Genetics of Aggression in Drosophila

描述(由申请人提供)： 攻击性几乎是一种普遍的行为。在群居动物中，适度平衡的攻击性行为通过创建和维持统治等级关系而形成稳定的社会组织。不适当的侵略行为会给社会带来有害的后果。反社会和暴力行为给人类社会带来了重大的社会经济负担。攻击性可由创伤性脑损伤、神经退行性疾病以及药物或酒精滥用的共病引起。攻击性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的座位上的分离变量，其影响对环境敏感。尽管有大量证据表明人类具有攻击行为的遗传易感性，但在人类群体中只发现了少数与攻击行为变异相关的候选基因。果蝇为自然发生的攻击性变异的系统遗传学分析提供了一个很好的模型。我们建立了果蝇遗传参考群体(DGRP)，它由192个来自美国罗利群体的全序列近交系组成，作为数量性状全基因组关联(GWA)分析的公共资源。该种群含有大量攻击性行为的遗传变异，为这一应用提供了必要的资源。我们的最终目标是全面了解攻击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影响。这项建议的具体目标是(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行为变异相关的假定因果等位基因图谱，并开发统计遗传模型来预测个体攻击行为；(2)推导影响攻击行为的因果转录共表达网络，将通过遗传图谱确定的新基因座置于适当的生物学环境中；以及(3)使用突变和RNAi从功能上测试自然变异和转录网络结构统计分析所涉及的基因对攻击行为的影响，并利用最近开发的在同一基因组位置整合转基因的系统来测试天然等位基因对攻击行为的因果影响。由于攻击性是一种普遍的行为，而且果蝇中的许多基因都与人类同源，因此我们的研究得出的一般性见解将对人类攻击性的遗传学研究具有翻译意义；此外，来自攻击性的系统遗传学研究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)的人的攻击性水平会增加。暴力行为和控制暴力行为的努力给我们的社会带来了巨大的社会和经济代价。这项研究利用一种新的遗传资源，全序列果蝇品系，以及最新的基因表达、统计和遗传分析来定位影响攻击行为的分子变异，并推导出与攻击行为相关的基因表达网络。鉴于攻击性等基本特征的功能在进化上的保守性，在模式生物中发现的基因和途径可以作为候选基因纳入人类连锁和关联研究中。

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.