The Genetic Basis of Specific Anosmia

描述（由申请人提供）：神经科学中的一个基本问题是将刺激的物理特性映射到感知特征。在视觉中，波长转化为颜色；在试听中，频率转化为音高。相比之下，从化学结构到嗅觉感知的映射是未知的。换句话说，世界上没有一个科学家或调香师能够观察到一种新的分子结构并预测它的气味。解决这个问题的第一步是将嗅觉受体的变化与感知的变化联系起来。感知变异的一种形式是特异性嗅觉缺失症，它描述了一个人对特定分子的敏感性降低，尽管其他嗅觉能力完好无损。这种表型被认为反映了嗅觉受体基因的多态性，就像色盲反映了视觉系统中一个锥体受体的缺陷一样。在此，我建议通过对特异性嗅觉缺失的研究来研究嗅觉感知的遗传基础。这一提议旨在研究嗅觉受体基因的变异如何影响嗅觉感知的变化。在目标1中，我将使用人类气味受体的异种表达系统来筛选对异戊酸和五戊内酯（两种与特定嗅觉缺失有关的气味化学物质）有反应的候选气味受体。在目标2中，我将把特定嗅觉缺失的心理物理检测阈值簇与潜在受体的基因型联系起来。通过关注易于心理物理表征且涉及较少基因的表型，我们希望提供嗅觉系统中遗传变异与感知表型之间的第一个联系。了解特异性嗅觉缺失是如何发生的，将允许人工诱导特异性嗅觉缺失或嗅觉减退，通过对某些受体类型产生激动剂和拮抗剂来消除或增强特定气味。此外，嗅觉是了解多因子性状遗传基础的理想模型系统。许多嗅觉基因似乎并不是人类健康所必需的，这使得基因型中存在大量的遗传变异。模型动物（人类）的这种巨大的自然变异可以清楚地描述基因型变异的感知后果，从而可以仔细研究基因型和表型之间的联系。

DESCRIPTION (provided by applicant): A fundamental problem in neuroscience is mapping physical properties of a stimulus to perceptual characteristics. In vision, wavelength translates into color; in audition frequency translates into pitch. By contrast, the mapping from chemical structure to olfactory percept is unknown. In other words, there is not a scientist or perfumer in the world who can view a novel molecular structure and predict how it will smell. The first step in solving this problem is to link variation in the olfactory receptor to variation in perception. One form of perceptual variation is specific anosmia, which describes an individual with a lowered sensitivity to a specific molecule despite otherwise intact olfactory abilities. This phenotype is thought to reflect polymorphisms in the olfactory receptor genes, much as color-blindness reflects a deficiency in one of the cone receptors in the visual system. Here I propose to study the genetic basis of olfactory perception through the investigation of specific anosmia. This proposal intends to examine how variation in olfactory receptor genes underlies variation in olfactory perception. In Aim 1 I will use a heterologous expression system of human odorant receptors to screen for candidate odorant receptors that respond to isovaleric acid and pentadecalactone-two odorant chemicals implicated in specific anosmia In Aim 2 I will correlate the psychophysical detection threshold clusters of specific anosmia with the underlying receptor's genotype. By focusing on phenotypes that are both easy to psychophysically characterize and involve few genes, we hope to provide the first links between genetic variation and perceptual phenotype in the olfactory system. . Understanding how specific anosmia occurs would allow either specific anosmia or hyposmia to be artificially induced to eliminate or enhance specific odors by producing agonists and antagonists for certain receptor types. In addition, olfaction represents an ideal model system for understanding the genetic basis of multi-factor traits. A number of olfactory genes do not appear to be essential for human fitness, which has allowed a large amount of genetic variation in the genotype. This large natural variation in a model animal (humans) that can clearly describe the perceptual consequences of genotypic variation allows for careful study of the link between genotype and phenotype.