QTLs in Drosophila

描述（由申请人提供）：与人类健康和适应性进化相关的大多数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基因的等位基因分离，具有环境敏感效应。该项目的长期目标是了解这些数量性状的遗传结构，包括单个基因座等位基因变异的分子基础和等位基因对多个性状的影响分布;以及这些影响在多大程度上依赖于环境，并取决于性别，遗传背景以及物理和社会环境。黑腹果蝇是一个很好的模型系统，阐明一般原则的复杂性状的遗传结构，使用全基因组关联（GWA）映射，因为高水平的分子多态性和低连锁不平衡，在果蝇促进识别不仅与复杂性状相关的基因，但实际的因果多态性。果蝇GWA作图的主要障碍是需要约200个果蝇品系的全基因组序列。国家人类基因组研究所最近批准了192个近交系D。来自美国罗利种群的黑腹果蝇品系，作为果蝇遗传参考组（DGRP）。这些品系和全基因组多态性数据将是一个社区资源，用于快速和高分辨率的基因作图，影响复杂的性状在一系列的环境。然而，分子多态性通过扰乱转录和其他生物网络来影响数量性状。如果我们要将统计学关联置于生物学背景下，就必须了解遗传变异对潜在网络和性状遗传变异的影响。该项目期间的具体目标是使用192个DGRP近交系在两种环境中对几个数量性状进行GWA分析;识别与两种环境中数量性状相关的遗传网络;并进行功能研究以确认关联并验证网络。这些研究将提供前所未有的深入了解影响一系列复杂性状的相互作用位点，每个性状的等位基因效应的分布和对多个性状的多效性效应，以及基因型与环境相互作用的分子基础。这些研究将全面了解常见与罕见变异、大效应与小效应等位基因、单核苷酸多态性与拷贝数变异、编码区非同义多态性与推定调控多态性对数量性状变异分子基础的相对贡献。这种系统遗传学方法使用果蝇模型将产生丰富的普遍适用的见解之间的关系，基因型变异和表型变异的表现复杂的性状。 公共卫生相关性：人类群体对常见疾病和行为障碍的易感性以及对药物治疗的反应的变化在遗传上是复杂的。然而，人类基因组的单倍型块的组织是一个障碍，以确定因果多态性与复杂的性状，和可变的遗传背景和环境暴露进一步限制了我们的能力，以确定在人类研究中的分子多态性的背景依赖性表型效应。本研究利用果蝇全基因组关联分析的能力和对192个果蝇品系的完整重新测序来鉴定与几个复杂性状相关的分子多态性和遗传网络，并研究环境压力如何调节这些关联和网络。对基因型-表型关系的一般原理的洞察将适用于人类疾病。

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.