Genomics of mosquito resistance to Plasmodium

描述（由申请人提供）：这是一个四年期项目#AI42361的竞争性继续提案，以前的标题是“An.冈比亚对疟原虫的易感性。“自开始以来，该项目首次系统地研究了自然界中蚊子对疟原虫的免疫和抵抗机制。了解这些相互作用的生物学可以允许开发新的策略来抑制寄生虫传播。在上一个项目期间，我们对主要的人类疟疾病媒冈比亚按蚊进行了实地遗传分析。这项工作首次确定了An中的基因。冈比亚，减少恶性疟原虫的自然传播。我们绘制了两个位点的寄生虫抗性，Pfin1和Pfin2。抗性纯合子在Pfin1基因座的平均0.17卵囊每蚊，而敏感的纯合子有50.6。我们发现了一个明显的高自然频率的抗性等位基因，这表明疟疾寄生虫（或类似的病原体）对媒介种群施加了显着的选择压力。在这里，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自然疟疾传播系统的背景下的遗传学和基因组学。我们将：1）筛选一个自然种群。gambiae的全基因组扫描在10厘米分辨率的基因座，控制恶性疟原虫在自然传播系统在马里，西非。2)以高遗传分辨率绘制目标1中确定的天然抗性基因座，以分离出易于处理的候选抗性基因。3)通过序列分析、转录谱分析和生理学研究筛选候选抗性基因，并定位克隆至少一个缺失的抗性性状。拟议的继续项目将是第一次在蚊子野外种群中进行基因筛选，以寻找对疟疾寄生虫具有抵抗力的基因。我们将确定寄生虫抗性性状的数量，频率和基因组组织，在10 cM的遗传分辨率。我们将保持蚊子家族分离选定的性状，我们可以选择稳定的品系，我们将绘制性状，描述细胞机制，我们将定位克隆一个或多个潜在的基因。

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.