Olfactory Mechanisms

If taste is the gatekeeper, the sense of smell is the sentinel, evaluating the food for danger before it enters the mouth. When offered an unfamiliar food, we will smell it before we taste it, and smell is one of the key first defenses against spoiled food and an important source of eating enjoyment. Thus, the sense of smell and its loss can have powerful consequences for food intake and quality of life.138,139 Before addressing genetics of smell and its potential connections to food intake, we introduce the olfactory system for background information.

A. The Olfactory System

When working normally, the sense of smell, or olfaction, enables us to detect a large number of different odorants and to perceive these volatile compounds as odors. Although the stimuli (odorants) are also sometimes called odors, in psychophysics, odor refers to a percept, the result of the process of odor perception, whereas odorant refers to the chemical that elicited the odor.

The airborne molecules from food take one of two paths to sensory cells in the olfactory epithelium: the orthonasal route (through the nostrils, before eating) or the retronasal route (through the nasopharynx, while eating). Both paths are important in food intake, for defense and for pleasure. In the olfactory epithelium, the airborne odorants are detected by olfactory receptors. The receptors lie embedded in the membrane of olfactory sensory neurons, each of which accommodates only one type of receptor.140Binding of an odorant molecule by an olfactory receptor initiates a signal transduction cascade, which ultimately leads to the transfer of the olfactory signal to the brain, where the odor percept is generated.

To be a potential odorant, a molecule has to be volatile enough to reach the olfactory epithelium with airflow. Although most volatiles are odorants, some small molecule volatiles, such as carbon monoxide and carbon dioxide, are odorless. In addition, structurally diverse molecules can elicit indistinguishable odors, while similar molecules, such as stereoisomers, can yield distinct odors (e.g., R(–)-carvone smells like spearmint, but S()-carvone smells like caraway).141,142 To date, the type of odor elicited by a volatile compound cannot be reliably predicted by the structure of the molecule.143

Humans have about 400 different olfactory receptor types, a number greatly exceeded by the number of potential odorants. Thus, it is unlikely that a particular receptor would bind only one type of odorant or that a certain odorant would attach specifically to only one type of receptor. Instead, the olfactory system is thought to make use of combinatorial receptor coding to gain the capacity to recognize the immense amount of odorants; several types of related receptors bind an odorant with varying affinities, and in turn, multiple related odorants can be detected by the same receptor.140 The combinatorial coding suggests that most olfactory receptors are selective (broadly tuned) rather than very specific (narrowly tuned). However, the breadth of tuning varies among olfactory receptors.144,145

Only a few of the human olfactory receptors have been linked with their odorant ligands (i.e., the molecules that they detect).146 Development of automated, high-throughput methods for matching the receptors and their ligands in cell-based model systems (or using computational models) will facilitate confirming the functionality of the receptors. These methods, however, cannot replace the measurement of actual human responses in studies of geneticinfluence on odor percepts. The psychophysical measurement of responses to odorous stimuli remains a time-consuming but essential step when the genetics of the sense of smell and its implications for food intake are studied.

B. Genetics of Olfaction

Humans have nearly 400 potentially functional olfactory receptor genes (OR genes), making this gene family one of the largest in the human genome.147 In addition to these intact genes, which are thought to produce functional olfactory receptors, humans have at least a similar number of nonfunctional OR genes (pseudogenes) and about 60 genes of which both functional and nonfunctional variants are known to exist (segregating pseudogenes). The exact number of functional genes will be known only after the functionality of the corresponding receptors is demonstrated. However, it is obvious that far more genes encode receptors for smell than for taste. The larger number of olfactory receptors likely reflects the need to detect a wider variety of compounds than is the case for taste. Further, the large number of compounds detected by the sense of smell reflects the wider role of this sense: While the sense of taste serves almost exclusively ingestion, the sense of smell has other functions, too. These include sensing environmental dangers (e.g., smoke) and potential interpersonal chemosignaling (e.g., sexual selection).

The heritability of a trait makes the search for genes influencing that trait reasonable. If little or no heritability is found, the underlying genes, if any, are difficult, if not impossible, to locate in gene-mapping studies. While the ability to smell some odorants is heritable, for other odorants, it is not. For instance, the ability to smell food odors like chocolate or lemon is associated with little or no heritability.148,149However, the pleasantness of cinnamon is heritable and has been mapped to chromosome 4 by linkage analysis.150 If the allelic genes that determine the pleasantness of odors like cinnamon are identified, studies of genotype and food intake might be worthwhile.

Individual variation in perception of some odors has been attributed partly to specific OR genes. The differences among people in the ability to smell androstenone are at least partially determined by genes,151,152 and an allele of an OR gene, OR7D4, contributes to this trait.153 However, unlike alleles of the taste receptor gene TAS2R38, which account for almost 70% of the person-to-person variation in perception of bitter taste from PTC,41 OR7D4 alleles account for only a small amount of variance in perception of androstenone.153 Two other OR genes have been associated with individual variation in the sense of smell: OR11H7 with isovaleric acid (sweaty odor)154 and OR2M7 with the smell of asparagus metabolites in urine.155 Association between the gene OR2J3 and detection of cis-3-hexen-1-ol (green leaf odor) has also been suggested.156 Why there is relatively little effect of the alleles of a singleolfactory receptor on perception lies in this sense’s complex nature: Many olfactory receptors combine to detect a particular odorant,140 and one odorant may stimulate many receptors, so if one is not working, others may compensate.

Systematic, repeated exposures to individual odorants have been demonstrated to lower detection thresholds (increased sensitivity) to these odorants, suggesting that genes do not entirely determine the perceptions.157,158 One possibility, yet to be proved, is that there are gene-environment interactions in odor perception (i.e., genes influencing the sense of smell are controlled differently in different environments). Whatever the mechanism, the flexibility of the sense of smell could have been evolutionarily appropriate. When first humans moved to new environments and encountered novel odorants from new threats (e.g., toxins) and opportunities (e.g., food sources), the flexible sense of smell may have helped the population to survive.

C. Implications for Food Intake

Although there may also be some innate preferences, smell is probably more flexible and amenable to learning159 when compared to taste. This point is particularly relevant when we consider olfaction as a sentry against spoiled food: The products of fermentation can be perceived as wholesome or harmful, depending on context. As an example, isovaleric acid has a pungent odor that people like if they are told it is from cheddar cheese and dislike if they are told it is from body odor.160 Likewise, people will eat food with a bad smell (e.g., durians or limburger cheese) if they know it is safe and they like the taste. In addition, the pleasant odor of food can stimulate appetite, but the potency of these genetic differences in determining food intake and obesity is unclear.

nvestig Genet. 2015; 6: 2.
Published online 2015 Feb 17. doi:  10.1186/s13323-015-0021-3
PMCID: PMC4331135

On the nose: genetic and evolutionary aspects of smell

Among my Christmas presents this year was some perfume – Acqua di Parma, in a beautiful cylindrical buttercup-yellow box. It was from my son, who since his transition to adulthood has developed an interest in such things, and in return we gave him (as requested) Terre d’Hermès. To my ill-educated nose, both smell pretty good – but there’s a more expert source to turn to for an opinion. This is Perfumes: the A-Z Guide, by Luca Turin and Tania Sanchez [1]. Behind its unpromising title lies an entertaining, witty and informative book. The authors write with withering style about the scents they most dislike. So it’s with trepidation you look up the perfume you’ve acquired – luckily those mentioned above both rate a respectable three out of five stars. One-star reviews include ‘smells like a New York sidewalk in July’, ‘less a fragrance than a headache force-field’, and ‘useful as a contraceptive, but little else’.

The ~1800 perfumes sniffed for The A-Z Guide are testament to the lengths to which we humans will go to make us smell like something else. We wash ourselves with soaps and shampoos, anoint our sweatiest bits with deodorants and antiperspirants, and then spray on expensive cocktails of scented chemicals and natural extracts. This is curious, because it appears that nature’s clear intention was for us to smell abundantly of ourselves.

When our ancestors lost their body hair, they retained the associated sebaceous glands designed to anoint each hair with water-repellent secretions. In fact, we have denser aggregates of such glands than almost any other mammal. In addition, we each have 3 million sweat glands capable of exuding 12 litres of cooling fluid daily. There are two varieties – eccrine, which secrete 99% water, and apocrine, which secrete an oily fluid including proteins, lipids, fatty acids and steroids. The apocrine glands are confined to the hairy parts of the body, including the genital area and armpits (axillae). Indeed, in most humans the axillary density is so great that the array of glands is considered an organ. So, with our inherently smelly sebaceous secretions, and our apocrine sweat, made odorous by skin bacteria, we are without doubt the ‘scented ape’ [2].

Scented humans may be, but some are more scented than others. A few unfortunate people are homozygous for mutations in the gene encoding an enzyme, flavin-containing monooxygenase 3 [3], whose job is to metabolise amino-trimethylamine, produced by bacterial action in the gut. In the absence of the enzyme, the chemical is secreted in the sweat, urine and breath – its smell, reminiscent of decaying fish, makes the lives of sufferers very difficult indeed. In the general population travellers and anthropologists have remarked upon differences between the groups they encountered. Some of the early anecdotal accounts are, to modern minds, highly derogatory, and do not bear repeating. The major observation, however, seems real and evolutionarily interesting: in general, East Asians are less smelly than everyone else. This is connected to the number of apocrine glands in the axillary organ; while Europeans and Africans have glands packed so closely that they resemble a sponge, in Koreans (for example) they are either spread thinly or absent altogether [2].

The genetic basis of apocrine gland density is unknown, but genetics has illuminated population differences in odour via the seemingly unrelated subject of earwax. There are two kinds – the grey and flaky ‘dry’, prevalent in East Asians, and the yellow and waxy ‘wet’. A single nucleotide variant in the genome is responsible for this difference [4] – individuals who carry an A nucleotide at the relevant position in both copies of their ABCC11 gene (AA homozygotes) have dry earwax, while GA heterozygotes or GG homozygotes have the wet variety. The population distribution suggests positive selection for the A-allele in Asia, but earwax itself seems an improbable candidate. However, earwax emerges from specialised apocrine glands, and analysis of sweat from people carrying different genotypes indicates that the ABCC11 A variant is also responsible for reduced axillary odour [5], thanks to a failure to transport a smelly-molecule precursor into the sweat [6]. How selection came to act so strongly on this variant is not clear – perhaps choice of partner (sexual selection) was influenced strongly by odour, though why this should be so in some parts of the world but not in others, is puzzling.

There are two sides to smell, of course – as well as production, there is perception, and here most emphasis has been on differences between individuals. At one extreme, some people are born with no sense of smell at all (anosmia). Kallmann Syndrome is usually caused by mutations in the KAL1 gene on the X chromosome, and is often associated with complete anosmia in the male sufferers [7]. This phenotype arises from the failure of neurons in early development to migrate to form the olfactory bulb, where the sense of smell arises; the neurons also fail to reach their next destination, the hypothalamus, with the result that gonadotropin-releasing hormone is not produced. This in turn leads to failure of puberty, and to infertility.

Odour detection is mediated through olfactory receptors (ORs) in the cell membranes of olfactory neurons, encoded by a family of over 300 genes [8]. A combinatorial code of different ORs interacts with odorant molecules, so mutations involving OR genes could lead to specific anosmias – the inability to smell particular odorants. Indeed, genome-wide association studies have found variants within OR gene clusters linked to sensitivity to methanethiol (secreted in the urine after eating asparagus) [9], androstenone (produced in human sweat, by truffles, and by pigs in the mating season) [10], and also to the floral-smelling compound β-ionone [11]. The latter probably explains why some people cannot smell β-ionone-rich freesias [12].

So, what’s the purpose of human scent and our sense of smell? Other animals use scented chemicals (pheromones) to attract the opposite sex, and to indicate fertility – they induce stereotypical behaviours, as anyone who has owned a cat or dog in heat will know. Humans become highly scented animals when they reach sexual maturity, and poets from Catullus to Herrick have written with passion about the fragrances of their lovers. In the nineteenth century rustic Austrian girls used to keep a slice of apple in their armpits during a dance, and would afterwards offer it to their favoured partner to eat, as a token of interest [2]. Despite these sexual connections, compared to other animals, the human sense of smell is of little biological use. The relative proportion of the brain occupied by smell has decreased steadily in the primate lineage from lemurs to humans, and we lack the vomeronasal organ – the ‘second nose’ above the palate that causes our cats and dogs to act in response to pheromones. Plenty of websites offer fragrances such as ‘Alpha Dream’ and ‘PheroMen’, with promises of instant sexual irresistibility. But, despite reports of odour-mediated menstrual synchrony in female roommates [13], there is little evidence that human pheromones exist.

It seems that our production and perception of smell may be evolutionary vestiges, relegated when we stood upright and our visual systems became of primary importance, and when the need for pair-bonding made advertising female receptiveness disadvantageous. Yet scent enriches our lives, and its animal roots are never far away – among the ingredients of fine perfumes are substances scraped from the anal glands of indignant civet cats, or extracted from the musk glands of rutting male Himalayan deer.


1. Turin L, Sanchez T. Perfumes: The A-Z Guide. London: Profile Books Ltd.; 2008.
2. Stoddart DM. The Scented Ape: The Biology and Culture of Human Odour. Cambridge: Cambridge University Press; 1990.
3. Dolphin CT, Janmohamed A, Smith RL, Shephard EA, Phillips IR. Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome. Nat Genet. 1997;17:491–4. doi: 10.1038/ng1297-491. [PubMed] [Cross Ref]
4. Yoshiura K, Kinoshita A, Ishida T, Ninokata A, Ishikawa T, Kaname T, et al. A SNP in the ABCC11 gene is the determinant of human earwax type. Nat Genet. 2006;38:324–30. doi: 10.1038/ng1733.[PubMed] [Cross Ref]
5. Martin A, Saathoff M, Kuhn F, Max H, Terstegen L, Natsch A. A functional ABCC11 allele is essential in the biochemical formation of human axillary odor. J Invest Dermatol. 2010;130:529–40. doi: 10.1038/jid.2009.254. [PubMed] [Cross Ref]
6. Baumann T, Bergmann S, Schmidt-Rose T, Max H, Martin A, Enthaler B, et al. Glutathione-conjugated sulfanylalkanols are substrates for ABCC11 and gamma-glutamyl transferase 1: a potential new pathway for the formation of odorant precursors in the apocrine sweat gland. Exp Dermatol. 2014;23:247–52. doi: 10.1111/exd.12354. [PMC free article] [PubMed] [Cross Ref]
7. MacColl G, Bouloux P, Quinton R. Kallmann syndrome: adhesion, afferents, and anosmia. Neuron. 2002;34:675–8. doi: 10.1016/S0896-6273(02)00720-1. [PubMed] [Cross Ref]
8. Malnic B, Godfrey PA, Buck LB. The human olfactory receptor gene family. Proc Natl Acad Sci U S A. 2004;101:2584–9. doi: 10.1073/pnas.0307882100. [PMC free article] [PubMed] [Cross Ref]
9. Eriksson N, Macpherson JM, Tung JY, Hon LS, Naughton B, Saxonov S, et al. Web-based, participant-driven studies yield novel genetic associations for common traits. PLoS Genet. 2010;6:e1000993. doi: 10.1371/journal.pgen.1000993. [PMC free article] [PubMed] [Cross Ref]
10. Keller A, Zhuang H, Chi Q, Vosshall LB, Matsunami H. Genetic variation in a human odorant receptor alters odour perception. Nature. 2007;449:468–72. doi: 10.1038/nature06162. [PubMed] [Cross Ref]
11. McRae JF, Jaeger SR, Bava CM, Beresford MK, Hunter D, Jia Y, et al. Identification of regions associated with variation in sensitivity to food-related odors in the human genome. Curr Biol. 2013;23:1596–600. doi: 10.1016/j.cub.2013.07.031. [PubMed] [Cross Ref]
12. Wooding S. Olfaction: it makes a world of scents. Curr Biol. 2013;23:R677–9. doi: 10.1016/j.cub.2013.07.009. [PubMed] [Cross Ref]
13. Stern K, McClintock MK. Regulation of ovulation by human pheromones. Nature. 1998;392:177–9. doi: 10.1038/32408. [PubMed] [Cross Ref]

In 2004 Linda B. Buck and Richard Axel won the Nobel Prize in Physiology or Medicine for their work[46] on olfactory receptors.[47] In 2006, it was shown that another class of odorant receptors – known as trace amine-associated receptors (TAARs) – exist for detecting volatile amines.[48] Except for TAAR1, all functional TAARs in humans are expressed in the olfactory epithelium.[49] A third class of olfactory receptors known as vomeronasal receptors has also been identified; vomeronasal receptors putatively function as pheromone receptors.


Olfactory receptor

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Olfactory receptors (ORs), also known as odorant receptors, are expressed in the cell membranes of olfactory receptor neurons and are responsible for the detection of odorants (i.e., compounds that have an odor) which give rise to the sense of smell. Activated olfactory receptors trigger nerve impulses which transmit information about odor to the brain. These receptors are members of the class A rhodopsin-like family of G protein-coupled receptors (GPCRs).[1][2] The olfactory receptors form a multigene family consisting of around 800 genes in humans and 1400 genes in mice.[3]















See also




External linksExpression[edit]

In vertebrates, the olfactory receptors are located in both the cilia and synapses of the olfactory sensory neurons[4] and in the epithelium of the human airway.[5] In insects, olfactory receptors are located on the antennae and other chemosensory organs.[6] Sperm cells also express odor receptors, which are thought to be involved in chemotaxis to find the egg cell.[7]


Rather than binding specific ligands, olfactory receptors display affinity for a range of odor molecules, and conversely a single odorant molecule may bind to a number of olfactory receptors with varying affinities,[8] which depend on physio-chemical properties of molecules like their molecular volumes.[9] Once the odorant has bound to the odor receptor, the receptor undergoes structural changes and it binds and activates the olfactory-type G protein on the inside of the olfactory receptor neuron. The G protein (Golf and/or Gs)[10] in turn activates the lyase – adenylate cyclase – which converts ATP into cyclic AMP (cAMP). The cAMP opens cyclic nucleotide-gated ion channels which allow calcium and sodium ions to enter into the cell, depolarizing the olfactory receptor neuron and beginning an action potential which carries the information to the brain.

The primary sequences of thousands of olfactory receptors are known from the genomes of more than a dozen organisms: they are seven-helix transmembrane proteins, but there are (as of May 2016) no known structures of any OR. Their sequences exhibit typical class A GPCR motifs, useful for building their structures with molecular modeling.[11] Golebiowski, Ma and Matsunami showed that the mechanism of ligand recognition, although similar to other non-olfactory class A GPCRs, involves residues specific to olfactory receptors, notably in the sixth helix.[12] There is a highly conserved sequence in roughly three quarters of all ORs that is a tripodal metal ion binding site,[13] and Suslick has proposed that the ORs are in fact metalloproteins (mostly likely with zinc, copper and possibly manganese ions) that serve as a Lewis acid site for binding of many odorant molecules. Crabtree, in 1978, had previously suggested that Cu(I) is “the most likely candidate for a metallo-receptor site in olfaction” for strong-smelling volatiles which are also good metal-coordinating ligands, such as thiols.[14] Zhuang, Matsunami and Block, in 2012, confirmed the Crabtree/Suslick proposal for the specific case of a mouse OR, MOR244-3, showing that copper is essential for detection of certain thiols and other sulfur-containing compounds. Thus, by using a chemical that binds to copper in the mouse nose, so that copper wasn’t available to the receptors, the authors showed that the mice couldn’t detect the thiols. However, these authors also found that MOR244-3 lacks the specific metal ion binding site suggested by Suslick, instead showing a different motif in the EC2 domain.[15]

In a recent but highly controversial interpretation, it has also been speculated that olfactory receptors might really sense various vibrational energy-levels of a molecule rather than structural motifs via quantum coherence mechanisms.[16] As evidence it has been shown that flies can differentiate between two odor molecules which only differ in hydrogen isotope (which will drastically change vibrational energy levels of the molecule).[17] Not only could the flies distinguish between the deuterated and non-deuterated forms of an odorant, they could generalise the property of “deuteratedness” to other novel molecules. In addition, they generalised the learned avoidance behaviour to molecules which were not deuterated but did share a significant vibration stretch with the deuterated molecules, a fact which the differential physics of deuteration (below) has difficulty in accounting for.

Deuteration changes the heats of adsorption and the boiling and freezing points of molecules (boiling points: 100.0 °C for H2O vs. 101.42 °C for D2O; melting points: 0.0 °C for H2O, 3.82 °C for D2O), pKa (i.e., dissociation constant: 9.71×10−15 for H2O vs. 1.95×10−15 for D2O, cf. heavy water) and the strength of hydrogen bonding. Such isotope effects are exceedingly common, and so it is well known that deuterium substitution will indeed change the binding constants of molecules to protein receptors.[18]

It has been claimed that human olfactory receptors are capable of distinguishing between deuterated and undeuterated isotopomers of cyclopentadecanone by vibrational energy level sensing.[19] However this claim has been challenged by another report that the human musk-recognizing receptor, OR5AN1 that robustly responds to cyclopentadecanone and muscone, fails to distinguish isotopomers of these compounds in vitro. Furthermore, the mouse (methylthio)methanethiol-recognizing receptor, MOR244-3, as well as other selected human and mouse olfactory receptors, responded similarly to normal, deuterated, and carbon-13 isotopomers of their respective ligands, paralleling results found with the musk receptor OR5AN1.[20] Hence it was concluded that the proposed vibration theory does not apply to the human musk receptor OR5AN1, mouse thiol receptor MOR244-3, or other olfactory receptors examined. In addition, the proposed electron transfer mechanism of the vibrational frequencies of odorants could be easily suppressed by quantum effects of nonodorant molecular vibrational modes. Hence multiple lines of evidence argue against the vibration theory of smell.[21] This later study was criticized since it used “cells in a dish rather than within whole organisms” and that “expressing an olfactory receptor in human embryonic kidney cells doesn’t adequately reconstitute the complex nature of olfaction…”. In response, the authors of the second study state “Embryonic kidney cells are not identical to the cells in the nose .. but if you are looking at receptors, it’s the best system in the world.”[22][23][24]

Malfunction of the metalloproteins in the olfactory system is hypothesized to have a connection with amyloidal based neurodegenerative diseases.[25]


There are a large number of different odor receptors, with as many as 1,000 in the mammalian genome which represents approximately 3% of the genes in the genome. However, not all of these potential odor receptor genes are expressed and functional. According to an analysis of data derived from the Human Genome Project, humans have approximately 400 functional genes coding for olfactory receptors, and the remaining 600 candidates are pseudogenes.[26]

The reason for the large number of different odor receptors is to provide a system for discriminating between as many different odors as possible. Even so, each odor receptor does not detect a single odor. Rather each individual odor receptor is broadly tuned to be activated by a number of similar odorant structures.[27][28] Analogous to the immune system, the diversity that exists within the olfactory receptor family allows molecules that have never been encountered before to be characterized. However, unlike the immune system, which generates diversity through in-situ recombination, every single olfactory receptor is translated from a specific gene; hence the large portion of the genome devoted to encoding OR genes. Furthermore, most odors activate more than one type of odor receptor. Since the number of combinations and permutations of olfactory receptors is very large, the olfactory receptor system is capable of detecting and distinguishing between a very large number of odorant molecules.

Deorphanization of odor receptors can be completed using electrophysiological and imaging techniques to analyze the response profiles of single sensory neurons to odor repertoires.[29] Such data open the way to the deciphering of the combinatorial code of the perception of smells.[30]

Such diversity of OR expression maximizes the capacity of olfaction. Both monoallelic OR expression in a single neuron and maximal diversity of OR expression in the neuron population are essential for specificity and sensitivity of olfactory sensing. Thus, olfactory receptor activation is a dual-objective design problem. Using mathematical modeling and computer simulations, Tian et al proposed an evolutionarily optimized three-layer regulation mechanism, which includes zonal segregation, epigenetic barrier crossing coupled to a negative feedback loop and an enhancer competition step [31] . This model not only recapitulates monoallelic OR expression but also elucidates how the olfactory system maximizes and maintains the diversity of OR expression.


A nomenclature system has been devised for the olfactory receptor family[32] and is the basis for the official Human Genome Project (HUGO) symbols for the genes that encode these receptors. The names of individual olfactory receptor family members are in the format “ORnXm” where:

•OR is the root name (Olfactory Receptor superfamily)

•n = an integer representing a family (e.g., 1-56) whose members have greater than 40% sequence identity,

•X = a single letter (A, B, C, …) denoting a subfamily (>60% sequence identity), and

•m = an integer representing an individual family member (isoform).

For example, OR1A1 is the first isoform of subfamily A of olfactory receptor family 1.

Members belonging to the same subfamily of olfactory receptors (>60% sequence identity) are likely to recognize structurally similar odorant molecules.[33]

Two major classes of olfactory receptors have been identified in humans:[34]

•class I (fish-like receptors) OR families 51-56

•class II (tetrapod specific receptors) OR families 1-13


The olfactory receptor gene family in vertebrates has been shown to evolve through genomic events such as gene duplication or gene conversion.[35] Evidence of a role for tandem duplication is provided by the fact that many olfactory receptor genes belonging to the same phylogenetic clade are located in the same gene cluster.[36] To this point, the organization of OR genomic clusters is well conserved between humans and mice, even though the functional OR count is vastly different between these two species.[37] Such birth-and-death evolution has brought together segments from several OR genes to generate and degenerate odorant binding site configurations, creating new functional OR genes as well as pseudogenes.[38]

Compared to many other mammals, primates have a relatively small number of functional OR genes. For instance, since divergence from their most recent common ancestor (MRCA), mice have gained a total of 623 new OR genes, and lost 285 genes, whereas humans have gained only 83 genes, but lost 428 genes.[39] Mice have a total of 1035 protein-coding OR genes, humans have 387 protein-coding OR genes.[39] The vision priority hypothesis states that the evolution of color vision in primates may have decreased primate reliance on olfaction, which explains the relaxation of selective pressure that accounts for the accumulation of olfactory receptor pseudogenes in primates.[40] However, recent evidence has rendered the vision priority hypothesis obsolete, because it was based on misleading data and assumptions. The hypothesis assumed that functional OR genes can be correlated to the olfactory capability of a given animal.[40] In this view, a decrease in the fraction of functional OR genes would cause a reduction in the sense of smell; species with higher pseudogene count would also have a decreased olfactory ability. This assumption is flawed. Dogs, which are reputed to have good sense of smell,[41] do not have the largest number of functional OR genes.[39] Additionally, pseudogenes may be functional; 67% of human OR pseudogenes are expressed in the main olfactory epithelium, where they possibly have regulatory roles in gene expression.[42] More importantly, the vision priority hypothesis assumed a drastic loss of functional OR genes at the branch of the OWMs, but this conclusion was biased by low-resolution data from only 100 OR genes.[43] High-resolution studies instead agree that primates have lost OR genes in every branch from the MRCA to humans, indicating that the degeneration of OR gene repertories in primates cannot simply be explained by the changing capabilities in vision.[44]

It has been shown that negative selection is still relaxed in modern human olfactory receptors, suggesting that no plateau of minimal function has yet been reached in modern humans and therefore that olfactory capability might still be decreasing. This is considered to provide a first clue to the future human genetic evolution.[45]


In 2004 Linda B. Buck and Richard Axel won the Nobel Prize in Physiology or Medicine for their work[46] on olfactory receptors.[47] In 2006, it was shown that another class of odorant receptors – known as trace amine-associated receptors (TAARs) – exist for detecting volatile amines.[48] Except for TAAR1, all functional TAARs in humans are expressed in the olfactory epithelium.[49] A third class of olfactory receptors known as vomeronasal receptors has also been identified; vomeronasal receptors putatively function as pheromone receptors.

As with many other GPCRs, there is still a lack of experimental structures at atomic level for olfactory receptors and structural information is based on homology modeling methods.[50]

The limited functional expression of olfactory receptors in heterologous systems, however, has greatly hampered attempts to deorphanize them (analyze the response profiles of single sensory neurons).[51] This was first completed by genetically engineered receptor, OR-I7 to characterize the “odor space” of a population of native aldehyde receptors.[52]

See also[edit]



Trace amine-associated receptor



Gene family


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External links[edit]

Olfactory Receptor Database

Human Olfactory Receptor Data Exploratorium (HORDE)

Olfactory+Receptor+Protein at the US National Library of Medicine Medical Subject Headings (MeSH)


Happiness Medicine & Holistic Medicine Posts



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