Gene drive-mediated population elimination for biodiversity conservation. When you come to a fork in the road, take it

B. A. Hay and M. Guo,  Proceedings of the National Academy of Sciences,  119:e2218020119. 2022.

How can the ability of t w2 to spread at super-Mendelian frequencies be utilized even if it is unable to directly drive the population to an unfit state? Gierus, Birand, and colleagues proposed placing Cas9 and a gRNA at a neutral position within the t haplotype. In this hybrid gene drive element, which they refer to as tCRISPR, Cas9 and the gRNA cleave and (hopefully) create loss-of-function (LOF) alleles in the male germ line of the prolactin (Prl) gene, which is required for female fertility. The goal with tCRISPR is for t-based segregation distortion in males to pump the Cas9/gRNAs cassette to high frequency within the population. The latter, through cleavage followed by inaccurate repair in males, will continuously produce LOF alleles at the independently segregating Prl locus. The hope is that the combination of t-based drive and accumulation of Prl LOF alleles will drive the population to an unfit state that contains a high frequency of infertile homozygous Prl mutant females along with some frequency of infertile homozygous t males. The combination of these two effects, they propose, could eliminate populations under a wider range of parameters than with t w2 alone

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