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.
Copy-number variants (CNVs) are deletions and duplications of DNA segments, responsible for most of the genome variation in mammals. To help elucidate the impact of CNVs on evolution and function, we provide a high-resolution CNV map of the largest gene superfamily in humans, i.e., the olfactory receptor (OR) gene superfamily. Our map reveals twice as many olfactory CNVs per person than previously reported, indicating considerable OR dosage variations in humans. In particular, our findings indicate that CNVs are specifically enriched among evolutionary “young” ORs, some of which originated following the human-chimpanzee split, implying that CNVs may play an important role in the gene-birth and gene-loss processes that continuously shape the human OR repertoire. Furthermore, we describe 15 OR gene loci showing frequent human-specific deletion alleles. Additionally, we present evidence for a recent non-allelic homologous recombination event involving a pair of OR genes, forming a novel fusion OR that may harbor novel odorant-binding properties. Such events may potentially relate to individual functional “holes” in the human smell-detection repertoire, and future studies will address the specific chemosensory impact of our genomic variation map.