions, non-functional drive-resistant alleles can accumulate in the population and reduce the extent of population control

Models

Results

Findings

Discussion