Olfactory Receptors

OR proteins, of which the Nobel-awarded discovery took place 13 years ago (5), belong to the G protein-coupled receptors (GPCRs) superfamily, transducers of a wide array of extracellular signaling molecules that constitute important targets in the pharmaceutical industry (6). Members of this protein superfamily share features of sequence and structure, including seven hydrophobic transmembrane helices, as well as three intracellular and three extracellular loops that link these helices. ORs belong to GPCR family A, or rhodopsin-like GPCRs, which is the largest and most well-studied. Although the overall sequence similarity between the various members of this family is very low, with mean amino acid pairwise identity of 17% (6), they share several highly conserved sequence motifs that are thought to play an essential role in either maintaining the structure and functional conformational transitions of these proteins, or in interacting with upstream and downstream partners (7).

In most mammals, the olfactory repertoire has 1000-1400 OR genes, constituting the largest gene family within their genomes (8-10). The OR coding region spans approx 1 kb, almost always without introns, a property that facilitates their identification and cloning from genomic DNA. OR genes are divided into two classes containing 17 families, which further divided into

Fig. 1. A schematic drawing of olfactory perception and potential underlying mechanisms of olfactory deficits. The three principal olfactory traits in human beings are depicted. (A) Normosmic—both the olfactory receptors (ORs) and the subsequent signaling cascade molecules are intact, allowing the perception of all available odorous volatile molecules (odorants). (B) General anosmia—damaging mutation in one or more of the olfactory signal transduction proteins would extinguish the olfactory signal stemming from all OR types. (C) Specific anosmia—inactivation of one OR would eliminate the response or significant decrease the threshold toward one or a few particular odorants. Such specific OR inactivation would likely not affect perception of other odorants.

Fig. 1. A schematic drawing of olfactory perception and potential underlying mechanisms of olfactory deficits. The three principal olfactory traits in human beings are depicted. (A) Normosmic—both the olfactory receptors (ORs) and the subsequent signaling cascade molecules are intact, allowing the perception of all available odorous volatile molecules (odorants). (B) General anosmia—damaging mutation in one or more of the olfactory signal transduction proteins would extinguish the olfactory signal stemming from all OR types. (C) Specific anosmia—inactivation of one OR would eliminate the response or significant decrease the threshold toward one or a few particular odorants. Such specific OR inactivation would likely not affect perception of other odorants.

subfamilies, all based on sequence similarity scores. ORs with more than 40% protein sequence identity are considered within the same family and if they share more than 60%—as belonging to the same subfamily (H). It was suggested that ORs of the same subfamily might recognize

Fig. 2. A tentative schematic view of olfactory receptor (OR) genes genomic expansion. The proposed steps, in rough chronological order, are: (1) a duplication on chromosome 11 that resulted in the formation of the first class II cluster out of an original class I cluster (thick cyan). (2) A duplication that led to the formation of a cluster on chromosome 1, most likely in the framework of a whole genome diploidization (thick magenta). (3) Internal duplications within chromosome 11 (thin green), and expansion from chromosome 1 onto a number of other chromosomes (thick green). (4) Additional isolated duplications (thin black), gene scattering of family 4 (red "radio waves") and family 7 (blue "radio waves"). Only the generation of clusters larger than five members is explicitly shown. The small red histograms to the right of the chromosomal bands indicate OR gene cluster locations, with the area proportional to cluster size (see http://bip.weizmann.ac.il/HORDE for details). (Reproduced with permission from ref. 8.)

Fig. 2. A tentative schematic view of olfactory receptor (OR) genes genomic expansion. The proposed steps, in rough chronological order, are: (1) a duplication on chromosome 11 that resulted in the formation of the first class II cluster out of an original class I cluster (thick cyan). (2) A duplication that led to the formation of a cluster on chromosome 1, most likely in the framework of a whole genome diploidization (thick magenta). (3) Internal duplications within chromosome 11 (thin green), and expansion from chromosome 1 onto a number of other chromosomes (thick green). (4) Additional isolated duplications (thin black), gene scattering of family 4 (red "radio waves") and family 7 (blue "radio waves"). Only the generation of clusters larger than five members is explicitly shown. The small red histograms to the right of the chromosomal bands indicate OR gene cluster locations, with the area proportional to cluster size (see http://bip.weizmann.ac.il/HORDE for details). (Reproduced with permission from ref. 8.)

molecules with similar chemical and/or physical characteristics (3,12,13). However, more experimental evidences are needed to fully confirm this assumption (14,15).

Vertebrate OR genes are organized in genomic clusters and are distributed on almost all chromosomes. As an example, in humans they are absent only on chromosomes 20 and Y. This wide genomic distribution is believed to have evolved from a single OR gene cluster on human chromosome 11 (11 at 4.96) that contains only OR genes of class I. An intrachromosomal duplication may have originated the first class II OR gene cluster. This cluster is inferred to have further duplicated to the q-telomeric region of human chromosome 1 and from there to have expanded to many other genomic loci (Fig. 2). This evolutionary process of OR genes migration was favored by strong selective pressure toward expanding and diversifying the OR

gene repertoire, as increased OR count likely enhances both sensitivity and selectivity (4). Interestingly, this repertoire augmentation process appears to have been reversed in primates in the last 20 million years, probably because they became less dependent on olfactory cues (16-18). This is manifested in the observation that in such species OR genes underwent a massive accumulation of pseudogenizing mutations, generating in-frame stop codons. This process of OR gene loss has remarkably accelerated in the human lineage leaving less than half of the OR genes intact (8,16,17,19,20). The high prevalence of defective human OR coding regions is a wide evolutionary deterioration, and its phenotypic impact awaits elucidation. Each such pseudogene may be regarded as a natural knockout, potentially affecting the human ability to detect and discriminate odorants.

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