Center for Bioinformatics, School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
ACS Synth Biol. 2023 Mar 17;12(3):809-819. doi: 10.1021/acssynbio.2c00611. Epub 2023 Feb 24.
Though engineered gene drives hold great promise for spreading through and suppressing populations of disease vectors or invasive species, complications such as resistance alleles and spatial population structure can prevent their success. Additionally, most forms of suppression drives, such as homing drives or driving Y chromosomes, will generally spread uncontrollably between populations with even small levels of migration. The previously proposed CRISPR-based toxin-antidote system called toxin-antidote dominant embryo (TADE) suppression drive could potentially address the issues of confinement and resistance. However, it is a relatively weak form of drive compared to homing drives, which might make it particularly vulnerable to spatial population structure. In this study, we investigate TADE suppression drive using individual-based simulations in a continuous spatial landscape. We find that the drive is actually more confined than in simple models without space, even in its most efficient form with low cleavage rate in embryos from maternally deposited Cas9. Furthermore, the drive performed well in continuous space scenarios if the initial release requirements were met, suppressing the population in a timely manner without being severely affected by chasing, a phenomenon in which wild-type individuals avoid the drive by recolonizing empty areas. At higher embryo cut rates, the drive loses its ability to spread, but a single, widespread release can often still induce rapid population collapse. Thus, if TADE suppression gene drives can be successfully constructed, they may play an important role in control of disease vectors and invasive species when stringent confinement to target populations is desired.
尽管基因驱动工程具有很大的潜力，可以在疾病媒介或入侵物种的种群中传播并抑制其数量，但诸如抗性等位基因和空间种群结构等复杂因素可能会阻碍其成功。此外，大多数形式的抑制驱动，如归巢驱动或驱动 Y 染色体，通常会在种群间不受控制地传播，即使是在迁徙水平较低的情况下。之前提出的基于 CRISPR 的毒素-解毒剂系统称为毒素-解毒剂显性胚胎（TADE）抑制驱动，可能能够解决隔离和抗性的问题。然而，与归巢驱动相比，它是一种相对较弱的驱动形式，这可能使其特别容易受到空间种群结构的影响。在这项研究中，我们使用基于个体的模拟方法在连续的空间景观中研究 TADE 抑制驱动。我们发现，即使在母体 Cas9 中胚胎的切割率较低的最有效形式下，驱动实际上比没有空间的简单模型更受限制。此外，如果满足初始释放要求，驱动在连续空间场景中表现良好，可以及时抑制种群，而不会受到追逐现象的严重影响，即野生型个体通过重新殖民空地区域来躲避驱动。在较高的胚胎切割率下，驱动会失去传播能力，但单次广泛的释放通常仍能迅速导致种群崩溃。因此，如果 TADE 抑制基因驱动可以成功构建，当需要严格限制目标种群时，它们可能在疾病媒介和入侵物种的控制中发挥重要作用。
