Transposition of the Gnome MITE Family and its Development Toward a Gene Driver for Genetic Control of Mosquito-Borne Diseases

黄热病蚊是黄热病、登革热、基孔肯雅热等疾病病原体的重要传播媒介。大规模的蚊虫控制是一项具有挑战性的任务。蚊子的遗传控制是有前途的，而且比化学应用更环保。一种有吸引力的方法是种群替代，即少数对病原体具有抗性的蚊子可以在种群中传播耐药性，将防线推到病媒之外。这种方法的成功依赖于基因驱动系统来传播抗药性。

Yellow fever mosquito is an important vector for pathogens of diseases such as Yellow Fever, Dengue Fever and Chikungunya. Large scale mosquito control is a challenging task. Genetic control of mosquitoes is promising and more environmentally friendly than chemical applications. One attractive approach is population replacement where a small number of mosquitoes resistant to pathogens can spread the resistance in a population, pushing the defense line beyond the disease vectors. The success of this approach relies on a gene drive system to spread the resistance. Transposable elements (TEs), known as jumping genes, can increase their frequency in a population rapidly and are considered excellent candidates for a gene drive system. However, currently used TEs in the studies on the mosquito are from other species and typically remobilize inefficiently once they integrate into the chromosomes of the mosquito. Elements in mosquito that transpose and amplify efficiently are highly desirable. A group of TEs in plants and animals named miniature inverted repeat transposable elements (MITEs) bear these desirable features. Genome wide analyses of MITEs in the yellow fever mosquito in my lab identified its youngest and most likely active MITE family we named Gnome. However, this element does not carry the gene that produces the protein responsible for its mobilization. With major improvements of a computational tool name MITE Analysis Kit that I previously developed, an elusive single copy element we named Ozma was discovered to be the ancestral element of Gnome. Using an experimental system I previously established for rice elements, preliminary studies suggest that the Ozma transposase, protein that moves TEs, is capable of mobilizing Gnome in yeast. Here I propose detailed studies on these elements to deepen our knowledge on the transposition mechanisms of Gnome and related elements, understand their current activity in mosquito and use them as genetic tools. To achieve these goals, we will perform the following studies: (1) Characterization of Gnome transposition and Ozma transposase to reveal important features; (2) Analyses of the activities of MITE families and their autonomous element in mosquito; (3) Development of MITE based cargo gene vectors and remobilization systems. We will use a combined approach of molecular biology and computational biology in these studies. The proposed studies will reveal the secrets of the mechanisms underlying the transposition and amplification of the youngest MITE family in the mosquito genome. It will make important contributions to our knowledge on genome evolution. The elements we will analyze in these studies are potentially efficient novel genetic tools for scientific research and practical applications such as transgenesis, gene therapy and genetic control of pest insects. During the studies, highly qualified personnel including postdoctoral fellows, graduate students and undergraduate students will be trained in my lab. Therefore, the proposed research will not only generate new knowledge for the research community, but will also contribute to the Canadian economy in the areas of education, medicine and environment protection.