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Abstract
The sense of smell in humans makes an appealing model system to explore genotype-phenotype associations, as the human olfactory receptor (OR) gene family is intensely affected by genetic variations. These variations were hypothesized and later shown to contribute to the diversity of odor-specific phenotypes. In my thesis I performed a genetic association study aimed to further expand such odor-specific associations, and in parallel examine a possible genetic basis for general olfactory sensitivity (GOS), a phenotype that has been scantly studied, comprising of overall inter-individual differences in smell sensitivities. The working hypothesis was that genetic variations in olfactory auxiliary genes, including genes mediating olfactory signal transduction or involved in olfactory sensory neuron development and integrity, constitute the genetic basis for GOS. For this purpose I performed a systematic exploration for olfactory auxiliary genes and their genomic variations (http://genome.weizmann.ac.il/GOSdb) using 11 data sources. One source for data was next-generation transcriptome sequencing of human and mouse olfactory tissues and identification of differentially expressed genes.
Subsequently I employed a custom array of single nucleotide polymorphisms (SNPs) that consisted of functional variations in selected 124 olfactory auxiliary genes and 363 ORs. Analyzing thresholds for five odorants in a cohort of 356 Caucasian subjects I have found that a rare intact allele of the auxiliary gene cytochrome P450 CYP2G2, commonly considered as a fixed human pseudogene, was associated with hypersensitivity to the steroid odorant androstenone, a sex pheromone in some mammals. In a collaborative study, this association was corroborated in two other cohorts. The result indicates that CYP2G2 is functional in some humans, and is interpretable in terms of enzymatic processing of androstenone within the olfactory epithelium, leading to a modified odorant with higher receptor affinity. Twelve additional putative association signals for OR genes with specific odorant sensitivities await replication and conceptual elucidation.
