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Some Species May Have Variants That Confer Immunity to Gene Drives

NEW YORK (GenomeWeb) – Using CRISPR/Cas9-based genome editing to create gene drives has been suggested as a way to control populations of pests that can damage crops or spread diseases such as Zika. However, a new study published today in Science Advances notes that some pest populations may have genetic variants that render them immune to such drives, and that researchers aiming to control these populations will have to take their genetic variability and mating systems into account when designing gene drives.

Using genetic data from four populations of the flour beetle Tribolium castaneum — from India, Spain, Peru, and Indiana — a team of Indiana University researchers assessed the effects of naturally occurring genetic variation on CRISPR/Cas9-based efficiency for three separate regions of Cas9 gene drive target sites: the protospacer-adjacent motif (PAM), the seed region, and the outer protospacer. They found a SNP in the seed region of the beetle populations from Spain and Indiana, which they noted could "severely reduce Cas9 association and subsequent cleavage and so is considered [immune to drive (ITD)]."

The researchers also considered the effects of a CRISPR guide RNA (gRNA) on the Ace2 gene, which is involved in development, female fertility, and insecticide resistance in T. castaneum. They expected a disruption to this gene to "carry a heavy fitness penalty" for the beetle, but again found a single SNP in the populations from Indiana and Peru that rendered it immune to the drive.

Another gRNA meant to hamper the fertility of male beetles was itself hampered by a third SNP the researchers found in the outer protospacer region of the Peruvian beetles.

Although the researchers didn't find these SNPs in the beetle population from India, they did note that this population is incompatible for mating with populations from North and South America, meaning the ITD-conferring SNPs in the populations from Peru and Indiana would not be able to be bred out with exposure to the India population.

"Our results suggest that even a low-frequency ITD can severely limit the spread of a highly deleterious drive and cause its elimination from a population," the researchers wrote. "A key result of our analysis is that ITDs were selected for and present at a higher frequency in the population following drive elimination, substantially increasing the resistance of the population to future attempts to propagate this drive."

The team also tested the effect of inbreeding on gene drive propagation and found that inbreeding caused the rapid loss of strongly deleterious gene drives and also accelerated the loss of moderately deleterious gene drives.

"Our analyses suggest that standing genetic variation and inbreeding could have wide-ranging and sometimes severe consequences on the efficiency of drive propagation in a wild population," the authors wrote. "To minimize the potential impacts of ITDs on drive spread, we propose that a survey of genetic diversity at the locus of interest in the target population is a necessary first step in designing a CRISPR-based gene drive. If a target region of a locus of interest is highly variable, it may be prudent to select a different region of the gene to be disrupted to avoid the potential complications of ITDs."

The team also noted that recent advances in finding or engineering Cas9 variants may present a solution to this problem. For example, molecular evolution of S. pyogenes Cas9 has yielded variants with different PAM specificities. "If the PAM specificity can be suitably matched to the variation of the target population, these alternative CRISPR nucleases would not be susceptible to the problems highlighted in our model," the team said.

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