Maternal-effect selfish element as gene drive for Anopheles mosquitoes

描述（由申请人提供）：按蚊是疟疾的主要媒介，疟疾是人类历史上最致命和最昂贵的疾病之一。随着杀虫剂和药物抗药性的增加，控制疟疾的措施越来越不有效。显然，迫切需要新的办法。一种控制蚊媒疾病的新策略提出将所谓的效应基因或抗性基因引入蚊子，使蚊子成为病原体的无效载体。开发在自然群体中驱动效应基因的方法是当务之急。这项研究的长期目标是开发一种有效和安全的基因驱动机制，使控制蚊媒传染病的遗传策略成为可能。最近，Chen及其同事（2007）报道了在果蝇中创建一种名为Medea的合成遗传元件，该元件在实验室中成功地驱动了种群更替。果蝇美狄亚元件由两部分组成，一个是以人工microRNA形式表达的母体毒素，它抑制Myd 88，这是早期胚胎发育的必需基因，另一个是以Myd 88变体形式表达的合子解毒剂，它缺乏microRNA靶标，因此对毒素不敏感。基于我们的初步结果，我们将测试的假设，合成美狄亚基因驱动系统可以在斯氏按蚊开发。我们将1）确定在卵子发生和早期胚胎发生在An的转录组谱。（2）选择和测试安. stephensi Medea; 3）构造一个完整的An. stephensi Medea元件，并对其母效自私特性和基因驱动能力进行了测试。

DESCRIPTION (provided by applicant): Anopheline mosquitoes are the primary vectors of malaria, one of the deadliest and most costly diseases in human history. Measures to control malaria are becoming less effective as both insecticide- and drug-resistance increases. It is clear that new approaches are urgently needed. A new strategy to control mosquito-borne diseases proposes to introduce so-called effector genes or refractory genes into the mosquito that will render the mosquitoes ineffective vectors for pathogens. Developing the means to drive effector genes in natural populations is an urgent priority. The long term objective of this study is to develop an efficient and safe gene drive mechanism that will enable genetic strategies for the control of mosquito-borne infectious diseases. Recently, Chen and colleagues (2007) reported the creation of a synthetic genetic element called Medea in Drosophila that successfully drove population replacement in laboratory. The Drosophila Medea element consists of two parts, a maternally expressed toxin in the form of artificial microRNAs that suppress Myd88, an essential gene for early embryonic development, and a zygotic antidote in the form of a variant of Myd88 that lacks the microRNA targets thus insensitive to the toxin. Building on our preliminary results, we will test the hypothesis that a synthetic Medea gene drive system can be developed in Anopheles stephensi. We will 1) determine the transcriptome profiles during oogenesis and early embryogenesis in An. stephensi; 2) select and test components of An. stephensi Medea; and 3) construct a complete An. stephensi Medea element and test for its maternal-effect selfish characteristics and gene drive ability.