Genomics of mosquito resistance to Plasmodium

描述（由申请人提供）：这是一个为期四年的项目#AI42361的竞争性延续提案，之前的标题是“An的遗传学”。冈比亚人对疟原虫的敏感性。”自启动以来，该项目首次系统地研究了蚊子对自然界疟原虫的免疫和抗性机制。了解这些相互作用的生物学原理可以开发出抑制寄生虫传播的新策略。在上一个项目期间，我们对主要的人类疟疾媒介冈比亚按蚊进行了实地遗传分析。本工作首次鉴定了安氏线虫的基因。减少恶性疟原虫的自然传播。我们定位了两个寄生虫抗性位点，Pfin1和Pfin2。Pfin1位点的抗性纯合子平均每只蚊子有0.17个卵囊，而易感纯合子平均每只蚊子有50.6个卵囊。我们发现抗性等位基因的自然频率明显很高，这表明疟疾寄生虫（或类似病原体）对病媒种群施加了显著的选择压力。在此，我们提出了新的综合目标，直接建立在以前的工作，研究蚊子免疫和寄生虫抗性的遗传和基因组学在自然疟疾传播系统的背景下。我们将：1)筛选安氏自然种群。2)在高遗传分辨率下绘制Aim 1中鉴定的自然抗性位点，以分离出数量可控制的候选抗性基因。3)通过序列分析、转录谱分析和生理研究筛选候选抗性基因，并对至少一个抗性性状进行定位克隆。拟议的继续项目将是第一次在蚊子种群中进行遗传筛选，以获得对疟疾寄生虫具有抗性的基因。我们将在10 cM遗传分辨率下确定抗寄生虫性状的数量、频率和基因组组织。我们将保持蚊子家族分离选定的性状，我们可能会选择稳定的品系，我们将绘制性状图，描述细胞机制，我们将定位克隆一个或多个潜在基因。

DESCRIPTION (provided by the applicant): This is a competing continuation proposal for the four-year project #AI42361, previously entitled, "Genetics of An. gambiae susceptibility to Plasmodium." Since its inception, this project has comprised the first systematic examination of mechanisms of mosquito immunity and resistance to Plasmodium in nature. Understanding the biology of these interactions could permit development of novel strategies to inhibit parasite transmission. In the last project period, we carried out a field-based genetic analysis of the major human malaria vector, Anopheles gambiae. This work for the first time identified genes in An. gambiae that reduce the natural transmission of P. falciparum. We mapped two loci for parasite resistance, Pfin1 and Pfin2. Resistant homozygotes at the Pfin1 locus had a mean of 0.17 oocysts per mosquito, while susceptible homozygotes had 50.6. We found an apparent high natural frequency of resistance alleles, which suggests that malaria parasites (or a similar pathogen) exert a significant selective pressure on vector populations. Here, we present new integrated Aims that build directly upon the previous work to study the genetics and genomics of mosquito immunity and parasite resistance in the context of the natural malaria transmission system. We will: 1) Screen a natural population of An. gambiae by genome-wide scanning at 10 cM resolution for loci that control resistance to P. falciparum in the natural transmission system in Mali, West Africa. 2) Map natural resistance loci identified in Aim 1 at high genetic resolution to isolate a tractable number of candidate resistance genes. 3) Filter the candidate resistance genes by sequence analysis, transcriptional profiling, and physiological studies, and positionally clone at least one resistance trait gone. The proposed continuation project will be the first genetic screen in a mosquito field population for genes conferring resistance to malaria parasites. We will determine the number, frequencies, and genomic organization of parasite-resistance traits, at 10 cM genetic resolution. We will maintain mosquito families segregating chosen traits and we may select stable lines, we will map the traits, describe the cellular mechanism, and we will positionally clone one or more underlying genes.