Genetics of Aggression in Drosophila

果蝇攻击性遗传学

• 批准号: 8517137
• 负责人: Robert R. H Anholt
• 金额: $ 32.08万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8517137
• 关键词: Affect; Aggressive behavior; Alcohol abuse; Alleles; Alzheimer' s Disease; Animal Model; Animals; Architecture; Behavior; Behavior Disorders; Biological; Biological Models; Borderline Personality Disorder; Brain; Candidate Disease Gene; Chromosome Mapping; DNA Sequence; Drosophila genus; Drug abuse; Environment; Equilibrium; Frequencies; Gene Expression; Gene Mutation; Genes; Genetic; Genetic Models; Genetic Predisposition to Disease; Genetic Variation; Genomics; Goals; Human; Human Genetics; Inbred Strain; Individual; Intermittent Explosive Disorders; Link; Location; Maps; Mediating; Molecular; Mushroom Bodies; Mutation; Neurodegenerative Disorders; Pathway interactions; Patients; Phase; Population; RNA Interference; Research; Resolution; Resources; Single Nucleotide Polymorphism; Site; Social Dominance; Societies; Structure; System; Testing; Transgenes; Transgenic Organisms; Traumatic Brain Injury; Variant; Violence; base; economic cost; fitness; genetic analysis; genetic resource; genome wide association study; insight; interest; novel; null mutation; predictive modeling; problem drinker; programs; social; social organization; socioeconomics; trait

DESCRIPTION (provided by applicant): Aggression is a near universal behavior. Among social animals, appropriately balanced aggressive behavior gives rise to a stable social organization by creating and maintaining dominance hierarchies. Inappropriate aggression has detrimental consequences for a society. Sociopathic and violent behaviors place a significant socioeconomic burden on human societies. Aggression can result from traumatic brain injury, neurodegenerative diseases, and as a comorbid condition of drug or alcohol abuse. Aggressive behavior is a typical quantitative trait, with natural variation attributable to segregating variants at multiple interacting loci, th effects of which are sensitive to the environment. Despite substantial evidence for genetic predisposition to aggressive behavior in humans, only a handful of candidate genes associated with variation in aggression have been identified in human populations. Drosophila provides an excellent model for systems genetics analysis of naturally occurring variation in aggression. We generated the Drosophila Genetic Reference Population (DGRP), which consists of 192 fully sequenced inbred strains derived from the Raleigh, USA population as a public resource for genome-wide association (GWA) analysis of quantitative traits. This population harbors substantial genetic variation for aggressive behavior and provides an essential resource for this application. Our ultimate goal is to obtain a complete understanding of the genetic architecture of aggressive behavior and biological effects of natural variants on transcriptional genetic networks. The specific aims of this proposal are (1) to use the power of Drosophila genetics and genomics to map putative causal alleles associated with variation in aggression with high resolution and develop a statistical genetic model to predict individual aggressive behavior; (2) to derive causal transcriptional co-expression networks affecting aggressive behavior, placing novel loci identified by genetic mapping in appropriate biological context; and (3) to use mutations and RNAi to functionally test effects on aggressive behavior of genes implicated by the statistical analyses of natural variation and architecture of transcriptional networks, and to use the recently developed system for integrating transgenes in the same genomic location to perform tests for causal effects of natural alleles on aggressive behavior. Because aggression is a universal behavior and many genes in Drosophila have human orthologues, general insights derived from our proposed studies will have translational implications for human genetic studies on aggression; moreover, insights derived from systems genetic studies on aggression, will have a broad impact on our general understanding of quantitative traits, including the genetics of human behavioral disorders.

描述（由申请人提供）： 侵略是一种几乎普遍的行为。在社会动物中，适当平衡的侵略行为通过建立和维持优势等级来产生稳定的社会组织。不适当的侵略对社会造成了不利的后果。社会疗法和暴力行为给人类社会带来了重大的社会经济负担。侵略性可能是由于脑损伤，神经退行性疾病以及药物或酗酒的合并症所致。侵略性行为是一种典型的定量性状，其自然变化归因于在多个相互作用基因座处隔离变体，其影响对环境很敏感。尽管有大量证据表明遗传易感性对人类的侵略行为，但在人类人群中仅发现了少数与侵略变异相关的候选基因。果蝇为系统遗传学分析提供了出色的模型，以分析自然发生的攻击性变异。我们生成了果蝇遗传参考人群（DGRP），该果蝇由192个完全测序的近交菌株，源自美国的罗利人，作为全基因组关联的公共资源（GWA）的定量性状分析。该人群为攻击行为提供了实质性的遗传变异，并为该应用提供了必不可少的资源。我们的最终目标是完全了解侵略性行为的遗传结构以及自然变异对转录遗传网络的生物学作用。该提案的具体目的是（1）使用果蝇遗传学和基因组学的力量来绘制与侵略性变化相关的推定因果等位基因，并开发出一种统计遗传模型来预测个体的攻击行为； （2）得出影响攻击行为的因果转录共表达网络，将通过遗传学映射确定的新基因座在适当的生物学环境中鉴定出来； （3）使用突变和RNAI在功能上测试对基因的侵略行为的影响，该基因的侵略行为与转录网络的自然变异和结构的统计分析有关，并使用最近开发的系统在相同的基因组位置集成转基因，以对自然等位基因对侵略行为的因果效应进行测试。由于侵略是一种普遍的行为，果蝇中的许多基因具有人类直系同源物，因此我们提出的研究得出的一般见解将对人类遗传研究对侵略的影响具有转化的影响。此外，从系统的侵略性研究中得出的洞察力将对我们对定量特征（包括人类行为障碍的遗传学）的一般理解产生广泛的影响。