Molecular evolution of odorant receptor specificities in Drosophila

描述（由申请人提供）：行为是由大量基因之间的相互作用形成的。为了理解行为变异的遗传基础，必须剖析其潜在的遗传结构，并且必须确定导致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，因为最近的进展揭示了遗传因素和神经编码。化学感觉知觉是一个重要的人类健康问题。老年人嗅觉灵敏度的丧失会影响营养和生活质量，嗅觉缺陷是一些神经系统疾病的诊断，如阿尔茨海默氏症。人类的化学感觉知觉是多变的，某些特定的嗅觉缺失是由基因决定的。然而，尽管我们对气味编码的理解有所进步，但在初级气味受体水平上，嗅觉感知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，它们嗅觉系统的组织有类似的原理。在这两个系统中，气味受体家族被用来区分大量的气味。然而，果蝇的嗅觉系统在数量上不那么复杂，使用果蝇很容易控制遗传背景和环境。这个系统为我们提供了一个极好的机会来阐明嗅觉受体的分子多态性如何影响嗅觉行为的变化。该应用提出了三个具体目标：(1)测量黑腹果蝇（Drosophila melanogaster）野生自交系群体嗅觉行为的自然变异；(2)量化气味受体分子变异对自然行为变异的贡献；(3)测试气味受体等位基因变异的功能效应。将评估一系列气味的行为变化，并通过对气味受体基因家族进行测序来鉴定单核苷酸多态性。对嗅觉行为自然变异有贡献的多态性随后将被识别，并通过野生衍生系之间的杂交进一步验证。此外，还将对导致嗅觉行为变化的潜在机制进行功能研究。这些实验将为识别特定气味的受体集合如何在单核苷酸多态性水平上促进行为的自然变化提供新的见解。更广泛地说，这些结果将为理解候选基因座的遗传变异如何导致行为的功能差异以及自然界复杂性状变异的起源和维持机制提供一个模型。公共卫生相关性：化学感觉知觉是一个重要的人类健康问题，因为老年人嗅觉灵敏度的丧失会影响营养和生活质量，嗅觉缺陷是几种神经系统疾病的诊断。然而，尽管我们对气味编码的理解有所进步，但在初级气味受体水平上，嗅觉感知变化的分子基础仍然知之甚少。提出的研究通过剖析嗅觉行为的潜在遗传结构和检查候选行为位点的变异形成行为变异的机制来解决这个问题。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Chemosensory perception is an important human health issue as loss of olfactory acuity in the elderly can compromise nutrition and quality of life and olfactory deficits are diagnostic of several neurological disorders. 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 proposed research addresses this question by dissecting the underlying genetic architecture of olfactory behavior and examining the mechanism(s) by which variation in candidate behavioral loci shape behavioral variation.