MOLECULAR BASIS OF OLFACTORY DISCRIMINATION

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The mechanisms by which mammals discriminate a vast array of diverse odors are poorly understood. In previous studies we identified a novel multigene family in rat that codes for hundreds of different odorant receptors (ORs) that are expressed on olfactory sensory neurons in the olfactory epithelium of the nasal cavity. ORs exhibit characteristic sequence motifs, but as a group are extremely variable. The tremendous size and diversity of the OR family are consistent with an ability to recognize a wide variety of structurally diverse odorants. We have recently found spatial patterns of OR gene expression in the olfactory epithelium that indicate that there may be a broad organization of sensory information in the epithelium that is maintained in the axonal projection to the olfactory bulb. In order to understand the functional significance of this organization, it is critical that information be obtained about the functional specificity of individual ORs. One clearcut approach to this problem is to examine the role of individual ORs in human perception. By taking such an approach, it may be possible to not only gain information important to an understanding of olfactory information processing, but also gain insight into the bases of perceptual differences in the human population. In the studies described in this proposal we will initiate efforts to correlate individual OR genes with the ability of humans to perceive particular odorants. We will first attempt to isolate and characterize the entire human OR gene family. In preliminary experiments, we have thus far isolated approximately 500 different human OR genes. We will now search for additional clones containing genes missed in our initial screen and isolate the OR genes that they contain. The OR genes will then be grouped into subfamilies by nucleic acid hybridization and nucleotide sequence analyses will be performed to investigate the extent of diversity in the human OR family. Our previous studies in the mouse predict that clusters of human OR genes will be located at numerous different chromosomal sites. To define the chromosomal organization of human OR genes we will first assign individual OR genes to specific chromosomes using probes prepared from somatic cell hybrid lines containing different human chromosomes. We will then localize clusters of OR genes to specific regions of these chromosomes by fluorescence in situ hybridization. Finally, we will use the isolated OR genes we have isolated and the information we have accumulated on human OR genes to analyze the extent of variation in OR repertoire in the human population.