Abstract
BackgroundOlfactory receptors (ORs) constitute a large family of sensory proteins that enable us to recognize a wide range of chemical volatiles in the environment. By contrast to the extensive information about human olfactory thresholds for thousands of odorants, studies of the genetic influence on olfaction are limited to a few examples. To annotate on a broad scale the impact of mutations at the structural level, here we analyzed a compendium of 119,069 natural variants in human ORs collected from the public domain.ResultsOR mutations were categorized depending on their genomic and protein contexts, as well as their frequency of occurrence in several human populations. Functional interpretation of the natural changes was estimated from the increasing knowledge of the structure and function of the G protein-coupled receptor (GPCR) family, to which ORs belong. Our analysis reveals an extraordinary diversity of natural variations in the olfactory gene repertoire between individuals and populations, with a significant number of changes occurring at the structurally conserved regions. A particular attention is paid to mutations in positions linked to the conserved GPCR activation mechanism that could imply phenotypic variation in the olfactory perception. An interactive web application (hORMdb, Human Olfactory Receptor Mutation Database) was developed for the management and visualization of this mutational dataset.ConclusionWe performed topological annotations and population analysis of natural variants of human olfactory receptors and provide an interactive application to explore human OR mutation data. We envisage that the utility of this information will increase as the amount of available pharmacological data for these receptors grow. This effort, together with ongoing research in the study of genetic changes in other sensory receptors could shape an emerging sensegenomics field of knowledge, which should be considered by food and cosmetic consumer product manufacturers for the benefit of the general population.
Highlights
Olfactory receptors (ORs) constitute a large family of sensory proteins that enable us to recognize a wide range of chemical volatiles in the environment
Vertebrate olfactory systems have evolved to sense volatile substances through their recognition by olfactory receptors (ORs) located on the membrane of olfactory sensory neurons in the olfactory epithelium [1] and consequent initiation of signaling cascades that transform odorant-receptor chemical interactions into electrochemical signals [2, 3]. These receptors belong to the class A G protein-coupled receptors (GPCRs), a major drug target protein family [4] involved in the transduction of extracellular signals through second messenger cascades controlled by different heterotrimeric guanine nucleotide-binding proteins (Golf in the case of ORs) coupled at their intracellular regions [5, 6]
The lowest variation rates correspond to the OR14 family and few more than a dozen receptors with less than 100 mutation counts (Additional file 1: Tables S2-S3)
Summary
Olfactory receptors (ORs) constitute a large family of sensory proteins that enable us to recognize a wide range of chemical volatiles in the environment. ORs are characterized by intronless coding regions of an average length of 310 codons (~ 1 kb) and constitute the largest multigene family in humans, with around 400 intact (functional) loci, divided into two main classes, 18 families and more than 150 subfamilies [7, 8] This broad array of receptors, like in other terrestrial mammals, is shared with tetrapods (families 1–14) and marine vertebrates (families 51–56) [9] and seems necessary to respond efficiently to the extraordinary chemical diversity of odorants in Earth’s ecosystems [10]. Human genomic data reveal that OR loci harbor a considerable number of genetic variants and a high proportion of pseudogenes [13, 14] Many of these changes may interfere with the receptor expression, interaction with odorants, or signal transduction and could modify the physiological response to a determinate olfactory stimulus. To further study this issue, we used publicly available human sequencing data to conduct in silico data mining and analysis of OR natural variants in 141,456 human exomes and genomes from more than one hundred thousand unrelated individuals [21]
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