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Identification of copy number variants defining genomic differences among major human groups.

Armengol L, Villatoro S, González JR, Pantano L, García-Aragonés M, Rabionet R, Cáceres M, Estivill X - PLoS ONE (2009)

Bottom Line: We have identified and experimentally validated 33 genomic loci that show significant copy number differences from one population to the other.Interestingly, we found an enrichment of genes related to environment adaptation (immune response, lipid metabolism and extracellular space) within these regions and the study of expression data revealed that more than half of the copy number variants (CNVs) translate into gene-expression differences among populations, suggesting that they could have functional consequences.Overall, our results provide a comprehensive view of relevant copy number changes that might play a role in phenotypic differences among major human populations, and generate a list of interesting candidates for future studies.

View Article: PubMed Central - PubMed

Affiliation: Genetic Causes of Disease Group, Genes and Disease Program, Center for Genomic Regulation (CRG-UPF) and CIBERESP, Barcelona, Catalonia, Spain.

ABSTRACT

Background: Understanding the genetic contribution to phenotype variation of human groups is necessary to elucidate differences in disease predisposition and response to pharmaceutical treatments in different human populations.

Methodology/principal findings: We have investigated the genome-wide profile of structural variation on pooled samples from the three populations studied in the HapMap project by comparative genome hybridization (CGH) in different array platforms. We have identified and experimentally validated 33 genomic loci that show significant copy number differences from one population to the other. Interestingly, we found an enrichment of genes related to environment adaptation (immune response, lipid metabolism and extracellular space) within these regions and the study of expression data revealed that more than half of the copy number variants (CNVs) translate into gene-expression differences among populations, suggesting that they could have functional consequences. In addition, the identification of single nucleotide polymorphisms (SNPs) that are in linkage disequilibrium with the copy number alleles allowed us to detect evidences of population differentiation and recent selection at the nucleotide variation level.

Conclusions: Overall, our results provide a comprehensive view of relevant copy number changes that might play a role in phenotypic differences among major human populations, and generate a list of interesting candidates for future studies.

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General Strategy Used in the Analysis of Copy Number Variants (CNVs) with Population-Specific frequency changes.(A) Pools of genomic DNA of 25 unrelated males and 25 females from the four HapMap populations were prepared and hybridized to the different array platforms. In total, sixteen inter-population CGH experiments were performed in each platform. The circular design of the hybridization pairs (panel A) allowed us to assign the most likely population to carry the variation, assuming the most parsimonious scenario. (B) This combination of hybridizations also allowed us to minimize the calling of CNVs on spurious positive signals. For instance, for a CNV to be called as a YRI-specific loss, the hybridizations of CEU, CHB and JPT male pools were required to show an increased hybridization signal with respect to the YRI female pool (log2 ratio≥0.3, green squares), the hybridization of the YRI male pool versus the rest of pools had to show decreased signals (log2 ratio≤−0.3, red squares), and the rest of combinations should show values around 0 and not above the /0.3/ threshold (dark squares).
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pone-0007230-g001: General Strategy Used in the Analysis of Copy Number Variants (CNVs) with Population-Specific frequency changes.(A) Pools of genomic DNA of 25 unrelated males and 25 females from the four HapMap populations were prepared and hybridized to the different array platforms. In total, sixteen inter-population CGH experiments were performed in each platform. The circular design of the hybridization pairs (panel A) allowed us to assign the most likely population to carry the variation, assuming the most parsimonious scenario. (B) This combination of hybridizations also allowed us to minimize the calling of CNVs on spurious positive signals. For instance, for a CNV to be called as a YRI-specific loss, the hybridizations of CEU, CHB and JPT male pools were required to show an increased hybridization signal with respect to the YRI female pool (log2 ratio≥0.3, green squares), the hybridization of the YRI male pool versus the rest of pools had to show decreased signals (log2 ratio≤−0.3, red squares), and the rest of combinations should show values around 0 and not above the /0.3/ threshold (dark squares).

Mentions: We have used aCGH [51], [52] on Agilent and BAC-based platforms to identify CNVs with different frequencies in three representative human populations of African (YRI – Yoruba in Ibadan, Nigeria), Asian (JPT – Japanse in Tokyo, Japan, and CHB – Han Chinese in Beijing, China), and European (CEU – Utah residents with ancestry from Northern and Western Europe) ancestry. In order to dilute inter-individual variation and to enrich inter-population differences, we pooled 50 unrelated DNA samples from each of the four human groups studied in the HapMap project [5], [28]. For each group, we set up independent pools of males and females, and carried out a total of sixteen aCGH hybridization experiments on each platform, by confronting sex-unmatched pools of individuals from the different populations (Figure 1A). As a control, we performed an intra-population male versus female hybridization to discard the probes that called a copy number difference in this situation (see Methods), since we do not expect copy number variability between genders of the same group, other than those affecting the sexual chromosomes. The circular design of the hybridization experiments (Figure 1A) allowed us to determine the most likely population that carries the variant (increase or decrease in copy number) with respect to the other populations, assuming the most parsimonious scenario. In addition, this design also allowed us to minimize the presence of spurious positive signals (Figure 1B).


Identification of copy number variants defining genomic differences among major human groups.

Armengol L, Villatoro S, González JR, Pantano L, García-Aragonés M, Rabionet R, Cáceres M, Estivill X - PLoS ONE (2009)

General Strategy Used in the Analysis of Copy Number Variants (CNVs) with Population-Specific frequency changes.(A) Pools of genomic DNA of 25 unrelated males and 25 females from the four HapMap populations were prepared and hybridized to the different array platforms. In total, sixteen inter-population CGH experiments were performed in each platform. The circular design of the hybridization pairs (panel A) allowed us to assign the most likely population to carry the variation, assuming the most parsimonious scenario. (B) This combination of hybridizations also allowed us to minimize the calling of CNVs on spurious positive signals. For instance, for a CNV to be called as a YRI-specific loss, the hybridizations of CEU, CHB and JPT male pools were required to show an increased hybridization signal with respect to the YRI female pool (log2 ratio≥0.3, green squares), the hybridization of the YRI male pool versus the rest of pools had to show decreased signals (log2 ratio≤−0.3, red squares), and the rest of combinations should show values around 0 and not above the /0.3/ threshold (dark squares).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2747275&req=5

pone-0007230-g001: General Strategy Used in the Analysis of Copy Number Variants (CNVs) with Population-Specific frequency changes.(A) Pools of genomic DNA of 25 unrelated males and 25 females from the four HapMap populations were prepared and hybridized to the different array platforms. In total, sixteen inter-population CGH experiments were performed in each platform. The circular design of the hybridization pairs (panel A) allowed us to assign the most likely population to carry the variation, assuming the most parsimonious scenario. (B) This combination of hybridizations also allowed us to minimize the calling of CNVs on spurious positive signals. For instance, for a CNV to be called as a YRI-specific loss, the hybridizations of CEU, CHB and JPT male pools were required to show an increased hybridization signal with respect to the YRI female pool (log2 ratio≥0.3, green squares), the hybridization of the YRI male pool versus the rest of pools had to show decreased signals (log2 ratio≤−0.3, red squares), and the rest of combinations should show values around 0 and not above the /0.3/ threshold (dark squares).
Mentions: We have used aCGH [51], [52] on Agilent and BAC-based platforms to identify CNVs with different frequencies in three representative human populations of African (YRI – Yoruba in Ibadan, Nigeria), Asian (JPT – Japanse in Tokyo, Japan, and CHB – Han Chinese in Beijing, China), and European (CEU – Utah residents with ancestry from Northern and Western Europe) ancestry. In order to dilute inter-individual variation and to enrich inter-population differences, we pooled 50 unrelated DNA samples from each of the four human groups studied in the HapMap project [5], [28]. For each group, we set up independent pools of males and females, and carried out a total of sixteen aCGH hybridization experiments on each platform, by confronting sex-unmatched pools of individuals from the different populations (Figure 1A). As a control, we performed an intra-population male versus female hybridization to discard the probes that called a copy number difference in this situation (see Methods), since we do not expect copy number variability between genders of the same group, other than those affecting the sexual chromosomes. The circular design of the hybridization experiments (Figure 1A) allowed us to determine the most likely population that carries the variant (increase or decrease in copy number) with respect to the other populations, assuming the most parsimonious scenario. In addition, this design also allowed us to minimize the presence of spurious positive signals (Figure 1B).

Bottom Line: We have identified and experimentally validated 33 genomic loci that show significant copy number differences from one population to the other.Interestingly, we found an enrichment of genes related to environment adaptation (immune response, lipid metabolism and extracellular space) within these regions and the study of expression data revealed that more than half of the copy number variants (CNVs) translate into gene-expression differences among populations, suggesting that they could have functional consequences.Overall, our results provide a comprehensive view of relevant copy number changes that might play a role in phenotypic differences among major human populations, and generate a list of interesting candidates for future studies.

View Article: PubMed Central - PubMed

Affiliation: Genetic Causes of Disease Group, Genes and Disease Program, Center for Genomic Regulation (CRG-UPF) and CIBERESP, Barcelona, Catalonia, Spain.

ABSTRACT

Background: Understanding the genetic contribution to phenotype variation of human groups is necessary to elucidate differences in disease predisposition and response to pharmaceutical treatments in different human populations.

Methodology/principal findings: We have investigated the genome-wide profile of structural variation on pooled samples from the three populations studied in the HapMap project by comparative genome hybridization (CGH) in different array platforms. We have identified and experimentally validated 33 genomic loci that show significant copy number differences from one population to the other. Interestingly, we found an enrichment of genes related to environment adaptation (immune response, lipid metabolism and extracellular space) within these regions and the study of expression data revealed that more than half of the copy number variants (CNVs) translate into gene-expression differences among populations, suggesting that they could have functional consequences. In addition, the identification of single nucleotide polymorphisms (SNPs) that are in linkage disequilibrium with the copy number alleles allowed us to detect evidences of population differentiation and recent selection at the nucleotide variation level.

Conclusions: Overall, our results provide a comprehensive view of relevant copy number changes that might play a role in phenotypic differences among major human populations, and generate a list of interesting candidates for future studies.

Show MeSH