Abstract
Olfactory receptors (ORs), which are involved in odorant recognition, form the largest mammalian protein superfamily. The genomic content of OR genes is considerably reduced in humans, as reflected by the relatively small repertoire size and the high fraction (∼55%) of human pseudogenes. Since several recent low-resolution surveys suggested that OR genomic loci are frequently affected by copy-number variants (CNVs), we hypothesized that CNVs may play an important role in the evolution of the human olfactory repertoire. We used high-resolution oligonucleotide tiling microarrays to detect CNVs across 851 OR gene and pseudogene loci. Examining genomic DNA from 25 individuals with ancestry from three populations, we identified 93 OR gene loci and 151 pseudogene loci affected by CNVs, generating a mosaic of OR dosages across persons. Our data suggest that ∼50% of the CNVs involve more than one OR, with the largest CNV spanning 11 loci. In contrast to earlier reports, we observe that CNVs are more frequent among OR pseudogenes than among intact genes, presumably due to both selective constraints and CNV formation biases. Furthermore, our results show an enrichment of CNVs among ORs with a close human paralog or lacking a one-to-one ortholog in chimpanzee. Interestingly, among the latter we observed an enrichment in CNV losses over gains, a finding potentially related to the known diminution of the human OR repertoire. Quantitative PCR experiments performed for 122 sampled ORs agreed well with the microarray results and uncovered 23 additional CNVs. Importantly, these experiments allowed us to uncover nine common deletion alleles that affect 15 OR genes and five pseudogenes. Comparison to the chimpanzee reference genome revealed that all of the deletion alleles are human derived, therefore indicating a profound effect of human-specific deletions on the individual OR gene content. Furthermore, these deletion alleles may be used in future genetic association studies of olfactory inter-individual differences.
Highlights
Olfaction, the sense of smell, is characterized by the remarkable ability to detect and discriminate millions of odorous compounds
Analyzing the microarray results we identified olfactory receptors (ORs) loci with median normalized microarray log2-intensity ratios R that significantly deviated from expected measures, and were scored as copy-number variants (CNVs)
We have carried out a high-resolution analysis of CNVs affecting OR gene and pseudogene loci, and identified many ORrelated CNVs for which copy-number variability has not been reported previously
Summary
The sense of smell, is characterized by the remarkable ability to detect and discriminate millions of odorous compounds. The human OR repertoire is comprised of 851 genes and pseudogenes, organized in clusters on almost every chromosome [4]. During human evolution these gene clusters underwent dynamic processes of expansion, diversification and duplication as well as diminution and pseudogenization [5], processes which may be still ongoing. Since members of the human species depend on their sense of smell to a lesser degree than other mammals, their OR repertoire has undergone an accelerated process of pseudogenization, resulting in functional inactivation of more than 50% of the ORs by frame-disrupting mutations. The lower degree of purifying selection in human olfaction appears to result in enhanced inter-individual genome diversity, e.g. the prevalence of high-frequency inactivating single nucleotide polymorphisms (SNPs), i.e. segregating pseudogenes [6]. The human OR repertoire serves as an interesting model for genome evolution and variability
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