A novel approach to identifying aggression genes in Drosophila

攻击性是一种普遍表达的高度保守的特征，代表了人类最大的痛苦。在过去的几年里，果蝇已经成为研究攻击性的一个很好的模型系统。许多研究报告说，当苍蝇被选择为高或低水平的攻击性时，数百甚至数千个基因改变了它们的表达模式。我们采用了一种新的方法，我们将基因相同的雄性配对，让它们战斗30分钟。有些人经常打架（兰博人），有些人不打架（甘地人）。我们比较了两组之间表达不同的基因，发现一小部分在Rambos中上调或下调。其中一些基因编码神经递质的特性，一些编码对嗅觉很重要的蛋白质，所有这些基因都可以合理地预期在攻击性中发挥作用。我们已经关注了其中的一种，Dat，它编码一种蛋白质，这种蛋白质破坏突触上称为单胺的神经递质。该基因编码的这种蛋白质有两种亚型，一种产生Rambos，另一种产生Gandhis，它们似乎在苍蝇大脑的不同部位表达。在人类中，一种叫做MAOA的基因发生了突变，它的作用与果蝇中的Dat基因相同，它会导致男孩的过度攻击性，在这个特殊的荷兰家庭中，大多数携带突变基因的男孩都被监禁了。因此，使用我们不寻常的方法，我们在苍蝇中发现了一种攻击性基因，它在人类中具有类似的功能。在这个提议中，我们将使用复杂的遗传工具来发现两种Dat亚型如何产生兰博和甘地行为。我们还将启动对其他一些似乎与攻击有关的攻击基因的研究，包括另外两个与神经递质功能有关的基因，DopR2，它编码神经递质多巴胺的受体，还有一个名为CG13794的基因，没有人知道它的作用，但它的蛋白质序列可能与神经递质血清素的运输有关。我们还将研究两种气味结合蛋白基因Obp99b和Obp56d的作用，这两种基因在兰博苍蝇中高度表达。我们的研究结果将启发果蝇攻击性的分子基础，并且，鉴于我们迄今为止的发现，我们的研究结果可能与理解人类攻击性的本质非常相关。

Aggression is a universally expressed highly conserved trait that represents humanity's greatest affliction. Over the past few years, the fruitfly has become an excellent model system for studying aggression. A number of studies have reported that many hundreds, even thousands of genes change their expression patterns when flies are selected for high or low levels of aggression. We have used a novel approach where we take genetically identical pairs of males and let them fight for 30 minutes. Some pairs fight a lot (the Rambos) and some do not (the Gandhis). We compared the genes that were expressed differently between the two groups and found a small number that were either upregulated or downregulated in Rambos. Some of these genes encoded properties of neurotransmitters and some encoded proteins important for olfaction, and all of these could rationally be expected to play a role in aggression. We have focused on one of these, Dat which encodes a protein that destroys a number of neurotransmitters called monoamines at the synapse. There are two isoforms of this protein encoded by the gene, one produces Rambos, the other produces Gandhis, and they appear to be expressed in different parts of the fly brain. In humans, a mutation in a gene called MAOA, which does the same job as Dat in the fly, causes hyperaggression in the boys in which it is expressed, and most of the boys in this partiucular Dutch family which carry the mutant gene are imprisoned. Consequently, using our unusual approach, we have discovered an aggression gene in the fly that has a functional parallel in humans. In this proposal we will use sophisticated genetic tools to discover how the two Dat isoforms can generate Rambo and Gandhi behaviour. We will also initiate studies of some of the other aggression genes that appear to be involved in aggression, including two other genes that are implicated in neurotransmitter function, DopR2 which encodes a receptor for the neurotransmitter dopamine, and a gene called CG13794, which nobody what it does, but by its protein sequence may be implicated in the transport of the neurotranmsmitter serotonin. We shall also investigate the roles of two odourant binding protein genes, Obp99b and Obp56d, both of which are expressed highly in Rambo flies. Our results will enlighten the molecular basis of aggression in the fly, and, given our findings so far, our results may be very relevant for understanding the nature of human aggression.