Split versions of < i > Cleave and Rescue < /i > selfish genetic elements for measured self limiting gene drive

by Georg Oberhofer, Tobin Ivy, Bruce A. Hay

Gene drive elements promote the spread of linked traits, providing methods for changing the composition or fate of wild populations. Drive mechanisms that are self-limiting are attractive because they allow control over the duration and extent of trait spread in time and space, and are reversible through natural selection as drive wanes. Self-sustainingCleave and Rescue (ClvR) elements include a DNA sequence-modifying enzyme such as Cas9/gRNAs that disrupts endogenous versions of an essential gene, a tightly linked recoded version of the essential gene resistant to cleavage (theRescue), and a Cargo.ClvR spreads by creating loss-of-function (LOF) conditions in which those withoutClvR die because they lack functional copies of the essential gene. We use modeling to show that when theRescue-Cargo and one or both components required for LOF allele creation (Cas9 and gRNA) reside at different locations (splitClvR), drive ofRescue-Cargo is self-limiting due to a progressive decrease in Cas9 frequency, and thus opportunities for creation of LOF alleles, as spread occurs. Importantly, drive strength and duration can be extended in a measured manner —which is still self-limiting—by moving the two components close enough to each other that they experience some degree of linkage. With linkage, Cas9 transiently experiences drive by hitchhiking withRescue-Cargo until linkage disequilibrium between the two disappears, a function of recombina...

Source: PLoS Genetics - February 18, 2021 Category: Genetics & Stem Cells Authors: Georg Oberhofer Source Type: research