Gene drives based on CRISPR-Cas9 technology are increasingly being considered as tools for reducing the capacity of mosquito populations to transmit malaria, and one of the most promising options is driving endonuclease genes that reduce the fertility of female mosquitoes. In particular, there is much interest in constructs that target the conserved mosquito doublesex (dsx) gene such that the emergence of functional drive-resistant alleles is unlikely. Proof of principle that these constructs can lead to substantial population suppression has been obtained in population cages, and they are being evaluated for use in sub-Saharan Africa. Here, we use simulation modelling to understand the factors affecting the spread of this type of gene drive over a one million-square kilometre area of West Africa containing substantial environmental and social heterogeneity. We found that a driving endonuclease gene targeting female fertility could lead to substantial reductions in malaria vector populations on a regional scale. The exact level of suppression is influenced by additional fitness costs of the transgene such as the somatic expression of Cas9, and its deposition in sperm or eggs leading to damage to the zygote. In the absence of these costs, or of emergent drive-resistant alleles that restore female fertility, population suppression across the study area is predicted to stabilise at ~ 95% 4 years after releases commence. Small additional fitness costs do not greatly affect levels of suppression, though if the fertility of females whose offspring transmit the construct drops by more than ~ 40%, then population suppression is much less efficient. We show the suppression potential of a drive allele with high fitness costs can be enhanced by engineering it also to express male bias in the progeny of transgenic males. Irrespective of the strength of the drive allele, the spatial model predicts somewhat less suppression than equivalent non-spatial models, in particular in highly seasonal regions where dry season stochasticity reduces drive efficiency. We explored the robustness of these results to uncertainties in mosquito ecology, in particular their method of surviving the dry season and their dispersal rates. The modelling presented here indicates that considerable suppression of vector populations can be achieved within a few years of using a female sterility gene drive, though the impact is likely to be heterogeneous in space and time.

中文翻译：

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使用 CRISPR-Cas9 基因驱动对疟疾载体的抑制进行建模，以降低女性生育能力。


基于 CRISPR-Cas9 技术的基因驱动越来越多地被认为是降低蚊子种群传播疟疾能力的工具，最有前途的选择之一是驱动核酸内切酶基因，从而降低雌性蚊子的生育能力。特别是，人们对针对保守的蚊子双性（dsx）基因的构建体非常感兴趣，因此不太可能出现功能性驱虫抗性等位基因。已经在种群笼中获得了这些结构可以导致大量种群抑制的原理证明，并且正在评估它们在撒哈拉以南非洲的使用。在这里，我们使用模拟模型来了解影响此类基因驱动在西非一百万平方公里地区传播的因素，该地区存在巨大的环境和社会异质性。我们发现，针对女性生育能力的驱动核酸内切酶基因可能会导致区域范围内疟疾媒介种群的大幅减少。确切的抑制水平受到转基因的额外适应成本的影响，例如 Cas9 的体细胞表达，以及它在精子或卵子中的沉积，导致受精卵受损。在没有这些成本的情况下，或者没有出现恢复女性生育能力的抗驱等位基因的情况下，预计在释放开始 4 年后，整个研究区域的种群抑制率将稳定在约 95%。少量的额外适应度成本不会对抑制水平产生太大影响，但如果其后代传播该结构的雌性的生育力下降超过 40%，那么种群抑制的效率就会低得多。 我们表明，具有高适应性成本的驱动等位基因的抑制潜力可以通过将其改造为在转基因雄性后代中表达雄性偏好来增强。无论驱动等位基因的强度如何，空间模型预测的抑制程度都比同等的非空间模型要少一些，特别是在旱季随机性降低驱动效率的季节性较强的地区。我们探讨了这些结果对蚊子生态学不确定性的稳健性，特别是它们在旱季的生存方法及其传播率。这里提出的模型表明，使用雌性不育基因驱动器的几年内可以实现对媒介种群的大量抑制，尽管其影响在空间和时间上可能是异质的。