Requirements for Driving Antipathogen Effector Genes into Populations of Disease Vectors by Homing.
Requirements for Driving Antipathogen Effector Genes into Populations of Disease Vectors by Homing.
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DOI：
10.1534/genetics.116.197632
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发表时间：
2017-04
期刊：
影响因子：
3.3
通讯作者：
Burt A
中科院分区：
文献类型：
--
作者：
Beaghton A;Hammond A;Nolan T;Crisanti A;Godfray HC;Burt A
需要采取新的干预措施，减轻疟疾和登革热等病媒传染疾病的持续负担。一种建议是开发编码效应分子的基因，这些效应分子在载体内阻断寄生虫的发育，然后使用基于核酸酶的归巢反应作为基因驱动的一种形式，将这些基因传播到目标人群中。如果效应基因降低了蚊子的适应性，并且对驱动力没有贡献，那么效应基因中的功能丧失突变最终将取代功能性拷贝，但保护仍然可以持续足够长的时间，以提供公共健康益处。在这里，我们提出了一个定量模型，允许一个预测的保护时间作为不同的分子过程中归巢反应，各种健身效果的概率的函数，以及在阻断传输的效应器的功效。增加保护持续时间的因素包括降低预先存在的抗性等位基因的频率、非重组DNA修复的可能性、效应子归巢相关损失的可能性、核酸酶和效应子的适应性成本以及寄生虫阻断的完整性。对于在比典型扩散距离大得多的区域上延伸的目标物种，保护的持续时间预计在释放位点处最高，并且远离那里减少，最终下降到零，因为效应器较少的驱动结构取代了包含效应器的驱动结构。我们还模拟了一种替代策略，即使用核酸酶靶向必需基因，然后将效应子连接到恢复必需功能并对核酸酶具有抗性的序列。根据参数值，这种方法可以延长保护的持续时间。我们的模型强调了实现理想水平的公共卫生效益所需的关键设计标准。
There is a need for new interventions against the ongoing burden of vector-borne diseases such as malaria and dengue. One suggestion has been to develop genes encoding effector molecules that block parasite development within the vector, and then use the nuclease-based homing reaction as a form of gene drive to spread those genes through target populations. If the effector gene reduces the fitness of the mosquito and does not contribute to the drive, then loss-of-function mutations in the effector will eventually replace functional copies, but protection may nonetheless persist sufficiently long to provide a public health benefit. Here, we present a quantitative model allowing one to predict the duration of protection as a function of the probabilities of different molecular processes during the homing reaction, various fitness effects, and the efficacy of the effector in blocking transmission. Factors that increase the duration of protection include reducing the frequency of pre-existing resistant alleles, the probability of nonrecombinational DNA repair, the probability of homing-associated loss of the effector, the fitness costs of the nuclease and effector, and the completeness of parasite blocking. For target species that extend over an area much larger than the typical dispersal distance, the duration of protection is expected to be highest at the release site, and decrease away from there, eventually falling to zero, as effector-less drive constructs replace effector-containing ones. We also model an alternative strategy of using the nuclease to target an essential gene, and then linking the effector to a sequence that restores the essential function and is resistant to the nuclease. Depending upon parameter values, this approach can prolong the duration of protection. Our models highlight the key design criteria needed to achieve a desired level of public health benefit.