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: 9.92). 05/2009; 25(4):178-84. DOI: 10.1016/j.tig.2009.02.002
Source: PubMed


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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    • "There are many genes and gene families which show copy number differences in population [9]–[11]. One among them is the OR family of genes, having high sequence identity and similar enzymatic functions [1], [12]. OR copy number polymorphisms (CNPs) have been reported in samples covering Africans, Middle Eastern Druze, Southeast Asians, South American Indians, Central American Indians, African-Americans, Yorubans from Nigeria, European descent from Utah, USA, Japanese and Chinese [13], [14]. "
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    ABSTRACT: Olfactory receptors (OR), responsible for detection of odor molecules, belong to the largest family of genes and are highly polymorphic in nature having distinct polymorphisms associated with specific regions around the globe. Since there are no reports on the presence of copy number variations in OR repertoire of Indian population, the present investigation in 43 Indians along with 270 HapMap and 31 Tibetan samples was undertaken to study genome variability and evolution. Analysis was performed using Affymetrix Genome-Wide Human SNP Array 6.0 chip, Affymterix CytoScan(®) High-Density array, HD-CNV, and MAFFT program. We observed a total of 1527 OR genes in 503 CNV events from 81.3% of the study group, which includes 67.6% duplications and 32.4% deletions encompassing more of genes than pseudogenes. We report human genotypic variation in functional OR repertoire size across populations and it was found that the combinatorial effect of both "orthologous obtained from closely related species" and "paralogous derived sequences" provide the complexity to the continuously occurring OR CNVs.
    PLoS ONE 07/2013; 8(7):e66843. DOI:10.1371/journal.pone.0066843 · 3.23 Impact Factor
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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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    • "While distribution of both sSNPs and nsSNPs was significantly enriched (FDR < = 0.05) in ECM-receptor interaction pathway genes, only the olfactory transduction pathway genes showed a statistically significant enrichment for nsSNPs (Figure  4A, Additional file 2: Figure S1). This is consistent with the higher levels of polymorphism observed in human olfactory gene family [36]. The nsSNPs included 11,107 missense substitutions and 109 non-sense mutations that lead to premature stop (Additional file 1: Table S2). "
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    ABSTRACT: Background With over 1.3 billion people, India is estimated to contain three times more genetic diversity than does Europe. Next-generation sequencing technologies have facilitated the understanding of diversity by enabling whole genome sequencing at greater speed and lower cost. While genomes from people of European and Asian descent have been sequenced, only recently has a single male genome from the Indian subcontinent been published at sufficient depth and coverage. In this study we have sequenced and analyzed the genome of a South Asian Indian female (SAIF) from the Indian state of Kerala. Results We identified over 3.4 million SNPs in this genome including over 89,873 private variations. Comparison of the SAIF genome with several published personal genomes revealed that this individual shared ~50% of the SNPs with each of these genomes. Analysis of the SAIF mitochondrial genome showed that it was closely related to the U1 haplogroup which has been previously observed in Kerala. We assessed the SAIF genome for SNPs with health and disease consequences and found that the individual was at a higher risk for multiple sclerosis and a few other diseases. In analyzing SNPs that modulate drug response, we found a variation that predicts a favorable response to metformin, a drug used to treat diabetes. SNPs predictive of adverse reaction to warfarin indicated that the SAIF individual is not at risk for bleeding if treated with typical doses of warfarin. In addition, we report the presence of several additional SNPs of medical relevance. Conclusions This is the first study to report the complete whole genome sequence of a female from the state of Kerala in India. The availability of this complete genome and variants will further aid studies aimed at understanding genetic diversity, identifying clinically relevant changes and assessing disease burden in the Indian population.
    BMC Genomics 08/2012; 13(1):440. DOI:10.1186/1471-2164-13-440 · 3.99 Impact Factor
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