Genetics of Aggression in Drosophila

描述（由申请人提供）： 攻击性是一种近乎普遍的行为。在社会动物中，适当平衡的攻击行为通过创造和维持统治等级来产生稳定的社会组织。不适当的侵略行为会对社会产生有害的后果。反社会和暴力行为给人类社会带来了巨大的社会经济负担。攻击性可以由创伤性脑损伤、神经退行性疾病以及药物或酒精滥用的共病状态引起。攻击行为是一种典型的数量性状，其自然变异可归因于多个相互作用位点的分离变异，其效应对环境敏感。尽管有大量的证据表明人类具有攻击性行为的遗传倾向，但在人类群体中仅发现了少数与攻击性变异相关的候选基因。果蝇为系统遗传学分析自然发生的攻击性变异提供了一个很好的模型。我们产生了果蝇遗传参考群体（DGRP），它由来自美国罗利群体的192个完全测序的近交系组成，作为数量性状全基因组关联（GWA）分析的公共资源。这一群体具有攻击性行为的大量遗传变异，并为这一应用提供了必要的资源。我们的最终目标是获得一个完整的理解的遗传结构的侵略行为和生物学效应的自然变异的转录遗传网络。该计划的具体目标是：（1）利用果蝇遗传学和基因组学的力量，以高分辨率绘制与攻击性变异相关的假定因果等位基因，并建立预测个体攻击性行为的统计遗传模型;（2）推导影响攻击性行为的因果转录共表达网络，将遗传作图确定的新基因座置于适当的生物学背景中;以及（3）使用突变和RNAi来功能性地测试对由自然变异和转录网络结构的统计分析所涉及的基因的攻击行为的影响，并且使用最近开发的用于将转基因整合到相同基因组位置中的系统来执行对自然等位基因对攻击行为的因果影响的测试。由于攻击性是一种普遍的行为，果蝇中的许多基因都有人类的直系同源物，因此从我们提出的研究中获得的一般见解将对攻击性的人类遗传学研究产生翻译影响;此外，从攻击性的系统遗传学研究中获得的见解将对我们对数量性状的一般理解产生广泛的影响，包括人类行为障碍的遗传学。 公共卫生相关性： 酗酒者、阿尔茨海默病患者和患有行为障碍（如边缘型人格障碍和间歇性爆发性障碍）的个体的攻击性水平会增加。暴力行为以及控制暴力行为的努力给我们的社会带来的社会和经济成本是巨大的。这项研究利用了一种新的遗传资源，全测序果蝇品系，以及最先进的基因表达，统计和遗传分析来绘制影响攻击性的分子变异，并推导出与攻击性行为因果相关的基因表达网络。鉴于基本性状（如攻击性）功能的进化保守性，在模式生物中发现的基因和途径可以作为人类连锁和关联研究的候选基因。

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. PUBLIC HEALTH RELEVANCE: Increased levels of aggression occur in alcoholics, Alzheimer's Disease patients, and individuals suffering from behavioral disorders, such as borderline personality disorder and intermittent explosive disorder. The social and economic costs to our society that result from violent behavior, and efforts to control it, are enormous. This study utilizes a new genetic resource, full sequenced Drosophila lines, and state-of-the-art gene expression, statistical and genetic analyses to map molecular variants affecting aggression, and derive gene expression networks causally associated with aggressive behavior. Given the evolutionary conservation of function for fundamental traits, such as aggression, genes and pathways discovered in model organisms can be incorporated as candidate genes in human linkage and association studies.