Requirements for Driving Antipathogen Effector Genes into Populations of Disease Vectors by Homing

Abstract

There is a need for new interventions against the ongoing burden of vector-borne diseases such as malaria and dengue. One suggestion has been to develop genes encoding effector molecules that block parasite development within the vector, and then use the nuclease-based homing reaction as a form of gene drive to spread those genes through target populations. If the effector gene reduces the fitness of the mosquito and does not contribute to the drive, then loss-of-function mutations in the effector will eventually replace functional copies, but protection may nonetheless persist sufficiently long to provide a public health benefit. Here, we present a quantitative model allowing one to predict the duration of protection as a function of the probabilities of different molecular processes during the homing reaction, various fitness effects, and the efficacy of the effector in blocking transmission. Factors that increase the duration of protection include reducing the frequency of pre-existing resistant alleles, the probability of nonrecombinational DNA repair, the probability of homing-associated loss of the effector, the fitness costs of the nuclease and effector, and the completeness of parasite blocking. For target species that extend over an area much larger than the typical dispersal distance, the duration of protection is expected to be highest at the release site, and decrease away from there, eventually falling to zero, as effector-less drive constructs replace effector-containing ones. We also model an alternative strategy of using the nuclease to target an essential gene, and then linking the effector to a sequence that restores the essential function and is resistant to the nuclease. Depending upon parameter values, this approach can prolong the duration of protection. Our models highlight the key design criteria needed to achieve a desired level of public health benefit.

Invasion and migration of spatially self-limiting gene drives: a comparative analysis

“…Additionally, over time the intermediate equilibrium frequency could enable recombination events that disable the two-locus underdominance drive and/or result in breakdown of the payload (Beaghton et al 2017). The number of wild-type individuals needed to reverse the daisy-chain system depends upon the frequencies of the non-payload elements of the drive, which in turn depend upon their costs, the initial release size and time since the initial release.…”

Integral Gene Drives: an “operating system” for population replacement

“…There are several noteworthy assumptions made in the model. It is assumed following previous work (Beaghton et al 2017a) that at baseline values, the cost of expressing the nuclease from the drive component ( s n =0.05) is lower than the cost of expressing an effector gene from an effector component ( s e2 = s e3 =0.1). This is justifiable when considering that germline genes tend to have lower expression levels than those present in the soma and that expression of antimalarial effectors needs to be sufficiently strong to ensure effective concentrations.…”

Priorities for Broadening the Malaria Vector Control Tool Kit

“…For example, there is considerable interest in the potential of new gene editing technologies for developing transgenic mosquitoes for use in population replacement or population suppression strategies [12–15]. Approaches to reduce vector competence by manipulating elements of the mosquito microbiome [16–18], or via transinfection with endosymbionts such as Wolbachia [19,20], are also being examined.…”