Comparative genomics of the 2La inversion breakpoints in Anopheles gambiae

冈比亚按蚊 2La 反转断点的比较基因组学

• 批准号: 7470389
• 负责人: IGOR V SHARAKHOV
• 金额: $ 27.13万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-15 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7470389
• 关键词: Affect; Alleles; Anopheles gambiae; Biological; Biological Assay; Candidate Disease Gene; Chromosomes; Code; Communicable Diseases; Comparative Genomic Analysis; Competence; Complex; Culicidae; DNA Resequencing; DNA Sequence; Desert Climate; Development; Engineering; Future; Gene Targeting; Genes; Genetic; Genetic Polymorphism; Genetic Recombination; Genetic Variation; Genome; Genomic Segment; Genomics; Goals; Haploidy; Haplotypes; Health; Heterozygote; Immunity; Infection; Island; Laboratories; Lead; Link; Location; Malaria; Mali; Methodology; Modeling; Molecular; Nature; Numbers; Parasites; Phenotype; Physiological; Plasmodium; Plasmodium falciparum; Population; Predisposition; Preparation; Public Health; RNA Interference; Rate; Research; Resistance; Role; Standards of Weights and Measures; Structure; Surveys; Time; Today; Transgenes; Upper arm; Variant; comparative; disease transmission; fighting; genome sequencing; innovation; laser capture microdissection; leucine-rich repeat protein; novel; novel strategies; social; tool; transmission process; vector

DESCRIPTION (provided by applicant): Malaria, with its great biological and social complexity, remains one of the most important global health problems today. One novel approach for controlling infectious diseases is targeting genes responsible for vector competence. The genome of the most efficient malaria vector, Anopheles gambiae, has a number of chromosomal polymorphisms linked to specific adaptations related to malaria transmission. The 2La polymorphic inversion is widespread important phenotypes: decreased Plasmodium falciparum infection rates and adaptation to arid climate. We propose a model where the alternative chromosomal arrangements of the 2La inversion affect vector competence and adaptation to aridity by capturing and stabilizing different haplotypic variants containing allelic complexes of specific genes. Our ability to control these "effector genes" would lead to interference with parasite development and, as a result, to elimination of malaria transmission. The long-term goal of this research is to understand the mechanism of association between inversion polymorphism and the epidemiologically important phenotypes in order to develop novel tools for inhibiting parasite transmission. A recent genetic survey of natural populations of A. gambiae in Mali has identified the strongest P. falciparum resistance loci cluster in a small region near the 2La proximal breakpoint. We hypothesize that i) there are unusually high levels of structural divergence between the 2L arm arrangements in the resistance cluster region, and ii) that genetic variation in the resistance cluster, including adaptive variation for APL1 and/or other immunity-related genes, influences malaria susceptibility and, therefore, physiological vector competence in nature. Similarly, allelic differentiation between the 2L arrangements could be responsible for association of the inversion polymorphism with adaptations to aridity. The major thrust of this exploratory R21 project is to perform detailed comparative analysis of the Plasmodium resistance island in inverted and standard arrangements from wild mosquitoes in order to identify differences in coding sequences. Using targeted resequencing with new, ultra-fast sequencing tools will provide novel methodology for the discovery of genome sequence and structure in wild populations. Our study of the genomic segments obtained from the inverted arrangements will, for the first time, provide for gene annotation over an extensive and epidemiologically significant chromosomal region in wild, non-colonized A. gambiae from a natural population. The specific aims are to: 1) Obtain ~1.5-2 Mb of haploid DNA sequences at both breakpoints of 2La and 2L+ arrangements from wild A. gambiae mosquitoes collected in Mali. 2) Annotate predicted coding sequences in 2La and 2L+ chromosomes, perform comparative genomic analysis of both sequence arrangements, and identify candidate genes for vector competence and ecological adaptation. PUBLIC HEALTH RELEVANCE: Malaria, with its great biological and social complexity, remains one of the most important global health problems today. The proposed research will identify candidate genes for vector competence. Our ability to control genes responsible for interference with parasite development will lead to the elimination of malaria transmission.

描述（由申请人提供）：疟疾因其巨大的生物学和社会复杂性，仍然是当今最重要的全球健康问题之一。控制传染病的一种新方法是针对负责载体能力的基因。最有效的疟疾载体冈比亚按蚊的基因组具有许多与疟疾传播相关的特定适应相关的染色体多态性。 2La多态性倒转是广泛存在的重要表型：降低恶性疟原虫感染率和适应干旱气候。我们提出了一个模型，其中 2La 倒位的替代染色体排列通过捕获和稳定包含特定基因等位基因复合物的不同单倍型变体来影响载体能力和对干旱的适应。我们控制这些“效应基因”的能力将干扰寄生虫的发育，从而消除疟疾传播。这项研究的长期目标是了解倒位多态性与流行病学重要表型之间的关联机制，以便开发抑制寄生虫传播的新工具。最近对马里冈比亚疟原虫自然种群进行的一项遗传调查发现，在 2La 近断点附近的一个小区域内，最强的恶性疟原虫抗性基因座簇。我们假设 i) 抗性簇区域的 2L 臂排列之间存在异常高水平的结构差异，ii) 抗性簇中的遗传变异，包括 APL1 和/或其他免疫相关基因的适应性变异，影响疟疾易感性，以及自然中的生理媒介能力。类似地，2L 排列之间的等位基因分化可能是倒位多态性与干旱适应的关联的原因。这个探索性 R21 项目的主要目标是对野生蚊子的倒置和标准排列的疟原虫抗性岛进行详细的比较分析，以识别编码序列的差异。使用新型超快速测序工具进行靶向重测序将为发现野生种群中的基因组序列和结构提供新的方法。我们对从倒置排列获得的基因组片段的研究将首次为来自自然群体的野生、非定植冈比亚冈比亚的广泛且具有流行病学意义的染色体区域提供基因注释。具体目标是： 1) 从马里收集的野生冈比亚蚊子中获得 2La 和 2L+ 排列两个断点处约 1.5-2 Mb 的单倍体 DNA 序列。 2)注释2La和2L+染色体中的预测编码序列，对两种序列排列进行比较基因组分析，并识别载体能力和生态适应的候选基因。 公共卫生相关性：疟疾具有巨大的生物学和社会复杂性，仍然是当今最重要的全球健康问题之一。拟议的研究将确定载体能力的候选基因。我们控制干扰寄生虫发育的基因的能力将导致消除疟疾传播。