Trends in Genetics
ReviewHuman olfaction: from genomic variation to phenotypic diversity
Section snippets
Understanding the olfactory molecular universe
Olfaction – the sense of smell – is a molecularly complex sensory processing system. It is capable of producing accurate odor perception, based on input from hundreds of sensory neuronal types equipped with diverse molecular sensors – olfactory receptor (OR) proteins (Figure 1a). Olfaction is characterized by a remarkable ability to detect and discriminate thousands of low molecular mass compounds (odorants). Most organisms rely on olfactory cues for a wide range of activities, such as food
Genome evolution of the OR repertoire: receptor birth and death
Key components of the molecular decoding device of the nose are OR proteins, belonging to the hyperfamily of seven-helix G-protein-coupled receptors (GPCRs), which are transducers of a wide array of extracellular molecular signals. ORs, like visual opsins, bitter taste receptors (T2Rs) and vomeronasal receptors (V1Rs), belong to the GPCR superfamily [5], and are characterized by a relatively compact helix–loop structure (Figure 1a). A design principle common to ORs and other similar families of
Genetic variation in human olfactory receptors: different noses for different folks
An important corollary of human olfactory repertoire diminution is the evidence that this process is still ongoing. Two types of genomic variation leading to OR inactivation are relevant in this respect: segregating pseudogenes 22, 23 and CNVs [24], which involve deletion alleles (Figure 1a and Box 3, Box 4). Such variations constitute natural knockout of specific ORs in some individuals, but not in others, potentially leading to phenotypic differences in olfactory acuity and perception.
Genetic variation begets phenotypic diversity
Possible corollaries of such evolutionary diversification mechanisms have long been gleaned through the observations that humans are highly variable in their olfactory sensitivity and quality perception. This variability includes differences in general olfactory acuity and in the sensitivity towards particular odorants. The latter was reported as early as a century ago in studies such as the one by Blakeslee [31]. Typically, the distribution of human thresholds (Box 2) towards a particular
Concluding remarks
Odorant-specific sensitivity variations and, in all likelihood, general sensitivity differences are highly prevalent, whereas congenital general anosmia is rather rare 42, 64. Although some efforts will probably be directed towards understanding the diverse molecular mechanisms that might underlie the general deficits, we predict that most research will focus on odorant-specific sensitivity phenotypes, with their obvious causative molecular target – OR genes. Thus, future studies are likely to
Acknowledgements
We would like to thank B. Brumshtein for the illustration of OR7D4 structure (Figure 1), and Edna Ben-Asher for critical reading and remarks. Supported by NIH (NIDCD) and the Crown Human Genome Center at the Weizmann Institute.
References (78)
- et al.
Spatiotemporal representations in the olfactory system
Trends Neurosci.
(2007) One neuron-one receptor rule in the mouse olfactory system
Trends Genet.
(2004)The current excitement about copy-number variation: how it relates to gene duplications and protein families
Curr. Opin. Struct. Biol.
(2008)Genetics, individuality, and medicine in the 21st century
Am. J. Hum. Genet.
(2004)Extensive copy-number variation of the human olfactory receptor gene family
Am. J. Hum. Genet.
(2008)Primate evolution of an olfactory receptor cluster: diversification by gene conversion and recent emergence of pseudogenes
Genomics
(1999)- et al.
Human olfactory psychophysics
Curr. Biol.
(2004) Androstadienone odor thresholds in adolescents
Horm. Behav.
(2005)Evidence for genetic determination in human twins of olfactory thresholds for a standard odorant
Neurosci. Lett.
(1992)- et al.
The Genetic basis for specific anosmia to isovaleric acid in the mouse
Cell
(1995)