QTLs in Drosophila

果蝇中的 QTL

• 批准号: 7901762
• 负责人: Robert R. H Anholt
• 金额: $ 43.89万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7901762
• 关键词: Affect; Alleles; Architecture; Behavior Disorders; Binding Sites; Biological; Biological Models; Candidate Disease Gene; Categories; Chills; Chromosome Mapping; Code; Coma; Communities; Complex; Copulation; Data; Disease; Drosophila genus; Drosophila melanogaster; Environment; Environmental Exposure; Evolution; Exhibits; Female; Gene Expression; Gene Frequency; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genome; Genotype; Goals; Haplotypes; Health; Human; Human Genome; Individual; Linkage Disequilibrium; Longevity; Maps; Measures; Modeling; Molecular; Motor Activity; Mutation; National Human Genome Research Institute; Ontology; Oxidative Stress; Pattern; Phenotype; Population; Predisposition; Relative (related person); Resistance; Resolution; Resources; Sensory; Single Nucleotide Polymorphism; Sleep; Social Environment; Starvation; Stress; System; Testing; Time; Transcript; Variant; base; cold temperature; fitness; fly; genome sequencing; genome wide association study; genome-wide; human disease; insight; male; protein protein interaction; public health relevance; research study; response; sex; trait; transcription factor

DESCRIPTION (provided by applicant): Most phenotypic variation relevant to human health and adaptive evolution is genetically complex, with population variation attributable to segregating alleles at many interacting genes with environmentally sensitive effects. The long-term goal of this project is to understand the genetic architecture of such quantitative traits in terms of the molecular basis of allelic variation at individual loci and the distribution of effects of alleles on multiple traits; and the extent to which these effects are context-dependent and vary depending on sex, genetic background, and the physical and social environment. Drosophila melanogaster is an excellent model system for elucidating general principles regarding the genetic architecture of complex traits using genome wide association (GWA) mapping, because high levels of molecular polymorphism and low linkage disequilibrium in Drosophila facilitate the identification of not only genes associated with complex traits, but actual causal polymorphisms. The major impediment to GWA mapping in Drosophila is that complete genome sequence from ~200 fly lines is necessary. The National Human Genome Research Institute recently approved the whole-genome sequencing of 192 inbred D. melanogaster lines, derived from the Raleigh, US population, as a Drosophila Genetic Reference Panel (DGRP). These lines and genome wide polymorphism data will be a community resource for rapid and high resolution mapping of genes affecting complex traits in a range of environments. However, molecular polymorphisms affect quantitative traits by perturbing transcriptional and other biological networks. Understanding the impact of genetic variation on both underlying networks and genetic variation for the traits is necessary if we are to place the statistical associations in biological context. The specific aims for this project period are to perform GWA analyses of several quantitative traits in two environments, using the 192 DGRP inbred lines; to identify genetic networks associated with quantitative traits in two environments; and to perform functional studies to confirm associations and validate networks. These studies will give unprecedented insight into the interacting loci affecting a range of complex traits, distributions of allelic effects for each trait and pleiotropic effects on multiple traits, and the molecular basis of genotype by environment interaction. These studies will provide a comprehensive understanding of the relative contribution of common vs. rare variants, alleles of large vs. small effects, single nucleotide polymorphisms vs. copy number variants, and non-synonymous polymorphisms in coding regions vs. putative regulatory polymorphisms to the molecular basis of variation for quantitative traits. This systems genetics approach using the Drosophila model will generate a wealth of generally applicable insights in the relationship between genotypic variation and phenotypic variation for the manifestation of complex traits. PUBLIC HEALTH RELEVANCE: Variation in human populations for susceptibility to common diseases and behavioral disorders, as well as responses to pharmacological therapies, is genetically complex. However, the organization of the human genome into haplotype blocks is an impediment to identifying causal polymorphisms associated with complex traits, and variable genetic backgrounds and environmental exposures further limit our ability to determine context-dependent phenotypic effects of molecular polymorphisms in human studies. This study takes advantage of the power of genome wide association analyses in Drosophila and the complete re-sequencing of 192 fly lines to identify molecular polymorphisms and genetic networks associated with several complex traits, and to investigate how the associations and networks are modulated by environmental stress. The insight into general principles of genotype-phenotype relationships will be applicable to human disease.

描述(申请人提供)：大多数与人类健康和适应性进化相关的表型变异在遗传上是复杂的，群体变异可归因于许多相互作用的基因上分离的等位基因与环境敏感的影响。这个项目的长期目标是了解这些数量性状的遗传结构，包括单个基因座的等位基因变异的分子基础和等位基因对多个性状的影响的分布；以及这些影响的程度取决于背景和性别、遗传背景以及物理和社会环境。果蝇是利用全基因组关联(GWA)图谱阐明复杂性状遗传结构的一般原理的一个很好的模式系统，因为果蝇的高水平分子多态和低连锁不平衡不仅有助于识别与复杂性状相关的基因，而且有助于识别实际的因果多态。果蝇GWA定位的主要障碍是需要从约200个果蝇品系中获得完整的基因组序列。美国国家人类基因组研究所最近批准了192个来自美国罗利种群的近交系黑腹果蝇的全基因组测序，作为果蝇遗传参考小组(DGRP)。这些品系和基因组范围的多态数据将成为社区资源，用于快速和高分辨率地绘制在一系列环境中影响复杂性状的基因。然而，分子多态通过干扰转录和其他生物网络来影响数量性状。如果我们要把统计关联放在生物学的背景下，了解遗传变异对潜在网络和性状遗传变异的影响是必要的。本项目期间的具体目标是利用192个DGRP自交系对两个环境中的几个数量性状进行GWA分析；识别与两个环境中的数量性状相关的遗传网络；以及进行功能研究，以确认关联和验证网络。这些研究将前所未有地深入了解影响一系列复杂性状的相互作用的基因座，每个性状的等位基因效应和多个性状的多效性效应的分布，以及基因与环境互作的分子基础。这些研究将全面了解常见变异与罕见变异、大效应与小效应等位基因、单核苷酸多态与拷贝数变异、编码区非同义多态与推测的调控多态对数量性状变异的分子基础的相对贡献。这种利用果蝇模型的系统遗传学方法将在复杂性状表现的基因变异和表型变异之间的关系方面产生丰富的普遍适用的见解。 公共卫生相关性：人类人群对常见疾病和行为障碍的易感性以及对药物治疗的反应在遗传上是复杂的。然而，将人类基因组组织成单倍型区块是识别与复杂性状相关的因果多态的障碍，而可变的遗传背景和环境暴露进一步限制了我们在人类研究中确定分子多态的上下文相关表型效应的能力。本研究利用果蝇全基因组关联分析的强大功能和192个果蝇品系的完全重新测序，确定了与几个复杂性状相关的分子多态和遗传网络，并研究了环境应激如何调节这些关联和网络。对基因-表型关系的一般原理的洞察将适用于人类疾病。