Propagation of seminal toxins through binary expression gene drives could suppress populations

Abstract

Gene drives can be highly effective in controlling a target population by disrupting a female fertility gene. To spread across a population, these drives require that disrupted alleles be largely recessive so as not to impose too high of a fitness penalty. We argue that this restriction may be relaxed by using a double gene drive design to spread a split binary expression system. One drive carries a dominant lethal/toxic effector alone and the other a transactivator factor, without which the effector will not act. Only after the drives reach sufficiently high frequencies would individuals have the chance to inherit both system components and the effector be expressed. We explore through mathematical modeling the potential of this design to spread dominant lethal/toxic alleles and suppress populations. We show that this system could be implemented to spread engineered seminal proteins designed to kill females, making it highly effective against polyandrous populations.

Figure 1

Binary expression drive constructs. Left: the transactivator construct (a). Right: the effector construct (b). The promoter of the transactivator gene is only active in the target tissue/organ, for instance, the ovaries or the male accessory glands. The transactivator protein will activate the expression of the effector gene, which encodes a dominant or semidominant toxin, in the target tissue/organ. In both constructs, the expression of Cas9 and the gRNA is under the regulation of a germline promoter that allows drive conversion during meiosis. Ideally, target loci are highly conserved genes that cannot tolerate mutations so resistance alleles are selected out of the population while each drive allele alone, carrying a re-coded target gene, will not impose an intended fitness cost.

Figure 2

Model stages and steps across a generation. Major invoked parameters are shown per step. (1) Female and male virgin adults mate randomly giving rise to mothers, i.e., inseminated females. Females may mate more than once. Male mating success of drive-carrying males is reduced by unintended drive effects, and terminator males may kill the female during mating. (2) For simplicity, meiosis and homing conversion are only modeled for surviving mothers and mating males. (3) Each mother produces a clutch of eggs where the expected number of eggs may be reduced for drive-carrying mothers. (4) Eggs have a probability of dying before reaching the larval stage, which may be higher for drive-carrying eggs. (5) Larvae have a probability of dying right after hatching. (6) Then, larvae are subject to density-dependent mortality. (7) Surviving larvae result in virgin adults, and sex is randomly determined.

Figure 3

Suppression potential of ffBED (a), sBED (b), and ffSD (c). Left: population size (relative to the initial population size), drive(s) allele frequency, and genetic load are shown across the first 25 generations for each design using ideal and reference drive parameters. Lines represent the 100-simulations mean value while the colored envelopes stand for the maximum and minimum values. For BED designs, frequencies of the two drives were averaged. Right: fast elimination rate (the percentage of simulations where the population was eliminated within 36 generations) is shown for a combined space of Homing efficiency and Unintended fitness costs (Unintended reproductive cost and Unintended viability cost). Resistance allele formation was assumed to be half the complement of Homing efficiency (e.g., if Homing efficiency is 0.8, Resistance allele formation is 0.1).

Figure 4

Impact of Dominance degree. Relative population size from generation 10 to 25 is shown with ideal and reference drive parameters for sBED (a) and ffSD (b) using in each case different values of Dominance degree. Lines represent the 100-simulations mean value while the colored envelopes stand for the maximum and minimum values.

Figure 5

Impact of low-density growth rate. Relative population size from generation 10 to 25 is shown with ideal and reference drive parameters for sBED (a) and ffSD (b) using in each case different values of Rm. Rm was adjusted with the Fecundity parameter. Lines represent the 100-simulations mean value while the colored envelopes stand for the maximum and minimum values.

Figure 6

Impact of Resistance allele functionality. Relative population size from generation 10 to 25 is shown with ideal and reference drive parameters for sBED (a) and ffSD (b) using in each case different values of Resistance allele functionality. Lines represent the 100-simulations mean value while the colored envelopes stand for the maximum and minimum values.

Figure 7

Impact of polyandry. Relative population size from generation 10 to 25 or 60 is shown with ideal and reference drive parameters for sBED (a) and ffSD (b) using in each case different values of Polyandry degree. Lines represent the 100-simulations mean value while the colored envelopes stand for the maximum and minimum values.