CRISPR gene drive systems allow the rapid spread of a genetic construct throughout a population. Such systems promise novel strategies for the management of vector-borne diseases and invasive species by suppressing a target population or modifying it with a desired trait. However, current homing-type drives have two potential shortcomings. First, they can be thwarted by the rapid evolution of resistance. Second, they lack any mechanism for confinement to a specific target population. In this study, we conduct a comprehensive performance assessment of several new types of CRISPR-based gene drive systems employing toxin-antidote (TA) principles, which should be less prone to resistance and allow for the confinement of drives to a target population due to invasion frequency thresholds. The underlying principle of the proposed CRISPR toxin-antidote gene drives is to disrupt an essential target gene while also providing rescue by a recoded version of the target as part of the drive allele. Thus, drive alleles tend to remain viable, while wild-type targets are disrupted and often rendered nonviable, thereby increasing the relative frequency of the drive allele. Using individual-based simulations, we show that Toxin-Antidote Recessive Embryo (TARE) drives targeting an haplosufficient but essential gene (lethal when both copies are disrupted) can enable the design of robust, regionally confined population modification strategies with high flexibility in choosing promoters and targets. Toxin-Antidote Dominant Embryo (TADE) drives require a haplolethal target gene and a germline-restricted promoter, but they could permit faster regional population modification and even regionally confined population suppression. Toxin-Antidote Dominant Sperm (TADS) drives can be used for population modification or suppression. These drives are expected to spread rapidly and could employ a variety of promoters, but unlike TARE and TADE, they would not be regionally confined and also require highly specific target genes. Overall, our results suggest that CRISPR-based TA gene drives provide promising candidates for flexible ecological engineering strategies in a variety of organisms.

中文翻译：

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新型毒素解毒剂CRISPR基因驱动系统的性能分析。

CRISPR基因驱动系统允许遗传构建体在整个种群中快速传播。这样的系统有望通过抑制目标种群或使其具有所需特性对其进行控制，从而为媒介传播疾病和入侵物种的管理提供了新的策略。但是，当前的归位型驱动器具有两个潜在的缺点。首先，抵抗运动的迅速发展可能会阻碍它们。其次，他们缺乏将机制局限于特定目标人群的任何机制。在这项研究中，我们对几种采用毒素-解毒剂（TA）原理的新型基于CRISPR的基因驱动系统进行了全面的性能评估，该系统应较不易产生耐药性，并且由于以下原因而只能将驱动作用局限于目标人群入侵频率阈值。拟议的CRISPR毒素解毒剂基因驱动器的基本原理是破坏必需的靶基因，同时还通过作为驱动等位基因一部分的靶标的重新编码版本提供拯救。因此，驱动等位基因倾向于保持活力，而野生型靶标则被破坏并且常常变得不可行，从而增加了驱动等位基因的相对频率。使用基于个体的模拟，我们显示了针对有毒的但必不可少的基因（当两个拷贝都被破坏时具有致命性）的毒素-解毒剂隐性胚胎（TARE）驱动器可以设计出鲁棒的，区域受限的种群修饰策略，并在选择启动子时具有高度灵活性和目标。毒素解毒剂优势胚胎（TADE）驱动器需要单倍体靶基因和种系限制性启动子，但它们可以允许更快地修改区域人口，甚至可以抑制区域限制的人口。毒素解毒剂占优势的精子（TADS）驱动器可用于群体修饰或抑制。这些驱动器有望迅速传播并可以使用多种启动子，但与TARE和TADE不同，它们不会受到区域限制，还需要高度特异性的靶基因。总体而言，我们的结果表明，基于CRISPR的TA基因驱动器为多种生物的灵活生态工程策略提供了有希望的候选者。但是与TARE和TADE不同，它们不会受到区域限制，还需要高度特异性的靶基因。总体而言，我们的结果表明，基于CRISPR的TA基因驱动器为多种生物的灵活生态工程策略提供了有希望的候选者。但是与TARE和TADE不同，它们不会受到区域限制，还需要高度特异性的靶基因。总体而言，我们的结果表明，基于CRISPR的TA基因驱动器为多种生物的灵活生态工程策略提供了有希望的候选者。