CRISPR gene drive systems offer a mechanism for transmitting a desirable transgene throughout a population for purposes ranging from vector‐borne disease control to invasive species suppression. In this simulation study, we assess the performance of several CRISPR‐based underdominance gene drive constructs employing toxin‐antidote (TA) principles. These drives disrupt the wild‐type version of an essential gene using a CRISPR nuclease (the toxin) while simultaneously carrying a recoded version of the gene (the antidote). Drives of this nature allow for releases that could be potentially confined to a desired geographic location. This is because such drives have a nonzero‐invasion threshold frequency required for the drive to spread through the population. We model drives which target essential genes that are either haplosufficient or haplolethal, using nuclease promoters with expression restricted to the germline, promoters that additionally result in cleavage activity in the early embryo from maternal deposition, and promoters that have ubiquitous somatic expression. We also study several possible drive architectures, considering both “same‐site” and “distant‐site” systems, as well as several reciprocally targeting drives. Together, these drive variants provide a wide range of invasion threshold frequencies and options for both population modification and suppression. Our results suggest that CRISPR TA underdominance drive systems could allow for the design of flexible and potentially confinable gene drive strategies.

中文翻译：

---

基于 CRISPR 的弱毒素解毒基因驱动的设计和分析


CRISPR 基因驱动系统提供了一种在整个群体中传输所需转基因的机制，其目的包括媒介传播疾病控制和入侵物种抑制等。在这项模拟研究中，我们利用毒素解毒剂 (TA) 原理评估了几种基于 CRISPR 的弱优势基因驱动结构的性能。这些驱动器使用 CRISPR 核酸酶（毒素）破坏必需基因的野生型版本，同时携带该基因的重新编码版本（解毒剂）。这种性质的驱动器允许将发布限制在所需的地理位置。这是因为此类驱动器具有在人群中传播所需的非零入侵阈值频率。我们使用表达限于种系的核酸酶启动子、额外导致早期胚胎从母体沉积中产生裂解活性的启动子以及具有普遍存在的体细胞表达的启动子，对针对单倍足或单致死的必需基因的驱动进行建模。我们还研究了几种可能的驱动器架构，考虑“同一站点”和“远程站点”系统，以及几种相互定位的驱动器。这些驱动变体共同提供了广泛的入侵阈值频率以及群体修改和抑制的选项。我们的结果表明，CRISPR TA 弱驱动系统可以允许设计灵活且可能受限的基因驱动策略。