Limits...
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.

Show MeSH

Related in: MedlinePlus

Correlation of OR copy-number variability with paralog-similarity.Red and blue dots indicate copy-number variable and non-variable ORs, respectively (copy-number variability is expressed in terms of the measure R, see Methods, which we found to correlate well with gene dosage). Percentage DNA sequence identity (“% identity”) to the closest paralog in the human genome is plotted versus the array-based (i.e., R-measure-based) variance. Correlation for ORs affected by CNVs is C = 0.26 (Pvalue = 10−5), whereas for non-variable ORs it is C = 0.15 (Pvalue = 10−4). Linear regression fits for each dataset are indicated with red and blue dashed lines, respectively.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2570968&req=5

pgen-1000249-g003: Correlation of OR copy-number variability with paralog-similarity.Red and blue dots indicate copy-number variable and non-variable ORs, respectively (copy-number variability is expressed in terms of the measure R, see Methods, which we found to correlate well with gene dosage). Percentage DNA sequence identity (“% identity”) to the closest paralog in the human genome is plotted versus the array-based (i.e., R-measure-based) variance. Correlation for ORs affected by CNVs is C = 0.26 (Pvalue = 10−5), whereas for non-variable ORs it is C = 0.15 (Pvalue = 10−4). Linear regression fits for each dataset are indicated with red and blue dashed lines, respectively.

Mentions: Our high-resolution map of CNVs affecting OR genes further enabled us to address questions relating to the evolution of the OR repertoire. We first tested whether the evolutionary age of an OR gene is correlated with its propensity to be affected by a CNV. Interestingly, we found that ORs with a closely related paralog in the human genome, evaluated using the level of sequence identity as a measure, are significantly more likely to be affected by CNVs than ORs lacking a closely related paralog (Figure 3). In other words, evolutionarily “younger” ORs tend to be more frequently affected by CNVs than more “ancient” ORs. To confirm this trend using a different approach to classify OR genes into “young” and “ancient” we used one-to-one orthology relationships with the chimpanzee genome and categorized OR genes into “young” if they lacked a one-to-one ortholog and “ancient” in the case of unambiguous orthology: indeed, we found that OR genes that recently exhibited a duplication/loss event in the human, or the chimpanzee genome (i.e. such genes lacking one-to-one orthologs between human and chimp), are significantly more likely to be affected by CNVs than OR genes with unambiguous one-to-one orthologs (Pvalue<0.001, Figure 4A). We note that these findings are compatible with a suggested general model of copy-number variation as an evolutionary basis of paralog birth [20],[21], whereby novel paralogs, manifested as CNVs, may later become fixed in the population.


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)

Correlation of OR copy-number variability with paralog-similarity.Red and blue dots indicate copy-number variable and non-variable ORs, respectively (copy-number variability is expressed in terms of the measure R, see Methods, which we found to correlate well with gene dosage). Percentage DNA sequence identity (“% identity”) to the closest paralog in the human genome is plotted versus the array-based (i.e., R-measure-based) variance. Correlation for ORs affected by CNVs is C = 0.26 (Pvalue = 10−5), whereas for non-variable ORs it is C = 0.15 (Pvalue = 10−4). Linear regression fits for each dataset are indicated with red and blue dashed lines, respectively.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1000249-g003: Correlation of OR copy-number variability with paralog-similarity.Red and blue dots indicate copy-number variable and non-variable ORs, respectively (copy-number variability is expressed in terms of the measure R, see Methods, which we found to correlate well with gene dosage). Percentage DNA sequence identity (“% identity”) to the closest paralog in the human genome is plotted versus the array-based (i.e., R-measure-based) variance. Correlation for ORs affected by CNVs is C = 0.26 (Pvalue = 10−5), whereas for non-variable ORs it is C = 0.15 (Pvalue = 10−4). Linear regression fits for each dataset are indicated with red and blue dashed lines, respectively.
Mentions: Our high-resolution map of CNVs affecting OR genes further enabled us to address questions relating to the evolution of the OR repertoire. We first tested whether the evolutionary age of an OR gene is correlated with its propensity to be affected by a CNV. Interestingly, we found that ORs with a closely related paralog in the human genome, evaluated using the level of sequence identity as a measure, are significantly more likely to be affected by CNVs than ORs lacking a closely related paralog (Figure 3). In other words, evolutionarily “younger” ORs tend to be more frequently affected by CNVs than more “ancient” ORs. To confirm this trend using a different approach to classify OR genes into “young” and “ancient” we used one-to-one orthology relationships with the chimpanzee genome and categorized OR genes into “young” if they lacked a one-to-one ortholog and “ancient” in the case of unambiguous orthology: indeed, we found that OR genes that recently exhibited a duplication/loss event in the human, or the chimpanzee genome (i.e. such genes lacking one-to-one orthologs between human and chimp), are significantly more likely to be affected by CNVs than OR genes with unambiguous one-to-one orthologs (Pvalue<0.001, Figure 4A). We note that these findings are compatible with a suggested general model of copy-number variation as an evolutionary basis of paralog birth [20],[21], whereby novel paralogs, manifested as CNVs, may later become fixed in the population.

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