Synthetic gene drive constructs could, in principle, provide the basis for highly efficient interventions to control disease vectors and other pest species. This efficiency derives in part from leveraging natural processes of dispersal and gene flow to spread the construct and its impacts from one population to another. However, sometimes (for example, with invasive species) only specific populations are in need of control, and impacts on non-target populations would be undesirable. Many gene drive designs use nucleases that recognise and cleave specific genomic sequences, and one way to restrict their spread would be to exploit sequence differences between target and non-target populations. In this paper we propose and model a series of low threshold double drive designs for population suppression, each consisting of two constructs, one imposing a reproductive load on the population and the other inserted into a differentiated locus and controlling the drive of the first. Simple deterministic, discrete-generation computer simulations are used to assess the alternative designs. We find that the simplest double drive designs are significantly more robust to pre-existing cleavage resistance at the differentiated locus than single drive designs, and that more complex designs incorporating sex ratio distortion can be more efficient still, even allowing for successful control when the differentiated locus is neutral and there is up to 50% pre-existing resistance in the target population. Similar designs can also be used for population replacement, with similar benefits. A population genomic analysis of PAM sites in island and mainland populations of the malaria mosquito Anopheles gambiae indicates that the differentiation needed for our methods to work can exist in nature. Double drives should be considered when efficient but localised population genetic control is needed and there is some genetic differentiation between target and non-target populations.

中文翻译：

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双驱动和私人等位基因用于局部种群遗传控制

原则上，合成基因驱动构建体可以为控制疾病载体和其他害虫物种的高效干预措施提供基础。这种效率部分源于利用自然的扩散和基因流动过程将构建体及其影响从一个种群传播到另一个种群。但是，有时（例如，对于入侵物种）仅需要控制特定的种群，因此对非目标种群的影响将是不可取的。许多基因驱动设计使用识别和切割特定基因组序列的核酸酶，而限制其扩散的一种方法是利用靶标和非靶标群体之间的序列差异。在本文中，我们提出并建模了一系列用于人口抑制的低阈值双驱动器设计，每个设计均由两个结构组成，一个将繁殖负荷强加到种群上，另一个插入差异化基因座并控制第一个的驱动力。简单的确定性，离散代计算机模拟用于评估替代设计。我们发现，最简单的双驱动器设计比差分驱动器在区分位点上对预先存在的抗劈裂性要强得多，并且结合性别比例失真的更复杂的设计仍然可以更加有效，即使在区分时也可以成功进行控制。基因座是中性的，在目标人群中存在高达50％的预先存在的抗药性。类似的设计也可以用于人口置换，具有类似的好处。疟疾冈比亚按蚊的海岛和大陆人群中PAM站点的人群基因组学分析表明，我们的工作方法所需的差异可以自然存在。当需要有效但局部的种群遗传控制并且目标人群和非目标人群之间存在某种遗传差异时，应考虑双重驱动。