Human olfaction: from genome variation to phenotypic diversity

Department of Molecular Genetics and the Crown Human Genome Center, Weizmann Institute of Science, Rehovot 76100, Israel.
Trends in Genetics (Impact Factor: 11.6). 05/2009; 25(4):178-84. DOI: 10.1016/j.tig.2009.02.002
Source: PubMed

ABSTRACT 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.

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Available from: Yehudit Hasin-Brumshtein, Aug 15, 2014
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    • "Thus the possible role of sex in CNV among olfactory receptor (OR) gene family was investigated. OR genes (Buck and Axel, 1991; Rouquier et al., 1998) comprise the largest gene family in the human genome, with nearly 900 members (Glusman et al., 2001; Hasin-Brumshtein et al., 2009) and also have been extensively studied, with regard to CNV (Trask et al., 1998; Waszak et al., 2010). OR gene family is also well-known to have a large number of pseudogenes (about 50%) among its members (Glusman et al., 2001). "
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    ABSTRACT: Gender plays a pivotal role in the human genetic identity and is also manifested in many genetic disorders particularly mental retardation. In this study its effect on copy number variation (CNV), known to cause genetic disorders was explored. As the olfactory receptor (OR) repertoire comprises the largest human gene family, it was selected for this study, which was carried out within and between three populations, derived from 150 individuals from the 1000 Genome Project. Analysis of 3872 CNVs detected among 791 OR loci, in which 307 loci showed CNV, revealed the following novel findings: Sex bias in CNV was significantly more prevalent in uncommon than common CNV variants of OR pseudogenes, in which the male genome showed more CNVs; and in one-copy number loss compared to complete deletion of OR pseudogenes; both findings implying a more recent evolutionary role for gender. Sex bias in copy number gain was also detected. Another novel finding was that the observed six bias was largely dependent on ethnicity and was in general absent in East Asians. Using a CNV public database for sick children (ISCA) the application of these findings for improving clinical molecular diagnostics is discussed by showing an example of sex bias in CNV among kids with autism. Additional clinical relevance is discussed, as the most polymorphic CNV-enriched OR cluster in the human genome, located on chr 15q11.2, is found near the PWS/AS bi-directionally imprinted region associated with two well-known mental retardation syndromes. As olfaction represents the primitive cognition in most mammals, arguably in competition with the development of a larger brain, the extensive retention of OR pseudogenes in females of this study, might point to a parent-of-origin indirect regulatory role for OR pseudogenes in the embryonic development of human brain. Thus any perturbation in the temporal regulation of olfactory system could lead to developmental delay disorders including mental retardation.
    Frontiers in Genetics 03/2013; 4:32. DOI:10.3389/fgene.2013.00032
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    ABSTRACT: Olfaction in vertebrates is mediated mainly by a large family of olfactory receptors in the olfactory epithelium that belong to the superfamily of G protein-coupled receptors. Olfactory systems are well conserved among vertebrates, including marsupials, but there is a large variation in the numbers of olfactory genes in different animals. Most marsupials are nocturnal so depend on their sense of smell to locate food, avoid predators and identify potential mates in similar ways to other mammals. The olfactory bulbs are quite large in adult marsupials, suggesting that the sense of smell is very important in these animals. In addition, very undeveloped newborn marsupials have the special challenge of locating the pouch unassisted. It is likely that these newborns utilise their sense of smell for this unique pouch-finding task. The olfactory system is one of the few systems that is sufficiently developed in newborn marsupials to accomplish the task of finding the pouch. The opossum OR repertoire of one marsupial, the American opossum, is one of the largest characterised in mammals so far, containing over 1,500 genes. Interestingly comparisons of the opossum OR repertoire with the repertoire in an Australian marsupial, the tammar wallaby, suggests that a large conserved OR repertoire may be a feature of marsupials. The OR repertoires of the two marsupials show a high degree of similarity in total gene numbers and range of genes. This is unlike placental mammals, where the OR repertoires show a greater range. Results from these comparisons provide evidence for both the major forces (adaptation and genomic drift) behind the “birth-and-death” theory for the evolution of OR genes. KeywordsOlfactory receptor genes-Marsupials-Olfaction
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    ABSTRACT: Odour perception is controlled by environmental and genetic influences. Most people can discriminate over 10,000 different odours, but the molecular basis of this ability is poorly understood. Little is known about which odorant receptors (ORs) detect what odour compounds, and additional research is required to gain knowledge of why detection thresholds for some odorants vary 1000-fold, or more, across people. The primary purpose of this paper is to describe a research strategy for investigating the genetic basis of human odour perception. Background information on human olfaction, human genetics and the associated research approaches is presented. This is followed by a case study on cis-3-hexen-1-ol, a compound which contributes to the ‘green leaf’ odour (and flavour) in fruit, vegetables and wine. Odour detection threshold data for 48 participants were obtained using the rating R-index methodology. The ability to perceive cis-3-hexen-1-ol odour was tested for association with genetic variability on a genome-wide scale by microarray probe genotyping. A group of significant SNPs on chromosome 6 around the SNP rs9295791 was identified and these localise with a cluster of OR genes which could potentially be involved in perception of cis-3-hexen-1-ol. Further steps required to identify genes and alleles that encode the different ability to perceive cis-3-hexen-1-ol are outlined.
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