互补基因驱动提供了一个灵活的实验室研究和潜在野外部署的平台。
A transcomplementing gene drive provides a flexible platform for laboratory investigation and potential field deployment.
机构信息
Section of Cell and Developmental Biology, University of California San Diego, La Jolla, CA, 92093, USA.
Division of Epidemiology and Biostatistics, School of Public Health, University of California, Berkeley, CA, 94720, USA.
出版信息
Nat Commun. 2020 Jan 17;11(1):352. doi: 10.1038/s41467-019-13977-7.
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.
基于 CRISPR 的基因驱动可以通过使自身的传播率高于孟德尔遗传预测的 50%，从而在野生种群中传播。这些技术为防治媒介传播疾病、管理作物害虫和支持生态系统保护工作提供了群体工程解决方案。当前的技术引发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 分割成单独的等位基因，形成一个转互补的分裂基因驱动（tGD），来解决这些担忧，并证明其能够促进单独转基因的超孟德尔遗传。这种双组分结构允许对转基因进行组合优化，并通过将逃逸问题限制在实验窗口期来提高安全性。我们使用 tGD 和一种小分子控制的版本来研究组分遗传和抗性等位基因形成的生物学特性，以及研究母系遗传和同源性受损对效率的影响。最后，对 tGD 在种群内传播的数学建模揭示了改善当前基因驱动技术以进行现场种群改造的潜在优势。
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