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High-resolution copy-number variation map reflects human olfactory receptor diversity and evolution.

Hasin Y, Olender T, Khen M, Gonzaga-Jauregui C, Kim PM, Urban AE, Snyder M, Gerstein MB, Lancet D, Korbel JO - PLoS Genet. (2008)

Bottom Line: Furthermore, our results show an enrichment of CNVs among ORs with a close human paralog or lacking a one-to-one ortholog in chimpanzee.Quantitative PCR experiments performed for 122 sampled ORs agreed well with the microarray results and uncovered 23 additional CNVs.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.

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 ( approximately 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 approximately 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.

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Related in: MedlinePlus

Zoom into a bi-allelic CNV affecting OR4C11.Plot depicting median normalized log2-ratios of microarray intensities for OR loci affected by deletion I (chr11: 55127497–55238834), a bi-allelic CNV. Each individual is color-coded as indicated in the legend shown to the right. Black arrows indicate samples that consistently failed to produce results in the qPCR and standard PCR assays, indicating a potential homozygous deletion.
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pgen-1000249-g005: Zoom into a bi-allelic CNV affecting OR4C11.Plot depicting median normalized log2-ratios of microarray intensities for OR loci affected by deletion I (chr11: 55127497–55238834), a bi-allelic CNV. Each individual is color-coded as indicated in the legend shown to the right. Black arrows indicate samples that consistently failed to produce results in the qPCR and standard PCR assays, indicating a potential homozygous deletion.

Mentions: Having established that “young” ORs are more prone to CNVs than the “ancient” ones, we further addressed which types of CNVs, i.e. gains or losses, are most common in the two OR groups. Interestingly, for both “ancient” and “young” ORs we observed significant imbalances between gains and losses (Figure 5A, Pvalue = 0.006, χ2 statistic = 10.3, DF = 2 and Pvalue = 0, χ2 statistic = 43.8, DF = 2, respectively). Notably, the two groups exhibited an opposite over-all trend, i.e. “ancient” ORs displayed significantly more gains than losses and “young” ORs showed significantly more losses than gains. As we arbitrarily picked a reference individual in our study, we also tested whether the observed trend was robust if neglecting the reference, by looking for ORs that exhibited only one type of CNV – gain or loss – in at least 50% of the samples (Text S1 material). Although this analysis revealed that some of the reported events are likely attributable to rare alleles in the reference individual, the trend of opposite balances between gains and losses in the two groups remained significant (Pvalue = 0.004, χ2 statistic = 11.1, DF = 2).


High-resolution copy-number variation map reflects human olfactory receptor diversity and evolution.

Hasin Y, Olender T, Khen M, Gonzaga-Jauregui C, Kim PM, Urban AE, Snyder M, Gerstein MB, Lancet D, Korbel JO - PLoS Genet. (2008)

Zoom into a bi-allelic CNV affecting OR4C11.Plot depicting median normalized log2-ratios of microarray intensities for OR loci affected by deletion I (chr11: 55127497–55238834), a bi-allelic CNV. Each individual is color-coded as indicated in the legend shown to the right. Black arrows indicate samples that consistently failed to produce results in the qPCR and standard PCR assays, indicating a potential homozygous deletion.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2570968&req=5

pgen-1000249-g005: Zoom into a bi-allelic CNV affecting OR4C11.Plot depicting median normalized log2-ratios of microarray intensities for OR loci affected by deletion I (chr11: 55127497–55238834), a bi-allelic CNV. Each individual is color-coded as indicated in the legend shown to the right. Black arrows indicate samples that consistently failed to produce results in the qPCR and standard PCR assays, indicating a potential homozygous deletion.
Mentions: Having established that “young” ORs are more prone to CNVs than the “ancient” ones, we further addressed which types of CNVs, i.e. gains or losses, are most common in the two OR groups. Interestingly, for both “ancient” and “young” ORs we observed significant imbalances between gains and losses (Figure 5A, Pvalue = 0.006, χ2 statistic = 10.3, DF = 2 and Pvalue = 0, χ2 statistic = 43.8, DF = 2, respectively). Notably, the two groups exhibited an opposite over-all trend, i.e. “ancient” ORs displayed significantly more gains than losses and “young” ORs showed significantly more losses than gains. As we arbitrarily picked a reference individual in our study, we also tested whether the observed trend was robust if neglecting the reference, by looking for ORs that exhibited only one type of CNV – gain or loss – in at least 50% of the samples (Text S1 material). Although this analysis revealed that some of the reported events are likely attributable to rare alleles in the reference individual, the trend of opposite balances between gains and losses in the two groups remained significant (Pvalue = 0.004, χ2 statistic = 11.1, DF = 2).

Bottom Line: Furthermore, our results show an enrichment of CNVs among ORs with a close human paralog or lacking a one-to-one ortholog in chimpanzee.Quantitative PCR experiments performed for 122 sampled ORs agreed well with the microarray results and uncovered 23 additional CNVs.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.

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 ( approximately 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 approximately 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.

Show MeSH
Related in: MedlinePlus