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）：疟疾具有极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型方法是针对负责向量能力的基因。最有效的疟疾载体Anopheles Gambiae的基因组具有许多与与疟疾传播相关的特定适应性相关的染色体多态性。 2LA多态性反转是广泛的重要表型：恶性疟原虫感染率降低和对干旱气候的适应性。我们提出了一个模型，其中2LA反演的替代染色体排列会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矢量能力和对干旱的适应。我们控制这些“效应基因”的能力将导致干扰寄生虫发育，从而消除疟疾的传播。这项研究的长期目标是了解反演多态性与流行病学上重要的表型之间关联的机制，以开发抑制寄生虫传播的新型工具。最近对马里冈比亚抗体天然种群的遗传调查确定了2LA近端断裂点附近的小区域中恶性疟原虫抗性的位点簇。我们假设i）i）在阻力簇区域的2L ARM排列之间存在异常高的结构差异，ii）ii）抗药性簇的遗传变异，包括APL1和/或其他免疫相关基因的自适应变化，影响了疟疾的敏感性，因此，生理学载体以及生理载体的能力。同样，2L排列之间的等位基因差异可能是导致反转多态性与改编干旱的关联的原因。该探索性R21项目的主要力量是对野生蚊子的倒置和标准排列中的疟原虫抗性岛进行详细的比较分析，以确定编码序列的差异。使用针对新的，超快速测序工具的有针对性的重新陈述将为发现野生种群的基因组序列和结构提供新的方法。我们对从倒布排列获得的基因组片段的研究将首次提供基因注释，对野生，非殖民化的gambiae的广泛且流行的意义上的染色体区域进行基因注释。具体目的是：1）在马里收集的野生A. gambiae蚊子的2LA和2L+排列的两个断点和2L+排列的单倍体DNA序列中获得〜1.5-2 Mb。 2）注释2LA和2L+染色体中的预测编码序列，对两个序列排列进行比较基因组分析，并鉴定候选基因的载体能力和生态适应性。 公共卫生相关性：疟疾具有巨大的生物学和社会复杂性，仍然是当今全球最重要的健康问题之一。拟议的研究将确定媒介能力的候选基因。我们控制负责干扰寄生虫发育的基因的能力将导致消除疟疾的传播。