Modelling the suppression of a malaria vector using a CRISPR-Cas9 gene drive to reduce female fertility
Modelling the suppression of a malaria vector using a CRISPR-Cas9 gene drive to reduce female fertility
复制标题
DOI：
10.1186/s12915-020-00834-z
复制
发表时间：
2020-08-11
期刊：
影响因子：
5.4
通讯作者：
Godfray, H. Charles J.
中科院分区：
文献类型：
--
作者：
North, Ace R.;Burt, Austin;Godfray, H. Charles J.
背景：基于CRISPR-Cas9技术的基因驱动越来越被认为是降低蚊子种群传播疟疾能力的工具，其中最有希望的选择之一是驱动降低雌蚊繁殖能力的内切酶基因。特别是，人们对针对保守的蚊子双性（dsx）基因的构建非常感兴趣，这样就不太可能出现功能性驱动抗性等位基因。在种群笼中已经获得了这些结构可导致大量种群抑制的原理证据，目前正在评估它们在撒哈拉以南非洲的使用情况。在这里，我们使用模拟模型来了解影响这种类型的基因驱动在西非一百万平方公里地区传播的因素，该地区包含大量的环境和社会异质性。结果：我们发现一种以女性生育能力为目标的驱动内切酶基因可以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额外适应度成本的影响，例如Cas9的体细胞表达，以及它在精子或卵子中的沉积导致合子损伤。在没有这些成本的情况下，或者由于出现了能够恢复女性生育能力的抗驱动等位基因，预计在释放开始4年后，整个研究区域的人口抑制将稳定在95%左右。小的额外适应度成本不会对抑制水平产生很大影响，但如果其后代的生育能力下降了40%以上，那么种群抑制的效率就会低得多。我们发现高适应度成本驱动等位基因的抑制潜力可以通过工程来增强，也可以在转基因雄性的后代中表达雄性偏见。无论驱动等位基因的强度如何，空间模型预测的抑制程度略低于等效的非空间模型，特别是在旱季随机性降低驱动效率的高度季节性地区。我们探讨了这些结果对蚊子生态不确定性的稳健性，特别是它们在旱季生存的方法和它们的扩散率。结论：这里提出的模型表明，使用雌性不育基因驱动可以在几年内实现对病媒种群的相当大的抑制，尽管影响可能在空间和时间上是异质的。
Background: 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.Results: 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 similar to 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 similar to 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.Conclusions: 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.