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Expression differences by continent of origin point to the immortalization process.

Davis AR, Kohane IS - Hum. Mol. Genet. (2009)

Bottom Line: Analysis of recently available microarray expression data sets obtained from immortalized cell lines of the individuals represented in the HapMap project have led to inconclusive comparisons across cohorts with different ancestral continent of origin (ACOO).We further demonstrate that these differences correlate with viral titer and that both the titer and expression differences are associated with ACOO.We use the 14 genes most differentially expressed to construct an ACOO-specific 'immortalization network' comprised of 40 genes, one of which show significant correlation with genomic variation (eQTL).

View Article: PubMed Central - PubMed

Affiliation: i2b2 National Center for Biomedical Computing, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. ardavis@partners.org

ABSTRACT
Analysis of recently available microarray expression data sets obtained from immortalized cell lines of the individuals represented in the HapMap project have led to inconclusive comparisons across cohorts with different ancestral continent of origin (ACOO). To address this apparent inconsistency, we applied a novel approach to accentuate population-specific gene expression signatures for the CEU [homogeneous US residents with northern and western European ancestry (HapMap samples)] and YRI [homogenous Yoruba people of Ibadan, Nigeria (HapMap samples)] trios. In this report, we describe how four independent data sets point to the differential expression across ACOO of gene networks implicated in transforming the normal lymphoblast into immortalized lymphoblastoid cells. In particular, Werner syndrome helicase and related genes are differentially expressed between the YRI and CEU cohorts. We further demonstrate that these differences correlate with viral titer and that both the titer and expression differences are associated with ACOO. We use the 14 genes most differentially expressed to construct an ACOO-specific 'immortalization network' comprised of 40 genes, one of which show significant correlation with genomic variation (eQTL). The extent to which these measured group differences are due to differences in the immortalization procedures used for each group or reflect ACOO-specific biological differences remains to be determined. That the ACOO group differences in gene expression patterns may depend strongly on the process of transforming cells to establish immortalized lines should be considered in such comparisons.

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(A) Correlation of WRN to relative EBV titer across the filtered CEU and YRI samples and (B) the distribution of non-normalized WRN values and the mean values of the 20 genes across the CEU and YRI populations and for all the transcripts measured on the arrays.
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DDP330F2: (A) Correlation of WRN to relative EBV titer across the filtered CEU and YRI samples and (B) the distribution of non-normalized WRN values and the mean values of the 20 genes across the CEU and YRI populations and for all the transcripts measured on the arrays.

Mentions: We started the analysis with the reproducibility of the COO-specific differences in the first study (4), across two trios (CEU and YRI) divided into four populations: HapMap parents (YRIp and CEUp) and separately HapMap children (YRIc and CEUc). We selected those genes that were expressed most consistently within the YRI and separately CEU populations, respectively, and then identified those of the intersecting set that were significantly differentially expressed. The intersection of the number of consistently expressed genes within COO across both populations differed for the parents (n = 1043) when compared with their children (n = 568). The shared set of genes that were highly consistently expressed in both parental and child populations and that also were significantly differentially expressed after Bonferroni correction numbered 228 (Supplementary Material, Table S2). The biological functions program significantly enriched [as per the Ingenuity IPA program (17)] in the differentially expressed genes included processing and splicing of mRNA, immortalization of cells, transcription and expression of DNA, synthesis and metabolism of proteins, processing and modification of rRNA, receptor-mediated endocytosis, transport and catabolism of proteins, colony formation, activation of HIV type 1, ubiquitination and cholangiocarcinoma (data not shown). Of the 228 genes differentially expressed across ACOO, the top 20 genes most correlated with WRN, using Pearson correlation, were identified and highlighted with an ‘*’ in Supplementary Material, Table S2. Of note, the viral titer (courtesy David Altshuler, see Materials and Methods) correlated significantly with WRN gene expression across the filtered CEU and YRI samples from Stranger et al. (5) with an R2 = 0.69 and regression-significant P = <2.2 × 10−16 (Fig. 2A). Separately, the children's EBV titer correlated with WRN expression with an R2 of 0.86 and P-value of 2.89 × 10−13, and the parents EBV titer correlated with WRN expression with an R2 of 0.70 and P-value of 1.18 × 10−13 (data not shown). The distribution of WRN values is much higher than the average expression of genes in the genome across all samples, which is consistent with previous reports of WRN having high levels of expression in immortalized cells. The 20 genes closely correlated with WRN also have higher mean expression across the CEU and YRI populations when compared with WRN and all the transcripts measured on the arrays (Fig. 2B).


Expression differences by continent of origin point to the immortalization process.

Davis AR, Kohane IS - Hum. Mol. Genet. (2009)

(A) Correlation of WRN to relative EBV titer across the filtered CEU and YRI samples and (B) the distribution of non-normalized WRN values and the mean values of the 20 genes across the CEU and YRI populations and for all the transcripts measured on the arrays.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2748894&req=5

DDP330F2: (A) Correlation of WRN to relative EBV titer across the filtered CEU and YRI samples and (B) the distribution of non-normalized WRN values and the mean values of the 20 genes across the CEU and YRI populations and for all the transcripts measured on the arrays.
Mentions: We started the analysis with the reproducibility of the COO-specific differences in the first study (4), across two trios (CEU and YRI) divided into four populations: HapMap parents (YRIp and CEUp) and separately HapMap children (YRIc and CEUc). We selected those genes that were expressed most consistently within the YRI and separately CEU populations, respectively, and then identified those of the intersecting set that were significantly differentially expressed. The intersection of the number of consistently expressed genes within COO across both populations differed for the parents (n = 1043) when compared with their children (n = 568). The shared set of genes that were highly consistently expressed in both parental and child populations and that also were significantly differentially expressed after Bonferroni correction numbered 228 (Supplementary Material, Table S2). The biological functions program significantly enriched [as per the Ingenuity IPA program (17)] in the differentially expressed genes included processing and splicing of mRNA, immortalization of cells, transcription and expression of DNA, synthesis and metabolism of proteins, processing and modification of rRNA, receptor-mediated endocytosis, transport and catabolism of proteins, colony formation, activation of HIV type 1, ubiquitination and cholangiocarcinoma (data not shown). Of the 228 genes differentially expressed across ACOO, the top 20 genes most correlated with WRN, using Pearson correlation, were identified and highlighted with an ‘*’ in Supplementary Material, Table S2. Of note, the viral titer (courtesy David Altshuler, see Materials and Methods) correlated significantly with WRN gene expression across the filtered CEU and YRI samples from Stranger et al. (5) with an R2 = 0.69 and regression-significant P = <2.2 × 10−16 (Fig. 2A). Separately, the children's EBV titer correlated with WRN expression with an R2 of 0.86 and P-value of 2.89 × 10−13, and the parents EBV titer correlated with WRN expression with an R2 of 0.70 and P-value of 1.18 × 10−13 (data not shown). The distribution of WRN values is much higher than the average expression of genes in the genome across all samples, which is consistent with previous reports of WRN having high levels of expression in immortalized cells. The 20 genes closely correlated with WRN also have higher mean expression across the CEU and YRI populations when compared with WRN and all the transcripts measured on the arrays (Fig. 2B).

Bottom Line: Analysis of recently available microarray expression data sets obtained from immortalized cell lines of the individuals represented in the HapMap project have led to inconclusive comparisons across cohorts with different ancestral continent of origin (ACOO).We further demonstrate that these differences correlate with viral titer and that both the titer and expression differences are associated with ACOO.We use the 14 genes most differentially expressed to construct an ACOO-specific 'immortalization network' comprised of 40 genes, one of which show significant correlation with genomic variation (eQTL).

View Article: PubMed Central - PubMed

Affiliation: i2b2 National Center for Biomedical Computing, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. ardavis@partners.org

ABSTRACT
Analysis of recently available microarray expression data sets obtained from immortalized cell lines of the individuals represented in the HapMap project have led to inconclusive comparisons across cohorts with different ancestral continent of origin (ACOO). To address this apparent inconsistency, we applied a novel approach to accentuate population-specific gene expression signatures for the CEU [homogeneous US residents with northern and western European ancestry (HapMap samples)] and YRI [homogenous Yoruba people of Ibadan, Nigeria (HapMap samples)] trios. In this report, we describe how four independent data sets point to the differential expression across ACOO of gene networks implicated in transforming the normal lymphoblast into immortalized lymphoblastoid cells. In particular, Werner syndrome helicase and related genes are differentially expressed between the YRI and CEU cohorts. We further demonstrate that these differences correlate with viral titer and that both the titer and expression differences are associated with ACOO. We use the 14 genes most differentially expressed to construct an ACOO-specific 'immortalization network' comprised of 40 genes, one of which show significant correlation with genomic variation (eQTL). The extent to which these measured group differences are due to differences in the immortalization procedures used for each group or reflect ACOO-specific biological differences remains to be determined. That the ACOO group differences in gene expression patterns may depend strongly on the process of transforming cells to establish immortalized lines should be considered in such comparisons.

Show MeSH
Related in: MedlinePlus