CRISPR-based gene drives can spread through wild populations by biasing their own transmission above the 50% value predicted by Mendelian inheritance. These technologies offer population-engineering solutions for combating vector-borne diseases, managing crop pests, and supporting ecosystem conservation efforts. Current technologies raise safety concerns for unintended gene propagation. Herein, we address such concerns by splitting the drive components, Cas9 and gRNAs, into separate alleles to form a trans-complementing split-gene-drive (tGD) and demonstrate its ability to promote super-Mendelian inheritance of the separate transgenes. This dual-component configuration allows for combinatorial transgene optimization and increases safety by restricting escape concerns to experimentation windows. We employ the tGD and a small-molecule-controlled version to investigate the biology of component inheritance and resistant allele formation, and to study the effects of maternal inheritance and impaired homology on efficiency. Lastly, mathematical modeling of tGD spread within populations reveals potential advantages for improving current gene-drive technologies for field population modification.

中文翻译：

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反式互补基因驱动为实验室调查和潜在的现场部署提供了一个灵活的平台。

基于 CRISPR 的基因驱动可以通过将自身的传播偏向高于孟德尔遗传预测的 50% 值来在野生种群中传播。这些技术为抗击病媒传播疾病、管理作物害虫和支持生态系统保护工作提供了人口工程解决方案。当前的技术引起了对意外基因传播的安全担忧。在此，我们通过将驱动组件 Cas9 和 gRNA 拆分为单独的等位基因以形成反式互补分裂基因驱动 (tGD) 并证明其促进单独转基因的超孟德尔遗传的能力来解决此类问题。这种双组分配置允许组合转基因优化，并通过将逃逸问题限制在实验窗口来提高安全性。我们采用 tGD 和小分子控制版本来研究成分遗传和抗性等位基因形成的生物学，并研究母系遗传和受损同源性对效率的影响。最后，tGD 在种群内传播的数学模型揭示了改进当前用于野外种群改造的基因驱动技术的潜在优势。