Department of Computational Biology, Cornell University, Ithaca, NY, 14853, USA.
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, 14853, USA.
BMC Biol. 2022 May 24;20(1):119. doi: 10.1186/s12915-022-01292-5.
Homing gene drives hold great promise for the genetic control of natural populations. However, current homing systems are capable of spreading uncontrollably between populations connected by even marginal levels of migration. This could represent a substantial sociopolitical barrier to the testing or deployment of such drives and may generally be undesirable when the objective is only local population control, such as suppression of an invasive species outside of its native range. Tethered drive systems, in which a locally confined gene drive provides the CRISPR nuclease needed for a homing drive, could provide a solution to this problem, offering the power of a homing drive and confinement of the supporting drive.
Here, we demonstrate the engineering of a tethered drive system in Drosophila, using a regionally confined CRISPR Toxin-Antidote Recessive Embryo (TARE) drive to support modification and suppression homing drives. Each drive was able to bias inheritance in its favor, and the TARE drive was shown to spread only when released above a threshold frequency in experimental cage populations. After the TARE drive had established in the population, it facilitated the spread of a subsequently released split homing modification drive (to all individuals in the cage) and of a homing suppression drive (to its equilibrium frequency).
Our results show that the tethered drive strategy is a viable and easily engineered option for providing confinement of homing drives to target populations.
归巢基因驱动系统在自然种群的遗传控制方面具有巨大的应用前景。然而，当前的归巢系统在通过迁移连接的种群之间会不可控地传播。这可能是对这些驱动系统进行测试或部署的一个重大社会政治障碍，而当目标只是对局部种群进行控制时，例如在其原生范围之外抑制入侵物种，这通常是不可取的。在这种情况下，采用束缚驱动系统（tethered drive system）可能是一种解决方案，这种系统中，局部受限的基因驱动系统提供了归巢驱动所需的 CRISPR 核酸酶，既提供了归巢驱动的功能，又限制了支持驱动的范围。
在这里，我们展示了在果蝇中设计束缚驱动系统的方法，使用局部受限的 CRISPR 毒素-抗毒素隐性胚胎（TARE）驱动来支持修饰和抑制归巢驱动。每个驱动都能够偏向于自身的遗传，并且只有在实验笼种群中释放的频率超过阈值时，TARE 驱动才会传播。在 TARE 驱动在种群中建立后，它促进了随后释放的分裂归巢修饰驱动（传播到笼子中的所有个体）和归巢抑制驱动（传播到其平衡频率）的传播。
我们的研究结果表明，束缚驱动策略是一种可行且易于设计的选择，可将归巢驱动限制在目标种群中。
