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

Abstract

One 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 guide RNAs (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. As a 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 homing-based drive and to bring about suppression and/or killing of specific individuals in response to other stimuli.

Allele Sails: launching traits and fates into wild populations with DNA sequence modifiers

“…(especially when using multiple gRNAs) in the Drosophila germline or the plant Arabidopsis thaliana at frequencies near 100% [24][25][26][27][28][29][30][31] . While base and prime editors also have significant levels of editing activity in Drosophila, they are not 100%; instead closer to 36% for a prime editor 32 , and >90% for a base editor 20 .…”

Cleave and Rescue gamete killers create conditions for gene drive in plants

“…In Drosophila , autonomous ClvR /TARE elements have been created and shown to spread in wildtype (WT) populations to transgene fixation (all individuals carry at least one copy) 14,15,22,24,25 . Other features, such as the ability to bring about strong, but self-limited drive 23 , engage in multiple cycles of population modification that replace old content with new 22 , and bring about population suppression using a conditional Rescue 24 have also been demonstrated.…”

“…In Drosophila , autonomous ClvR /TARE elements have been created and shown to spread in wildtype (WT) populations to transgene fixation (all individuals carry at least one copy) 14,15,22,24,25 . Other features, such as the ability to bring about strong, but self-limited drive 23 , engage in multiple cycles of population modification that replace old content with new 22 , and bring about population suppression using a conditional Rescue 24 have also been demonstrated. Multiple other configurations of the components that make up ClvR /TARE have been proposed, and modeling predicts they can bring about drive in animals with a diversity of interesting characteristics for population modification or suppression 16,26 .…”

“…Recently, in an effort to create a chromosomal TA-based gene drive system that utilizes a LOF toxin and consists of a simple and extensible set of components that can plausibly be implemented across diverse species we developed the Cleave and Rescue (ClvR) element 14,[22][23][24] , also referred to as Toxin Antidote Recessive Embryo (TARE) 15,25 in related implementations (hereafter referred to as ClvR, a name that captures the key mechanisms involved). A ClvR element encodes two activities.…”

Incorporating ecology into gene drive modelling

“…Environmental heterogeneity can also be used to control gene drives through temporal rather than spatial mechanisms. For example, heat‐sensitive gene drive designs can generate a ‘temporal barrier’, which could be delayed or reversed with seasonal temperature changes (Oberhofer et al, 2021). Natural endosymbiont systems that have temperature‐dependent phenotypes could provide insights into important parameters and features to be incorporated into models of such phenomena.…”