Some people are especially sensitive to isovaleric acid, a compound with a sweaty odor. A 2007 study found that part of this variation was associated with the olfactory receptor gene OR11H7P. Intriguingly, although it was registered as a pseudogene at the time, some people carried a version that could function as a receptor.
The researchers compared human detection thresholds with genetic variants, then confirmed a response to isovaleric acid in cell experiments. Alongside sensitivity to a particular odor, they also found a connection in sensitivity across several odors.
A pseudogene does not mean everyone carries the same version
Olfactory receptors are proteins that recognize odor molecules and initiate signals to the nervous system. A change in the gene that encodes a receptor, such as one that stops protein production prematurely, may prevent the production of a fully functional receptor.
This study focused on genes for which both receptor-producing and nonfunctional variants exist in human populations. The database label “pseudogene” does not, by itself, determine how the version carried by each person functions. The researchers investigated whether such differences were associated with odor detection sensitivity.
How dilute can four odors become and still be detected?
The researchers analyzed genetics and olfaction in 377 participants recruited in Israel for whom DNA was available. They measured detection thresholds for isovaleric acid, isoamyl acetate, L-carvone, and cineole. Cineole, however, was tested only in a randomly selected subgroup of 200 participants.
In the test, participants selected the odor-containing pen-like device from three alternatives. Samples were prepared at five concentrations in tenfold dilution steps in mineral oil. Each was presented near the nose for about three seconds. The threshold was determined using the concentration at which participants made four consecutive correct choices, with a further check at the preceding, more dilute concentration. Eighty-two participants were retested one to four weeks later to assess reproducibility.
On the genetic side, 43 of the original 52 candidate sites met the criteria for measurement quality and variant frequency and were analyzed. Combining them with the four odors produced 172 comparisons, so the researchers also applied a correction to reduce chance associations arising from multiple testing.
OR11H7P was associated with high sensitivity
A clear association emerged between OR11H7P genotype and the detection threshold for isovaleric acid. Among particularly sensitive participants, fewer people carried two nonfunctional copies, and more carried at least one functional copy. The association survived correction for multiple comparisons.
Here, “sensitive” means being able to detect the presence of dilute isovaleric acid more readily. The study did not assess how much people disliked the odor or how concerned they were about other people’s body odor. Actual sweat and body odor also contain mixtures of many molecules, so they should be distinguished from the result for this single compound.
OR11H7P genotype explained approximately 8% of the variation in isovaleric acid detection thresholds in this group. Rather than showing that one gene determines sensitivity, the result identifies one contributor to individual differences.
The functional receptor variant also responded to isovaleric acid in cells
An association in human data does not, by itself, establish that the receptor can actually recognize isovaleric acid. To test this separately, the researchers expressed human receptors and the machinery needed for signal transduction in African clawed frog oocytes and measured changes in electrical current in response to odor stimulation.
Cells expressing the functional OR11H7P variant responded to isovaleric acid. In contrast, the variant with a premature stop in protein production and three other olfactory receptors selected for comparison did not show the same specific response under those conditions.
The neighboring receptors OR11H4 and OR11H6 also responded to isovaleric acid. Although the functional OR11H7P variant produced a larger average response, differences in response magnitude among these three receptors were not significant. Several closely related receptors may contribute to recognizing isovaleric acid.
The concentration that elicited a response in the cell experiment was higher than the concentrations at which people detected the dilute odor. Stimuli also reach cells in solution differently from the way they reach a human nose, where airflow and mucus play a part. The cell experiment supports the receptor–molecule relationship; it should not be treated as a direct reproduction of nasal sensitivity.
Sensitivity to the four odors also had something in common
Another important finding was a significant correlation in detection thresholds for every pair of the four odors. People who were sensitive to one odor tended to be sensitive to others, and more people were highly sensitive to several odors than would be expected if sensitivities were unrelated.
Nevertheless, the association between OR11H7P and isovaleric acid remained after overall sensitivity was added to the statistical model as an adjustment. Differences in recognizing a particular molecule appear to coexist with differences in sensitivity shared across several odors.
The authors suggest that signaling downstream of receptors, brain processing, and environmental exposure might contribute to shared sensitivity. This study did not identify the genes responsible for that common mechanism. Thresholds also fluctuated when the same individuals were retested, underscoring the importance of not treating sensitivity as a fixed property defined by a single measurement.
Summary
People with high sensitivity to isovaleric acid were more likely to carry a functional OR11H7P variant, and that receptor variant also responded to isovaleric acid in cells. The study showed that a gene registered as a pseudogene can have a functional version in some individuals and be associated with how readily they perceive an odor.
At the same time, sensitivity to the four odors had a shared component, and OR11H7P could not explain most individual variation. Nearby genetic differences could also contribute. The authors therefore conclude that sensitivity needs to be understood through both specific receptors and multiple mechanisms affecting olfaction more generally.
The study was supported by the US NIH, the Crown Human Genome Center, and other funding. One author received an Eshkol fellowship from the Israeli Ministry of Science, Culture and Sports. The authors declared no competing interests.
References
Menashe I, Abaffy T, Hasin Y, et al. Genetic Elucidation of Human Hyperosmia to Isovaleric Acid. PLOS Biology. 2007;5(11):e284. doi:10.1371/journal.pbio.0050284.
