Topological Mapping of genetic variations in human Olfactory Receptors

Abstract

The human olfactory system has enormous discriminatory power, with the ability to detect millions of different odorants. The initial recognition of chemical volatiles is performed by the large family of seven-transmembrane (7-TM) olfactory receptors (ORs), expressed in the olfactory neurons. This multigene family with approximately four hundred functional genes in humans, contribute essentially to detect and discriminate an extraordinary range of odors. Interestingly, human olfactory sensitivity also differs between individuals and populations. This feature has been related in some cases to genetic variation among individuals, thus the contribution of the genotype plays an important role in the perceptual variations for a given odor. Despite the extensive information about human olfactory thresholds for hundreds of chemical volatiles, studies on the genotype-phenotype associations of ORs natural variants have been limited to a few examples. Here, we analyzed a large compendium of more than sixty-five thousand natural variants in the coding region of human OR genes available in the public database. To rationalize this data, a topological assignation of the collected variants was conducted according to the structural and functional knowledge of close related G-Protein coupled receptors (GPCRs). Our results suggest that missense natural variants occur extensively within the OR family, especially in the 7-TM domains. Interestingly, some of high frequency variations were located in conserved functional regions, which could imply the disruption of the receptor activity. Finally, a web application was developed to facilitate the public access and analysis of this information. The human Olfactory Receptor Variant Database ( https://ramoncierco.shinyapps.io/orvdb/) is a free online resource, which presents a complete compendium of 65.975 SNVs in 361 human OR genes and several tools for evaluate their localization and impact on the receptor structure and function.