Department of Life Sciences, Imperial College, South Kensington, London SW7 2AZ, UK.
Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK.
Proc Biol Sci. 2019 Nov 6;286(1914):20191586. doi: 10.1098/rspb.2019.1586. Epub 2019 Oct 30.
Gene drive is a natural process of biased inheritance that, in principle, could be used to control pest and vector populations. As with any form of pest control, attention should be paid to the possibility of resistance evolving. For nuclease-based gene drive aimed at suppressing a population, resistance could arise by changes in the target sequence that maintain function, and various strategies have been proposed to reduce the likelihood that such alleles arise. Even if these strategies are successful, it is almost inevitable that alleles will arise at the target site that are resistant to the drive but do not restore function, and the impact of such sequences on the dynamics of control has been little studied. We use population genetic modelling of a strategy targeting a female fertility gene to demonstrate that such alleles may be expected to accumulate, and thereby reduce the reproductive load on the population, if nuclease expression causes substantial heterozygote fitness effects or if parental (especially paternal) deposition of nuclease either reduces offspring fitness or affects the genotype of their germline. All these phenomena have been observed in synthetic drive constructs. It will, therefore, be important to allow for non-functional resistance alleles in predicting the dynamics of constructs in cage populations and the impacts of any field release.
基因驱动是一种偏向遗传的自然过程，原则上可以用于控制害虫和病媒种群。与任何形式的害虫控制一样，应该注意到可能会产生抗药性。对于基于核酸酶的基因驱动，其目的是抑制种群，抗性可能是由于靶序列的变化而产生的，这些变化保持了功能，并且已经提出了各种策略来降低出现这种等位基因的可能性。即使这些策略取得成功，几乎不可避免的是，在靶位点会出现对驱动有抗性但不能恢复功能的等位基因，而这些序列对控制动态的影响还很少被研究。我们使用针对雌性生育基因的策略的群体遗传模型来证明，如果核酸酶表达导致大量杂合子适合度效应，或者如果核酸酶的亲本（特别是父本）沉积降低了后代的适合度或影响了它们生殖系的基因型，那么这些等位基因可能会积累，并因此降低种群的生殖负荷。所有这些现象都在合成驱动结构中观察到过。因此，在预测笼养种群中构建体的动态和任何野外释放的影响时，允许出现非功能性抗性等位基因是很重要的。
