School of Biological Sciences, Washington State University, Pullman, WA 99164, USA.
Department of Biological Sciences, University of Idaho, Moscow, ID 83844, USA.
Genetics. 2021 Feb 9;217(2). doi: 10.1093/genetics/iyaa040.
Gene drives offer the possibility of altering and even suppressing wild populations of countless plant and animal species, and CRISPR technology now provides the technical feasibility of engineering them. However, population-suppression gene drives are prone to select resistance, should it arise. Here, we develop mathematical and computational models to identify conditions under which suppression drives will evade resistance, even if resistance is present initially. Previous models assumed resistance is allelic to the drive. We relax this assumption and show that linkage between the resistance and drive loci is critical to the evolution of resistance and that evolution of resistance requires (negative) linkage disequilibrium between the two loci. When the two loci are unlinked or only partially so, a suppression drive that causes limited inviability can evolve to fixation while causing only a minor increase in resistance frequency. Once fixed, the drive allele no longer selects resistance. Our analyses suggest that among gene drives that cause moderate suppression, toxin-antidote systems are less apt to select for resistance than homing drives. Single drives of moderate effect might cause only moderate population suppression, but multiple drives (perhaps delivered sequentially) would allow arbitrary levels of suppression. The most favorable case for evolution of resistance appears to be with suppression homing drives in which resistance is dominant and fully suppresses transmission distortion; partial suppression by resistance heterozygotes or recessive resistance are less prone to resistance evolution. Given that it is now possible to engineer CRISPR-based gene drives capable of circumventing allelic resistance, this design may allow for the engineering of suppression gene drives that are effectively resistance-proof.
基因驱动为改变甚至抑制无数动植物物种的野生种群提供了可能性，而 CRISPR 技术现在为基因工程提供了技术可行性。然而，种群抑制基因驱动容易选择抗性，如果出现抗性的话。在这里，我们开发了数学和计算模型来确定在什么条件下抑制驱动可以逃避抗性，即使最初存在抗性。以前的模型假设抗性与驱动等位基因。我们放宽了这个假设，并表明抗性和驱动基因座之间的连锁对于抗性的进化至关重要，并且抗性的进化需要两个基因座之间的（负）连锁不平衡。当两个基因座不连锁或只有部分连锁时，一个导致有限不育的抑制驱动可以进化到固定，而只导致抗性频率的轻微增加。一旦固定，驱动等位基因不再选择抗性。我们的分析表明，在导致中度抑制的基因驱动中，毒素-解毒系统比同源驱动不太容易选择抗性。中度效应的单一驱动可能只会导致中度的种群抑制，但多个驱动（可能依次传递）将允许任意水平的抑制。对于抗性进化最有利的情况似乎是抑制同源驱动，其中抗性是显性的，完全抑制了传播扭曲；抗性杂合子或隐性抗性的部分抑制不太容易产生抗性进化。鉴于现在已经可以设计基于 CRISPR 的基因驱动来规避等位基因抗性，这种设计可能允许设计出有效的抗性基因抑制驱动。
