Can You Smell Isovaleric Acid?

 
Isovaleric acid [3-Methylbutanoic acid] smells like sweat. It is responsible for some of the odor in a locker room, for example. Although we can all detect that odor, some of us are much more sensitive to it than others. In fact, the concentrations of isovaleric acid that can be detected differs by as much as 10,000-fold from one individual to the next.

It turns out that the ability to detect the molecule has a genetic component. It's quite likely that many people reading this blog can't smell isovaleric acid at low concentrations because they don't have one of the olfactory receptors for that ligand [A Sense of Smell: Olfactory Receptors].

Mice have about 1000 genes for olfactory receptors and this single gene family accounts for about 4% of all the genes in the mouse genome. Since each receptor is presumably capable of binding a specific odorant, it seems very likely that mice can detect a large number of different smells.

Humans have about 800 olfactory receptor genes but half of them are pseudogenes. They are incapable of producing a full-length functional receptor protein. Thus, it is reasonable to conclude that humans can detect far fewer smells than mice can.

These conclusions are based on the assumption that each olfactory receptor can bind to a single odorant molecule—or a small number of related molecules. If this assumption is correct then it should be possible to identify specific olfactory receptor genes that are responsible for the diversity in odor detection. Menashe et al. (2007) decided to test this by surveying 377 individuals for their ability to detect four odorants: isoamyl acetate, isovaleric acid, L-carvone, and cineole. The authors then tried to correlate ability to detect low levels of these odorants with the presence of specific markers for alleles of olfactory receptor genes.

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A Sense of Smell
There was a strong association between ability to detect low levels of isovaleric acid and an allele for OR gene OR11H7P. This particular allele (OR11H7Pi) is an active form of the gene whereas the other allele is a pseudogene. People who were homozygous for the pseudogene were much less sensitive to isovaleric acid whereas people who had one or two copies of the active gene could detect low levels of isovaleric acid.

It looks like OR11H7P encodes a receptor that binds isovaleric acid. In order to test this Menashe et al. cloned the active gene and inserted it into a frog oocyte detection system. The olfactory receptor encoded by this gene responded to isovaleric acid whereas the pseudogene produced no response and other intact genes did not respond to this ligand.


The OR11H7P gene is part of a large cluster of olfactory receptor genes on chromosome 14. (OR11H7P is the yellow triangle marked by two asterisks.) The two flanking genes (OR11H4 and OR11H6) are closely related to OR11H7P indicating recent duplication events. Menashe et al. also cloned and tested these genes in the in vitro assay and they responded to isovaleric acid as well. This probably explains the detectability of isovaleric acid in those people who lack a functional copy of OR11H7P.

The results demonstrate a direct link between phenotpypic variation in human olfaction and olfactory receptor gene polymorphisms. This linkage does not account for all of the variation in ability to detect isovaleric acid. In fact, the authors estimate that it accounts for less than 10% of the variation. The rest is probably due to polymorphisms or environmental differences in downstream parts of the olfactory detection pathway.

The results also show that there is a certain amount of redundancy in ligand binding to receptors. Closely related olfactory receptors molecules tend to bind similar odorants. The more kinds of active receptors present in the sensory neurons of the nasal cavity, the greater the capacity to detect low concentrations of odorant.

The authors note that the OR11H7P gene is identified as a pseudogene in the public databases [EntrezGene 390441]. The fact that they were able to discover a minor active allele is a warning to not assume that all annotated pseudogenes are necessarily inactive in all individuals.

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Menashe, I., Abaffy, T., Hasin, Y., Goshen, S., Yahalom, V., Luetje, C.W. and Lancet, D. (2007) Genetic Elucidation of Human Hyperosmia to Isovaleric Acid. PLoS Biology 5:e284 doi:10.1371/journal.pbio.0050284. [PLoS Biology]