Split drive killer-rescue provides a novel threshold-dependent gene drive

Abstract

A wide range of gene drive mechanisms have been proposed that are predicted to increase in frequency within a population even when they are deleterious to individuals carrying them. This also allows associated desirable genetic material (“cargo genes”) to increase in frequency. Gene drives have garnered much attention for their potential use against a range of globally important problems including vector borne disease, crop pests and invasive species. Here we propose a novel gene drive mechanism that could be engineered using a combination of toxin-antidote and CRISPR components, each of which are already being developed for other purposes. Population genetics mathematical models are developed here to demonstrate the threshold-dependent nature of the proposed system and its robustness to imperfect homing, incomplete penetrance of toxins and transgene fitness costs, each of which are of practical significance given that real-world components inevitably have such imperfections. We show that although end-joining repair mechanisms may cause the system to break down, under certain conditions, it should persist over time scales relevant for genetic control programs. The potential of such a system to provide localised population suppression via sex ratio distortion or female-specific lethality is also explored. Additionally, we investigate the effect on introduction thresholds of adding an extra CRISPR base element, showing that this may either increase or decrease dependent on parameter context.

Double drives and private alleles for localised population genetic control

“…other. Previously published examples that fit this definition include those for 2-locus underdominance [16,17,40,41], and Medusa [42], tethered [18], integral [30], and transcomplementing [43] gene drives. As with single-construct gene drives, these various proposed designs differ in purpose (suppression vs. modification), release rate needed to initiate spread (low vs high threshold), and the molecular basis for the superMendelian inheritance (homing, toxinantidote interactions, or a combination of the two), and the suggested rationales for adopting these designs over single drives include allowing more localised population control and a more modular product development pipeline.…”

“…First, one can use a strategy requiring relatively large releases, which can be restricted to the target population, with any introductions into non-target populations (by dispersal, or by accidental or unauthorised releases) being too small to have a significant impact. Potentially 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 [10,20,21], but, by necessity, all of them require a non-trivial production and release effort.…”

Potential use of gene drive modified insects against disease vectors, agricultural pests and invasive species poses new challenges for risk assessment

“…While current research is investigating the development of engineered GDs in insect populations and deploying them, it will take many years before they can be applied to practical disease vector/pest management. At present, some GDMIs are either in development or have been tested experimentally in the laboratory, often with multigenerational data and model simulations [17,19,20,27,28,33,35,39,43,45,46,[53][54][55][56][57][58][59][60][61][62][63][64][65][66][67]. However, no "contemporary" GDMIs have been assessed in small-scale physically and/or ecologically confined field trials, or open release trials [5,8,10,15,68].…”

Genetic Technologies for Sustainable Management of Insect Pests and Disease Vectors

“…This technology, which has been recently tested in D. melanogaster [122] and Ae. aegypti [100], achieves parameters of homing and emergence of resistance allele that are comparable to standard drives [102,122,123]. Recently, the population dynamics of a synthetic split drive that integrates the characteristics of the toxin-antidote systems (split drive killer rescue (SDKR)), have been explored [123].…”