Cross-species meta-analysis reveals determinants of homing gene drive performance

Abstract Homing gene drives can bias their inheritance above Mendelian expectations, but reported outcomes vary widely. We compiled a cross-species dataset of nearly one million scored progeny from 42 publications reporting CRISPR/Cas9 endonuclease-based gene drives in 10 model, pest, and vector species. Using multilevel meta-analytic models, we evaluate biological, cross, and transgene design factors as predictors of biased drive inheritance. Species is the strongest predictor, but most heterogeneity remains unexplained; design features each explain a modest fraction of the remaining variation, with large construct-to-construct differences pointing to the full combination of design choices rather than any single factor. Nuclease expression timing, the most common optimization target, has limited predictive value after accounting for correlated factors, and predictions do not transfer well between species. Maternal nuclease deposition has a marginal effect on drive inheritance but dramatically increases somatic phenotype rates in offspring, revealing a tissue-of-action rather than repair-outcome effect. An interactive web tool enables community analysis of this dataset, which will guide the design of more efficient gene drives for genetic vector control, invasive species management and other applications. https://sverkuijl.shinyapps.io/GeneDrive/ Competing Interest Statement The authors have declared no competing interest. Footnotes ↵+ These authors jointly supervised this work