BACKGROUND AND OBJECTIVES Genetic engineering combined with CRISPR technology has developed to the point that gene drives can, in theory, be engineered to cause extinction in countless species. Success of extinction programs now rests on the possibility of resistance evolution, which is largely unknown. Depending on the gene-drive technology, resistance may take many forms, from mutations in the nuclease target sequence (e.g. for CRISPR) to specific types of non-random population structures that limit the drive (that may block potentially any gene-drive technology). METHODOLOGY We develop mathematical models of various deviations from random mating to consider escapes from extinction-causing gene drives. A main emphasis here is sib mating in the face of recessive-lethal and Y-chromosome drives. RESULTS Sib mating easily evolves in response to both kinds of gene drives and maintains mean fitness above 0, with equilibrium fitness depending on the level of inbreeding depression. Environmental determination of sib mating (as might stem from population density crashes) can also maintain mean fitness above 0. A version of Maynard Smith's haystack model shows that pre-existing population structure can enable drive-free subpopulations to be maintained against gene drives. CONCLUSIONS AND IMPLICATIONS Translation of mean fitness into population size depends on ecological details, so understanding mean fitness evolution and dynamics is merely the first step in predicting extinction. Nonetheless, these results point to possible escapes from gene-drive-mediated extinctions that lie beyond the control of genome engineering. LAY SUMMARY Recent gene drive technologies promise to suppress and even eradicate pests and disease vectors. Simple models of gene-drive evolution in structured populations show that extinction-causing gene drives can be thwarted both through the evolution of sib mating as well as from purely demographic processes that cluster drive-free individuals.

中文翻译：

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种群结构和同胞交配的进化阻碍了基因驱动介导的灭绝。

背景和目标 基因工程与 CRISPR 技术相结合已经发展到基因驱动在理论上可以被设计成导致无数物种灭绝的程度。灭绝计划的成功现在取决于抗性进化的可能性，这在很大程度上是未知的。根据基因驱动技术，抗性可能有多种形式，从核酸酶靶序列的突变（例如对于 CRISPR）到限制驱动的特定类型的非随机群体结构（可能会阻止任何基因驱动技术） . 方法我们开发了随机交配的各种偏差的数学模型，以考虑从引起灭绝的基因驱动中逃脱。这里的一个主要重点是面对隐性致死和 Y 染色体驱动的同胞交配。结果 同胞交配很容易响应两种基因驱动而进化，并保持平均适应度高于 0，平衡适应度取决于近交抑制的水平。同胞交配的环境确定（可能源于人口密度崩溃）也可以将平均适应度保持在 0 以上。Maynard Smith 的干草堆模型的一个版本表明，预先存在的种群结构可以使无驱动的亚种群能够维持免受基因驱动。结论和意义 将平均适应度转化为种群规模取决于生态细节，因此了解平均适应度演化和动态仅仅是预测灭绝的第一步。尽管如此，这些结果表明基因驱动介导的灭绝可能会逃脱基因组工程的控制。总结 最近的基因驱动技术有望抑制甚至根除害虫和疾病媒介。结构化种群中基因驱动进化的简单模型表明，导致灭绝的基因驱动可以通过同胞交配的进化以及聚集无驱动个体的纯粹人口统计过程来阻止。