Gene drive that results in addiction to a temperature sensitive version of an essential gene triggers population collapse in Drosophila

Abstract

ABSTRACTOne strategy for population suppression seeks to use gene drive to spread genes that confer conditional lethality or sterility, providing a way of combining population modification with suppression. Stimuli of potential interest could be introduced by humans, such as an otherwise benign virus or chemical, or occur naturally on a seasonal basis, such as a change in temperature. Cleave and Rescue (ClvR) selfish genetic elements use Cas9 and gRNAs to disrupt endogenous versions of an essential gene, while also including a Rescue version of the essential gene resistant to disruption. ClvR spreads by creating loss-of-function alleles of the essential gene that select against those lacking it, resulting in populations in which the Rescue provides the only source of essential gene function. In consequence, if function of the Rescue, a kind of Trojan horse now omnipresent in a population, is condition-dependent, so too will be the survival of that population. To test this idea we created a ClvR in Drosophila in which Rescue activity of an essential gene, dribble, requires splicing of a temperature-sensitive intein (TS-ClvRdbe). This element spreads to transgene fixation at 23°C, but when populations now dependent on Ts-ClvRdbe are shifted to 29°C death and sterility result in a rapid population crash. These results show that conditional population elimination can be achieved. A similar logic, in which Rescue activity is conditional, could also be used in HEG-based drive, and to bring about suppression and/or killing of specific individuals in response to other stimuli..SIGNIFICANCE STATEMENTGene drive can be used to spread traits of interest through wild populations. In some contexts the goal is to suppress or eliminate the population. In principle, one way to achieve this goal is if the trait being spread confers on carriers conditional lethality in response to an environmental stimulus that is either introduced by humans into the target area at a specific time (a virus, otherwise benign chemical; a kind of species-specific insecticide), or that occurs naturally on a seasonal basis, such as a change in temperature. Here we show that ClvR selfish elements can be used to spread a gene that confers lethality and sterility in response to increased temperature, demonstrating that conditional population elimination can be achieved.