CRISPR/Cas9 gene drives in genetically variable and nonrandomly mating wild populations

Area of Science:

• Genetics
• Molecular Biology
• Ecology

Background:

• CRISPR/Cas9 gene drives offer potential for pest and disease vector population control.
• Their effectiveness in wild populations remains uncertain due to potential genetic resistance.

Purpose of the Study:

• To investigate the impact of genetic variation in Cas9 target sites on the efficacy of synthetic gene drives.
• To assess the influence of inbreeding on gene drive performance in wild populations.

Main Methods:

• Analysis of genetic data from four populations of the flour beetle *Tribolium castaneum*.
• Modeling the effect of pre-existing genetic variants and inbreeding on gene drive success.

Main Results:

• Most *Tribolium castaneum* populations possess genetic variants conferring immunity to CRISPR/Cas9 gene drives (ITD).
• Even rare ITD alleles significantly reduce or abolish gene drive efficacy.
• Mild inbreeding, common in disease vectors, exacerbates the negative impact of ITD alleles.

Conclusions:

• Designing effective gene drives necessitates thorough characterization of genetic variability within target populations.
• Understanding the mating system of wild populations is essential for successful gene drive implementation.
• Pre-existing genetic resistance and population structure can limit the utility of CRISPR/Cas9 gene drives.