ABSTRACT
Killer rescue systems were first identified in bacteria. They consist of two unlinked loci, one encoding a toxin (killer allele) and the other an antidote (rescue allele). This is a system of killing and rescuing that is used by the killer-rescue system to act antagonistically and bias their co-inheritance. A killer-rescue self-limiting gene drive, also known as a killer-rescue (K-R) gene drive, is a gene drive system that does not drive toward non-Mendelian inheritance like Cas9-based homing drives. Homozygous carriers for both genes are mass-released into wild populations. Offspring inheriting the killer allele but not the rescue allele will be nonviable. The K-R system utilizes the well-characterized Gal4/UAS binary expression system and the Gal4 inhibitor Gal80. Death is due to overexpression of Gal4, which is rescued by Gal4 activation of the Gal80 inhibitor in flies that have both UAS-Gal4 (K) and UAS-Gal80 (R) transgenes. A killer-rescue construct is placed into the pest genome containing a maternally deposited lethal toxin, a zygotically expressed antidote, and an effector (the cargo). Female pest deposits a lethal toxin into their entire progeny. However, those that inherit the Medea construct are protected by a neutralizing antidote expressed in the early embryo. These systems have the potential to reduce the impact of human disease vectors or agricultural pests at the individual, community, and global scale. However, systems pose challenges such as introgression into nontarget populations or movement across political borders. The novel killer-rescue (K-R) gene drive system has been tested in Drosophila melanogaster. In this system, traits or genes that will either modify the pest population to rid of its pestilent behaviors or suppress the population by disrupting a gene and reducing the average fitness of the population (such as reducing the lifespan) were assayed. The advantages of the K-R gene drive are that communities will likely feel more comfortable with initial field tests and applications and it is simpler to build. The disadvantage of this K-R gene drive system compared to a Cas9-based homing drive is that it could take longer for the desirable genes to spread on a relevant timescale.
