Functional Genomics of Inversion 2La in Anopheles gambiae

冈比亚按蚊反转 2La 的功能基因组学

• 批准号: 8230508
• 负责人: Nora Jessie Besansky
• 金额: $ 50.37万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8230508
• 关键词: Address; Africa; African; Anopheles gambiae; Area; Beds; Behavior; Behavioral; Behavioral Mechanisms; Biological Assay; Bite; Candidate Disease Gene; Chemoprophylaxis; Child; Chromosome inversion; Culicidae; Data; Desiccation; Development; Disease; Double-Stranded RNA; Environment; Epidemiology; Evaluation; Exposure to; Frequencies; Gene Expression; Gene Expression Profile; Gene Order; Gene Silencing; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Goals; Grant; Health; Heterogeneity; Human; Injection of therapeutic agent; Insecticide Resistance; Insecticides; Karyotype; Lead; Left; Link; Malaria; Maps; Mediating; Microsatellite Repeats; Molecular Analysis; Nigeria; Outcome; Phenotype; Physiological; Plasmodium falciparum; Population; Population Heterogeneity; Principal Investigator; Probability; Research; Residual state; Resistance; Resistance development; Rest; Reverse Transcriptase Polymerase Chain Reaction; Sampling; Seasons; Staging; Stress Tests; Study models; Testing; Time; Vaccines; Variant; Water; anthropogenesis; arm; base; design; flexibility; functional genomics; improved; innovation; multidisciplinary; novel; prevent; programs; response; success; trait; transmission process; uptake; vector; vector control

DESCRIPTION (provided by applicant): Malaria caused by Plasmodium falciparum claims the lives of three million children per year, mainly in Africa. A vaccine is not available and chemoprophylaxis alone is unlikely to significantly reduce transmission. Aside from the threat of insecticide resistance, existing vector control strategies that focus on indoor use of insecticides may not reach all of the disease-transmitting population or may induce a behavioral shift, given underlying population heterogeneities in vector resting and biting behavior-- even in vectors considered to be primarily "endophilic" and "endophagic" (indoor resting and biting) such as Anopheles gambiae. In Africa, A. gambiae is the most important vector. This mosquito has adapted rapidly to climatically diverse and anthropogenic environments. Instrumental to its adaptive flexibility are polymorphic chromosomal inversions. Of particular relevance are alternative arrangements on the left arm of chromosome 2 (2La or +a) that are preferentially associated with contrasting environments (arid and humid) through entirely unknown physiological and/or behavioral mechanisms. Based on frequency distribution maps of 2La, this arrangement reaches 100% in arid savannas while in humid rainforests only the alternative arrangement (2L+a) is found. Thus without the benefit of 2La, A. gambiae would be limited to rainforest areas where this mosquito is not necessarily the most abundant or even the best malaria vector. At a local level, 2La reaches its highest frequency during the dry season and in samples captured resting indoors at night where the nocturnal saturation deficit is higher. Thus 2La influences a key epidemiological trait-- the probability of vector-human contact-- as well as the likelihood of vector exposure to insecticide-treated walls and bed nets, through its effect on indoor biting and resting behavior. The ultimate goal of this project is to identify the genes and gene networks in 2La that confer resistance to aridity-- a phenotype or suite of phenotypes that leads to increased vector-human contact and malaria transmission at both local and geographic scales. To achieve this goal, we propose a multidisciplinary and integrative approach that combines phenotypic and molecular analysis to begin to tease apart the functional genomics of 2La through three specific aims: (1) Identify phenotypic traits associated with alternative arrangements of 2La; (2) Identify sequence differences between arrangements that may contribute to phenotypic differences; (3) Associate genotypic and phenotypic differences by comparing patterns of gene expression. The short-term outcome of this program will be linkages between adaptive phenotypes and underlying candidate genes, leading to specific hypotheses about how 2La confers resistance to aridity and impacts the probability of vector-human contact. The longer term benefits are two-fold. The first is improved implementation, evaluation and design of vector control, based on a mechanistic understanding of what we now call "adaptive flexibility". In other words, gaining a detailed understanding of genetic, physiological and behavioral attributes of 2La that are linked to aridity tolerance and indoor resting behavior will significantly improve our ability to predict the epidemiological impact of existing and novel vector control strategies, and can lead to the design of more comprehensive strategies resistant to evasion by components of the vector population. The second benefit is that a successful outcome in the study of functional genomics of aridity resistance in 2La will serve as a general model for studying the functional genomics of many other medically important traits in A. gambiae. PUBLIC HEALTH RELEVANCE Existing control strategies are inadequate and threatened due to development of resistance. Novel vector control strategies are needed, especially for the primary African malaria vector Anopheles gambiae. In this mosquito, genic variations carried on rearranged chromosomes (known as chromosomal inversions) confer traits that are essential to vector success in contrasting (arid or humid) environments. As such, they impact vector distribution seasonally and spatially, including indoor resting and biting behavior. Therefore, they influence a key epidemiological trait-- the probability of vector-human contact-- as well as the likelihood of vector exposure to insecticide-treated walls and bed nets. Unfortunately, the relevant genetic, physiological and behavioral mechanisms underlying these heterogeneities in the vector population are completely unknown. Detailed understanding of these traits will significantly improve our ability to predict the epidemiological impact of existing and novel vector control strategies, and can lead to the design of more comprehensive strategies resistant to evasion by components of the vector population.

描述（由申请人提供）：由恶性疟原虫引起的疟疾每年夺去300万儿童的生命，主要在非洲。没有疫苗，单靠化学预防不可能显著减少传播。除了杀虫剂抗药性的威胁外，现有的侧重于室内使用杀虫剂的病媒控制战略可能无法覆盖所有疾病传播人群，或者可能引起行为转变，因为病媒休息和叮咬行为存在潜在的人群异质性-即使是在被认为主要是“嗜内”和“嗜内”（室内休息和叮咬）的病媒中，如冈比亚按蚊。在非洲，A.冈比亚是最重要的病媒。这种蚊子迅速适应了气候多样性和人为环境。多态性染色体倒位是其适应性灵活性的工具。特别相关的是染色体2（2La或+a）的左臂上的替代安排，通过完全未知的生理和/或行为机制，优先与对比环境（干旱和潮湿）。在2La的频率分布图上，干旱稀树草原的这种排列达到100%，而在湿润雨林中只有交替排列（2L+a）。冈比亚将仅限于雨林地区，在那里这种蚊子不一定是最丰富的，甚至不一定是最好的疟疾媒介。在当地一级，2La达到其最高频率在旱季和在夜间室内休息的夜间饱和度赤字较高的捕获的样本。因此，2La通过其对室内叮咬和休息行为的影响，影响一个关键的流行病学特征-病媒与人接触的可能性，以及病媒接触经杀虫剂处理的墙壁和蚊帐的可能性。该项目的最终目标是确定2La中赋予干旱抗性的基因和基因网络-一种或一套表型，导致在地方和地理范围内增加病媒-人接触和疟疾传播。为了实现这一目标，我们提出了一个多学科和综合的方法，结合表型和分子分析，开始梳理除了功能基因组学的2La通过三个特定的目标：（1）确定表型性状与替代安排的2La;（2）确定序列差异之间的安排，可能有助于表型差异;（3）通过比较基因表达模式将基因型和表型差异联系起来。该计划的短期结果将是适应性表型和潜在的候选基因之间的联系，从而导致关于2La如何赋予对干旱的抗性并影响病媒-人接触概率的具体假设。长期利益是双重的。第一个是改进矢量控制的实施、评估和设计，基于对我们现在所称的“自适应灵活性”的机械理解。换句话说，获得一个详细的了解的遗传，生理和行为属性的2La与干旱耐受性和室内休息的行为将显着提高我们的能力来预测现有的和新的矢量控制策略的流行病学影响，并可以导致设计更全面的策略抵抗逃避的组成部分的矢量人口。第二个好处是，2La的抗旱性功能基因组学研究的成功结果将作为一个通用的模型，研究许多其他重要的医学性状的功能基因组学在A。冈比亚。现有的控制策略是不充分的，并由于耐药性的发展而受到威胁。需要新的病媒控制战略，特别是针对非洲疟疾的主要病媒冈比亚按蚊。在这种蚊子中，重排染色体上携带的基因变异（称为染色体倒位）赋予了在对比（干旱或潮湿）环境中载体成功所必需的特征。因此，它们影响病媒的季节性和空间分布，包括室内休息和叮咬行为。因此，它们影响一个关键的流行病学特征-病媒与人接触的可能性-以及病媒接触经杀虫剂处理的墙壁和蚊帐的可能性。不幸的是，相关的遗传，生理和行为机制的基础上，这些异质性的载体人口是完全未知的。详细了解这些特性将大大提高我们预测现有和新的病媒控制战略的流行病学影响的能力，并可导致设计更全面的战略，以抵抗病媒种群的组成部分逃避。