Guy1-conferred female lethality: mechanism and application for mosquito control

Guy1赋予女性致死性：蚊子控制机制及应用

• 批准号: 9008131
• 负责人: Zhijian Jake Tu
• 金额: $ 39.48万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-09 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9008131
• 关键词: Alleles; Anopheles Genus; Biology; Bite; Blood; Bombyx mori; Caenorhabditis elegans; Culicidae; DNA Binding; DNA Binding Domain; Data; Disease; Dosage Compensation (Genetics); Drosophila melanogaster; Embryo; Embryonic Development; Ensure; Female; Fertility; Gene Expression; Generations; Genes; Genetic; Genetic Transcription; Genomics; Genotype; Goals; Heterozygote; Individual; Initiator Codon; Insecta; Insecticide Resistance; Laboratories; Lead; Link; Malaria; Measures; Methods; Molecular; Morus; Mosquito Control; Mosquito-borne infectious disease; Nature; Nonsense Codon; Open Reading Frames; Partner in relationship; Pathway interactions; Pharmaceutical Preparations; Phenotype; Point Mutation; Population; Production; Property; Proteins; Province; Refractory; Regulation; Reproduction; Resources; Sex Behavior; Sex Ratio; Siblings; Signal Pathway; Spermatogenesis; Sterility; Synthetic Genes; Techniques; Testing; Time; Transgenes; Transgenic Organisms; Y Chromosome; combat; cost effective; disease transmission; disorder control; feeding; gene product; genetic approach; genetic resource; hatching; improved; interest; knock-down; loss of function; male; mating behavior; novel; novel strategies; pathogen; practical application; public health relevance; sex; sex determination; sexual debut; vector

 DESCRIPTION (provided by applicant): Anopheles mosquitoes are the primary vectors of malaria, one of humankind's most deadly and costly diseases. Malaria control measures are under increasing threat as drug- and insecticide- resistance spreads. Recently developed genomic resources and genetic methods provide unprecedented opportunities to improve our understanding of mosquito biology and develop new strategies to combat malaria and other mosquito-borne diseases. Y chromosome remains unexplored in Anopheles mosquitoes despite its importance in male determination and other aspects of male biology. Since blood feeding and, consequently, the transmission of disease pathogens is the sole province to female mosquitoes, it is critical to release only males when implementing genetic approaches for reducing mosquito populations or for replacing competent vector populations with populations that are refractory to disease transmission. Overcoming technical bottlenecks, we have recently uncovered four Y genes in An. stephensi. Among these, Guy1 is the best candidate for the male-determining M factor. Multiple Guy1-expressing transgenic lines were generated, which produced 6520 transgenic males and 0 transgenic females over multiple generations. Our preliminary data also suggest that the observed 100% female lethality in the Guy1 transgenic An. stephensi may result from mis-regulation of dosage compensation. Importantly, three known master switches of sex-determination, sex-lethal, Fem/Masc, xo-lethal 1, also directly or indirectly regulate dosage compensation in Drosophila melanogaster, Bombyx mori, and Caenorhabditis elegans, respectively. Loss of function sex- lethal alleles and knockdown of the target of Masc cause female embryonic lethality in D. melanogaster and B. mori, respectively. Here, we will test the hypothesis that the An. stephensi Guy1 is a master regulator of either sex-determination or dosage compensation or both. We will pursue the following specific aims: 1) To determine whether Guy1 controls dosage compensation and/or sex-determination; 2) To delineate the molecular mechanism underlying Guy1 function; and 3) To exploit Guy1 transgenics as a means for sex separation and population reduction in Anopheles mosquitoes.

 描述（由适用提供）：蚊子是疟疾的主要向量，疟疾是人类最致命，最昂贵的疾病之一。随着药物和杀虫剂的耐药性扩散，疟疾控制措施的威胁越来越大。最近开发的基因组资源和遗传学方法提供了前所未有的机会，以提高我们对蚊子生物学的理解，并制定新的策略来打击疟疾和其他蚊子传播疾病。 Y染色体在Anopheles Mosquitoes目的地中仍然是出乎意料的，其在男性决心和男性生物学的其他方面的重要性。由于血液喂养以及疾病病原体的传播是唯一的省蚊子到女性蚊子，因此在实施减少蚊子种群或用顽固的疾病传播的种群来替代阶层人群或替换竞争者的媒介种群时，仅释放雄性至关重要。克服了技术瓶颈，我们最近发现了四个Y基因。斯蒂芬西。其中，Guy1是男性确定M因素的最佳候选人。生成了多个表达Guy1的转基因线，在几代人中产生了6520个转基因男性和0个转基因女性。我们的初步数据还表明，Guy1转基因AN中观察到的100％女性致死性。斯蒂芬西可能是由于剂量补偿的错误调节而引起的。重要的是，分别直接或间接调节了果蝇Melanogaster，Bombyx Mori和Caenorhabditis elegans的三种已知的性别确定性的大师转换，性杀伤性，fem/aSC，xo lethal 1，也直接或间接调节剂量补偿。功能性性丧失性行为等位基因和MASC靶标的敲低分别导致雌性胚胎致死性，分别在D. melanogaster和B.莫里。在这里，我们将检验以下假设。 Stephensi Guy1是性别确定或剂量补偿或两者兼而有之的主要监管者。我们将追求以下具体目标：1）确定Guy1是否控制剂量补偿和/或性别确定； 2）描绘Guy1功能的分子机制； 3）利用Guy1转变，作为性别分离和蚊子中种群减少的一种手段。