Synthetically engineering population control systems in vectors of human disease

描述（由申请人提供）：拟议的工作是在登革热蚊子（埃及伊蚊）中设计多个独立的侵入性基因驱动系统，登革热蚊子是人类虫媒疾病的主要媒介，已知每年感染全球5000万至1亿人，造成数百万人死亡。目前用于登革热预防的方法，包括通过环境改造、杀虫剂和抗病原体药物来抑制病媒，根本是不够的。从理论上讲，用经过基因改造的“抗病”个体取代野生蚊子种群，应该为疾病预防提供一种可持续的长期方法。然而，介导疾病抗性的转基因不太可能给携带它们的昆虫带来全面的健康益处。此外，野生种群很大，部分繁殖隔离，分散在广泛的地区。因此，种群更替需要一种基因驱动机制，以便在野生种群中传播介导疾病难愈性的相关货物基因。我之前已经开发了多种合成的自私遗传元素，包括母系效应-显性-胚胎-抑制（Medea），以及最近在昆虫中发现的一种阈值依赖性劣势系统（UDmel），这种系统可以在种群中迅速传播，即使存在关联的货物难解基因，也可能导致适应性成本的大幅增加。在这里，我建议简单地将这些合成系统转移到一种传播疾病的昆虫，埃及伊蚊。因此，本提案的主要目标是开发三个系统：1)Medea, 2)阈值依赖性欠优势（UDmel），以及3)自私的遗传因素，可以迅速传播并摧毁一个种群，所有这些都在登革热媒介埃及伊蚊中。每一种基因驱动系统都有几个吸引人的特点，这对社会和科学接受野生转基因释放很重要：这些系统是物种特异性的，与其他物种的水平传播是有限的；与杀虫剂相比，生态影响最小；相对健壮和牢不可破，自私的遗传因素与它的货物紧密相连；如果需要，可以进行转基因召回（美狄亚）和完全转基因去除（劣势）。总之，本提案的总体目标是开发多种蚊子种群控制技术，这些技术可以成功和安全地应用于对抗人类疾病。

DESCRIPTION (provided by applicant): The proposed work is to engineer multiple independent invasive gene drive systems in the Dengue mosquito, Aedes aegypti, a major vector of human insect-borne disease known to annually infect 50-100 million people worldwide, killing millions. The current approaches used for Dengue disease prevention, including vector suppression by environmental modification, insecticides and anti-pathogen drugs are simply insufficient. The replacement of wild mosquito populations with genetically modified individuals that are engineered to be "disease resistant" in theory should provide a sustainable long-term method for disease prevention. However, the transgenes that mediate the disease refractoriness are unlikely to confer an overall fitness benefit on insects that carry them. Additionally, wild populations are large, partially reproductively isolated, and dispersed over wide areas. Therefore, population replacement requires a gene drive mechanism in order to spread linked cargo genes mediating disease refractoriness through wild populations. I have previously developed multiple synthetic selfish genetic elements including Maternal-Effect-Dominant-Embryonic-Arrest (Medea) and recently a threshold dependent underdominance system (UDmel) in insects that can rapidly spread through populations, even in the presence of a linked cargo refractory gene that may impose a large increase in fitness cost. Here I propose to simply transfer these synthetic systems into an insect that vectors disease, Aedes aegypti. Therefore, the major aims of this proposal are to develop three systems: 1) Medea, 2) Threshold dependent underdominance (UDmel), and 3) a selfish genetic element the can rapidly spread and crash a population, all in the Dengue vector, Aedes aegypti. Each of these gene drive systems have several attractive features important for social and scientific acceptance for wild transgene releases: the systems are species specific and horizontal spread with other species is limited; minimal ecological impact in contrast to insecticides; relatively robust and unbreakable with a tight linkage of the selfish genetic element with its cargo; transgene recall (for Medea) and complete transgene removal (underdominance) can be carried out if desired. In summary, the overall goal of this proposal is to develop multiple population control technologies in the mosquito that can be applied successfully and safely to fight human disease.