A transcomplementing gene drive provides a flexible platform for laboratory investigation and potential field deployment
A transcomplementing gene drive provides a flexible platform for laboratory investigation and potential field deployment
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DOI：
10.1038/s41467-019-13977-7
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发表时间：
2020-01-17
影响因子：
16.6
通讯作者：
Gantz, Valentino M.
中科院分区：
文献类型：
--
作者：
Del Amo, Victor Lopez;Bishop, Alena L.;Gantz, Valentino M.
基于CRISPR的基因驱动可以通过将其自身的传播偏置到孟德尔遗传预测的50%以上的值来在野生种群中传播。这些技术为防治病媒传播疾病、管理作物害虫和支持生态系统保护工作提供了种群工程解决方案。目前的技术引起了对非预期基因繁殖的安全性担忧。在本文中，我们通过将驱动组件Cas9和gRNA分裂成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这些问题。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增加安全性。我们采用tGD和小分子控制的版本，调查生物学的组件遗传和抗性等位基因的形成，并研究母性遗传和受损的同源性对效率的影响。最后，群体内tGD传播的数学建模揭示了改进当前用于田间群体修饰的基因驱动技术的潜在优势。基因驱动引发了人们对意外传播的安全担忧。在这里，作者提出了一个反式互补的分裂基因驱动，需要继承单独的转基因组装一个完整的功能驱动。
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. Gene drives raise safety concerns around unintended propagation. Here the authors present a trans-complementing split-gene drive that requires inheritance of separate transgenes to assemble a fully functional drive.