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，埃及伊蚊是人类虫媒疾病的主要载体，已知每年感染全球5000万至1亿人，造成数百万人死亡。目前用于预防登革热的方法，包括通过改变环境、杀虫剂和抗病原体药物来抑制病媒，根本不够。用经过基因改造的个体取代野生蚊子种群，从理论上讲，这些个体被改造成“抗病”的，这应该为疾病预防提供一种可持续的长期方法。然而，介导疾病难治性的转基因不太可能赋予携带它们的昆虫整体健康益处。此外，野生种群很大，部分生殖隔离，并分散在广阔的地区。因此，种群更替需要基因驱动机制，以便通过野生种群传播介导疾病难治性的连锁货物基因。我以前已经开发了多种合成自私的遗传元素，包括母亲效应显性胚胎逮捕（美狄亚），最近在昆虫中的阈值依赖的欠显性系统（UDmel），可以迅速通过种群传播，即使在存在一个链接的货物难治基因，可能会大幅增加健身成本。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中。因此，该提案的主要目的是开发三个系统：1）美狄亚，2）阈值依赖的欠显性（UDmel），以及3）可以快速传播和破坏种群的自私遗传元件，所有这些都在登革热媒介埃及伊蚊中。这些基因驱动系统中的每一个都具有对于野生转基因释放的社会和科学接受重要的几个有吸引力的特征：该系统是物种特异性的，并且与其他物种的水平传播是有限的;与杀虫剂相比，最小的生态影响;自私的遗传元件与其货物的紧密联系相对稳健和牢不可破;如果需要，可以进行转基因回忆（对于美狄亚）和完全转基因去除（显性不足）。总之，该提案的总体目标是在蚊子中开发多种种群控制技术，这些技术可以成功且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.