Trends in Genetics
Volume 25, Issue 4, April 2009, Pages 178-184
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Review
Human olfaction: from genomic variation to phenotypic diversity

https://doi.org/10.1016/j.tig.2009.02.002Get rights and content

The sense of smell is a complex molecular device, encompassing several hundred olfactory receptor proteins (ORs). These receptors, encoded by the largest human gene superfamily, integrate odorant signals into an accurate ‘odor image’ in the brain. Widespread phenotypic diversity in human olfaction is, in part, attributable to prevalent genetic variation in OR genes, owing to copy number variation, deletion alleles and deleterious single nucleotide polymorphisms. The development of new genomic tools, including next generation sequencing and CNV assays, provides opportunities to characterize the genetic variations of this system. The advent of large-scale functional screens of expressed ORs, combined with genetic association studies, has the potential to link variations in ORs to human chemosensory phenotypes. This promises to provide a genome-wide view of human olfaction, resulting in a deeper understanding of personalized odor coding, with the potential to decipher flavor and fragrance preferences.

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.

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