Molecular evolution of odorant receptor specificities in Drosophila

行为是由大量基因之间的相互作用形成的。为了了解基因 行为变异的基础，其潜在的遗传结构必须被解剖， 必须鉴定引起行为功能差异的特定遗传多态性。 化学感觉行为是解决这些目标的一个很好的系统，因为最近 揭示遗传因素和神经编码的进展。化学感受 感知是一个重要的人类健康问题。老年人嗅觉灵敏度的丧失 营养不良、生活质量下降和嗅觉缺陷是几种神经系统疾病的诊断依据， 疾病，如阿尔茨海默氏症。人类的化学感觉感知是可变的，有一些特定的 由基因决定。然而，尽管我们对气味编码的理解有所进步， 在初级气味受体水平上嗅觉变化的分子基础 仍然知之甚少。脊椎动物和昆虫气味编码的相似性表明 它们的嗅觉系统也有类似的原理。在这两种制度中，家庭 气味受体的功能被用来区分大量的气味。果蝇 然而，嗅觉系统在数量上不那么复杂，果蝇的使用很容易允许 控制遗传背景和环境。该系统为我们提供了一个很好的 有机会阐明气味受体的分子多态性如何有助于 嗅觉行为的变化。本申请提出了三个具体目标：（1）测量 果蝇野生近交系群体嗅觉行为的自然变异 （2）量化气味受体的分子变异对自然嗅觉的贡献。 行为的变化，以及（3）测试气味受体中等位基因变化的功能效应。 将评估对一系列气味剂的行为变化， 将通过对气味受体基因家族进行测序来鉴定。多态性有助于 嗅觉行为的自然变异将被识别，并通过杂交进一步验证 在野生衍生系中。此外，对潜在机制的功能研究， 有助于嗅觉行为的变化将进行。这些实验将提供新的 深入了解识别特定气味的受体集合如何有助于自然 单核苷酸多态性水平上的行为变异。更广泛地说，结果将 为理解候选基因座的遗传变异如何导致功能性 行为的差异以及变异的起源和维持机制， 复杂的特征

Behavior is shaped by interactions among a large number of genes. To understand the genetic underpinnings of variation in behavior, its underlying genetic architecture must be dissected and the specific genetic polymorphisms that cause functional differences in behavior must be identified. Chemosensory behavior is an excellent system for addressing these goals because of recent advances uncovering both the genetic factors and neural coding involved. Chemosensory perception is an important human health issue. Loss of olfactory acuity in the elderly can compromise nutrition and quality of life and olfactory deficits are diagnostic of several neurological disorders, such as Alzheimer's. Human chemosensory perception is variable, with some specific anosmias genetically determined. Yet despite advances in our understanding of odor coding, the molecular basis of variation in olfactory perception at the level of the primary odorant receptors remains poorly understood. The similarity of odor coding in both vertebrates and insects suggests analogous principles underlie the organization of their olfactory systems. In both systems, families of odorant receptors are used to discriminate among a vast repertoire of odorants. The Drosophila olfactory system, however, is quantitatively less complex and the use of Drosophila readily allows for the control of genetic background and environment. This system provides us with an excellent opportunity for elucidating how molecular polymorphisms in odorant receptors contribute to variation in olfactory behavior. This application proposes three specific aims: (1) to measure natural variation in olfactory behavior in a population of wild-derived inbred lines of Drosophila melanogaster; (2) to quantify the contribution of molecular variation in odorant receptors to natural variation in behavior, and (3) to test the functional effects of allelic variation in odorant receptors. Behavioral variation to an array of odorants will be assessed and single nucleotide polymorphisms will be identified by sequencing the odorant receptor gene family. Polymorphisms contributing to natural variation in olfactory behavior will then be identified and further validated using crosses among wild-derived lines. In addition, functional studies of the underlying mechanisms that contribute to variation in olfactory behavior will be conducted. These experiments will provide new insights into how ensembles of receptors that recognize defined odorants contribute to natural variation in behavior at the level of single nucleotide polymorphisms. More broadly, the results will provide a model for understanding how genetic variation in candidate loci results in functional differences in behavior and the mechanisms underlying the origin and maintenance of variation in complex traits in nature.