Engineered reciprocal chromosome translocations drive high threshold, reversible population replacement in Drosophila

Abstract

17Replacement of wild insect populations with transgene-bearing individuals 18 unable to transmit disease or survive under specific environmental conditions 19 provides self-perpetuating methods of disease prevention and population 20 suppression, respectively. Gene drive mechanisms that require the gene drive 21 element and linked cargo exceed a high threshold frequency to spread are 22 attractive because they offer several points of control: they bring about local, but 23 not global population replacement; and transgenes can be eliminated by 24 reintroducing wildtypes into the population so as to drive the frequency of 25 transgenes below the threshold required for drive. It has long been recognized 26 that reciprocal chromosome translocations could, in principal, be used to bring 27 about high threshold gene drive through a form of underdominance. However, 28 translocations able to drive population replacement have not been reported, 29leaving it unclear if translocation-bearing strains fit enough to mediate gene drive 30 can easily be generated. Here we use modeling to identify a range of conditions 31 under which translocations should spread, and the equilibrium frequencies 32 achieved, given specific introduction frequencies, fitness costs and migration 33 rates. We also report the creation of engineered translocation-bearing strains of 34 Drosophila melanogaster, generated through targeted chromosomal breakage 35 and homologous recombination. By several measures translocation-bearing 36 strains are fit, and drive high threshold, reversible population replacement in 37 laboratory populations. These observations, together with the generality of the 38 tools used to generate translocations, suggest that engineered translocations 39 may be useful for controlled population replacement in many species. 40 41 42 3

Modeling confinement and reversibility of threshold-dependent gene drive systems in spatially-explicitAedes aegyptipopulations

“…When translocation heterozygotes mate, several crosses result in unbalanced genotypes and hence unviable offspring, resulting in a heterozygote reproductive disadvantage. This results in bistable, threshold-dependent population dynamics, confirmed in laboratory drive experiments (14). The inheritance patterns produced by the UD MEL system are depicted in Figure 1B.…”

“…The use of translocations for transforming pest populations was initially suggested by Serebrovskii (1940) (35) and later Curtis (1968) (36) for the introduction of disease-refractory genes into mosquito populations. A number of models have been proposed to describe their spread through randomly-mating populations (14,16,37,38); however, with one recent exception addressing spatial structure (18), these have largely ignored insect life history and mating structure. Such models suggest that the translocation need only exceed a population frequency of 50%, in the absence of a fitness cost associated with the translocation, to spread to fixation in a population, which could conceivably be achieved through a single seeding release round.…”

The Developmental Transcriptome ofAe. albopictus,a Major Worldwide Human Disease Vector

“…In Aedes aegypti, several regulatory elements able to drive gene expression in a tissue-and temporal-specific manner have been identified through extensive study (Akbari et al 2013a) and transgenesis (Coates et al 1999;Kokoza et al 2000;Moreira et al 2000;Smith et al 2007). Future functional characterization of uncharacterized genes and regulatory elements may lead to the development of innovative genetic population control technologies such as precision guided sterile males (Kandul et al 2019b), and gene drive systems (Akbari et al 2013b(Akbari et al , 2014aChamper et al 2016;Buchman et al 2018bBuchman et al , 2018aKandul et al 2019aKandul et al , 2019bLi et al 2019) which can be linked to anti-pathogen effectors (Buchman et al , 2019b potentially providing paradigm-shifting technologies to control this worldwide human disease vector. Overall, our results provide a comprehensive snapshot of gene expression dynamics in the development of Ae.…”

Tethered homing gene drives: A new design for spatially restricted population replacement and suppression

“…The focus of most of the concern has been related to the risk of unrestricted gene drives aimed at population suppression or eradication. A number of strategies for spatially restricted gene drives have been outlined (Akbari et al, ; Buchman et al, ; Burt & Deredec, ; Davis et al, ; Marshall & Hay, ; Noble et al, ; Oberhofer et al, ; Rasgon, ) and a few have been tested on Drosophila in the laboratory (Akbari et al, , ; Buchman et al, ; Oberhofer et al, ; Reeves et al, ), but mathematical models indicate that while these approaches are reasonable for changing characteristics of local populations (i.e., population replacement), they are less likely to be effective in suppressing local populations that have realistic density‐dependent dynamics (but see Khamis et al, ; Marshall & Hay, ).…”