A novel approach to identifying aggression genes in Drosophila

侵略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。我们采用了一种新颖的方法，我们找来一对基因完全相同的雄性，让它们争斗30分钟。有些人经常打架（兰博），有些人不打架（甘地）。我们比较了两组之间表达不同的基因，发现Rambos中有一小部分基因要么上调，要么下调。这些基因中的一些编码神经递质的特性，一些编码对嗅觉很重要的蛋白质，所有这些都可以合理地预期在攻击中发挥作用。我们专注于其中的一种，Dat，它编码一种蛋白质，这种蛋白质会破坏突触上被称为单胺的神经递质。这种基因编码的蛋白质有两种同种异构体，一种产生兰博斯，另一种产生甘地，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，它的作用与苍蝇中的Dat基因相同，导致表达这种基因的男孩具有过度攻击性，在这个特殊的荷兰家庭中，携带突变基因的大多数男孩都被监禁了。因此，通过我们不同寻常的方法，我们在苍蝇身上发现了一种与人类功能相似的攻击性基因。在这个建议中，我们将使用复杂的遗传工具来发现这两种数据异构体是如何产生兰博和甘地行为的。我们还将开始研究其他一些似乎与攻击有关的攻击性基因，包括另外两个与神经递质功能有关的基因，DopR2编码神经递质多巴胺的受体，还有一个叫做CG13794的基因，没有人知道它的作用，但从它的蛋白质序列来看，可能与神经递质血清素的运输有关。我们还将研究两个气味结合蛋白基因Obp99b和Obp56d的作用，这两个基因在兰博蝇中都有高表达。我们的研究结果将揭示苍蝇攻击的分子基础，并且，鉴于我们目前的发现，我们的结果可能与理解人类攻击的本质非常相关。

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.