Genetic Association Mapping of Malaria Resistance in Anopheles gambiae

描述（由申请方提供）：非洲冈比亚按蚊家系的遗传连锁图谱确定了基因组的一个小疟原虫抗性岛（PRI），该基因组控制了蚊子对恶性疟原虫感染的抗性的大部分天然遗传变异。PRI在染色体2L上占据约15兆碱基对。系谱分析是初步发现抗性位点的有效方法，但系谱不包含足够的重组信息来从遗传上鉴定抗性岛内1，000个基因中的实际致病基因。与此相反，遗传关联的方法利用自然群体中的历史重组，将一个基因座分解到单基因水平。在这里，我们提出了一个遗传关联研究，以确定潜在的特定基因控制的抗性和敏感性的A。gambiae对恶性疟原虫的作用，目的如下。目的1，我们将通过饲养野生捕获的A.冈比亚幼虫在昆虫饲养场，并挑战他们与恶性疟原虫从自然感染的志愿者的血液。目的2：利用微卫星和单核苷酸多态性作为中性标记，进行间接关联研究，缩小控制抗性的目标区间。目标3，我们将通过对目标2中确定的部分或全部缩小的候选区域进行重测序来进行直接关联研究，以检测自然界中控制蚊子对疟原虫的抗性和易感性的基因。由此产生的信息将允许蚊子种群的遗传易感部分的具体歧视。先前的谱系连锁研究表明，有效的遗传抗性机制在病媒种群中广泛存在，并表明实际的疟疾传播是由遗传易感蚊子的离散子集进行的。我们建议，有可能开发一种新形式的疟疾控制的基础上，专门针对易感人群，以减少其在病媒人群中的频率。 相关性：有可能制定新的疟疾控制战略，重点放在蚊子媒介上。了解影响病媒蚊子传播疟疾的遗传机制将有助于制定这种基于病媒的控制战略。

DESCRIPTION (provided by applicant): Genetic linkage mapping of Anopheles gambiae pedigrees in Africa identified a small Plasmodium- Resistance Island (PRI) of the genome that controls most of the natural genetic variation for mosquito resistance to Plasmodium falciparum infection. The PRI occupies -15 megabase pairs on chromosome 2L. Pedigree analysis was an efficient method for initial discovery of resistance loci, but pedigrees do not contain enough recombinational information to genetically identify the actual causative gene(s) among the 1,000 genes within the resistance island. In contrast, the method of genetic association takes advantage of historic recombination in the natural population to dissect a locus to the single-gene level. Here we propose a genetic association study to identify the underlying specific genes that control resistance and susceptibility of A. gambiae to P. falciparum in nature, with the following Aims. Aim 1, we will construct an association panel by rearing wild-caught A. gambiae larvae in the insectary, and challenging them with P. falciparum from the blood of naturally-infected volunteers. Aim 2, we will carry out an indirect association study to narrow the target interval controlling resistance, using as neutral markers microsatellites and single-nucleotide polymorphisms. Aim 3, we will carry out a direct association study by resequencing part or all of the narrowed candidate region ascertained in Aim 2, to detect the genes that underlie control of mosquito resistance and susceptibility to malaria parasites in nature. The resulting information will allow specific discrimination of the genetically susceptible fraction of the mosquito population. The previous pedigree linkage study indicated that efficient mechanisms of genetic resistance are widespread in the vector population, and suggested that actual malaria transmission is carried out by a discrete subset of genetically susceptible mosquitoes. We propose that it may be possible to develop a novel form of malaria control based on specifically targeting the susceptibles to reduce their frequency in the vector population. Relevance: It may be possible to develop new strategies for malaria control focusing on the mosquito vector. Knowledge of the genetic mechanisms that affect transmission of malaria by vector mosquitoes would aid in the development of such vector-based control strategies.