Abstract
Synthetic gene drive constructs could, in principle, provide the basis for highly efficient interventions to control disease vectors and other pest species. This efficiency derives in part from leveraging natural processes of dispersal and gene flow to spread the construct and its impacts from one population to another. However, sometimes (for example, with invasive species) only specific populations are in need of control, and impacts on non-target populations would be undesirable. Many gene drive designs use nucleases that recognise and cleave specific genomic sequences, and one way to restrict their spread would be to exploit sequence differences between target and non-target populations. In this paper we propose and model a series of low threshold double drive designs for population suppression, each consisting of two constructs, one imposing a reproductive load on the population and the other inserted into a differentiated locus and controlling the drive of the first. Simple deterministic, discrete-generation computer simulations are used to assess the alternative designs. We find that the simplest double drive designs are significantly more robust to pre-existing cleavage resistance at the differentiated locus than single drive designs, and that more complex designs incorporating sex ratio distortion can be more efficient still, even allowing for successful control when the differentiated locus is neutral and there is up to 50% pre-existing resistance in the target population. Similar designs can also be used for population replacement, with similar benefits. A population genomic analysis of CRISPR PAM sites in island and mainland populations of the malaria mosquito Anopheles gambiae indicates that the differentiation needed for our methods to work can exist in nature. Double drives should be considered when efficient but localised population genetic control is needed and there is some genetic differentiation between target and non-target populations.
Highlights
Gene drive is a natural phenomenon in which some genes are able to increase in frequency and spread through populations by contriving to be inherited at a greater-than-Mendelian rate [1,2]
Invasive species, and other pests cannot be satisfactorily controlled with existing interventions, and new methods are required
Synthetic gene drive systems that are able to spread though populations because they are inherited at a greater-thanMendelian rate have the potential to form the basis for new, highly efficient pest control measures
Summary
Gene drive is a natural phenomenon in which some genes are able to increase in frequency and spread through populations by contriving to be inherited at a greater-than-Mendelian rate [1,2]. Suitable genetic constructs include those that do not drive (e.g., dominant lethals, autosomal X-shredders, or Y-linked editors; [10,11,12]), those that show transient drive due to a non-driving helper construct (e.g., killer-rescue systems and split drives; [13,14,15]) or those that drive, but only if they are above some threshold frequency (e.g., various underdominant [heterozygote inferiority] strategies, tethered drives, and split drive killer-rescue systems [16,17,18,19]) Some of these approaches are more efficient than others [12,20,21], but, by necessity, all of them require a non-trivial production and release effort
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