NEW YORK (GenomeWeb) – Variation within human olfactory receptor genes affects people's perception of smells, a new study has found.
The human genome harbors some 400 olfactory receptor genes, but individuals vary in which pseudogenes, copy number variants, and SNPs they have, all of which can influence their sense of smell.
Researchers led by the University of Pennsylvania's Joel Mainland sequenced the olfactory receptor gene repertoire of more than 300 individuals whose sense of smell was also tested using nearly 70 odorants. As they reported in the Proceedings of the National Academy of Sciences this week, the researchers found that genetic variation in a single olfactory receptor (OR) gene, such as a loss of function variant, could affect how a person perceived an odorant's intensity or pleasantness.
"This study demonstrates how natural variation can provide important clues to the normal translation of OR activation to odor information and places a constraint on the amount of redundancy in the olfactory code," the researchers wrote in their paper.
They sequenced the entire OR gene region — a span of about 800 kilobases covering 418 olfactory receptor genes and 256 olfactory-related genes — in 332 individuals. They reached 15X coverage for 96 percent of the targeted region and identified 19,535 variants, a subset of which they validated using Sanger sequencing.
The participants also underwent phenotyping to assess their perception of 68 odorants at two concentrations, their detection limit of three odorants, and the overall acuity of their sense of smell.
Eight odorant perception phenotypes were significantly related to variation within a single olfactory receptor locus, the researchers reported. This, they noted, was despite an odorant typically activating more than one olfactory receptor.
Performing a series of in vitro functional assays, the researchers confirmed these associations and began to tease out which olfactory receptor gene — as many are closely located — might be the causal one. For instance, when they examine three olfactory receptor genes linked to the perceived intensity of 2-ethylfenchol that are closely located on chromosome 6, they found that only one haplotype — OR11A1 — responded on their heterologous assay, suggesting it was the best candidate for a causal locus there.
The researchers similarly analyzed their top 50 olfactory receptor-odorant phenotype pairs to find three dozen unique olfactory receptor loci-odorant associations. As they expected their false-positive rate to be high because of the limits of heterologous assays, the researchers also tested them in a cell-based assay. From this, they found 11 instances in which the OR-odorant pair was active, higher than expected.
For some of the cases, the researchers found that individuals with less responsive OR haplotypes rated the perceived intensity of the receptor ligands as less intense, as compared to those with more responsive haplotypes. This, they noted, was in line with previous studies. However, in other cases, less responsive haplotypes were associated with a boost in perceived intensity.
The researchers also examined the contribution of genetic ancestry, age, and gender to the variance in odorant perception. Genetic ancestry could account for more than 4 percent in the variance of the perception of six phenotypes, especially in the perceived pleasantness of vanillin, but had a more limited influence on other olfactory phenotypes. The researchers noted that their analysis could not tease apart the influence of culture, other genetic factors, and social factors that are tightly linked to ancestry.
Still, when bundled together, they estimated that single OR genotype, age, genetic ancestry, and gender could explain between 10 percent and 20 percent of variation on 15 olfactory perception phenotypes.
This suggested to the researchers that these natural variations within smell perception could — like colorblindness did in vision studies — help determine how receptors encode odors.