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Effects of copy number variable regions on local gene expression in white blood cells of Mexican Americans.

Blackburn A, Almeida M, Dean A, Curran JE, Johnson MP, Moses EK, Abraham LJ, Carless MA, Dyer TD, Kumar S, Almasy L, Mahaney MC, Comuzzie A, Williams-Blangero S, Blangero J, Lehman DM, Göring HH - Eur. J. Hum. Genet. (2015)

Bottom Line: We found a ~1-Mb window size to be optimal for capturing cis effects of CNVs.Up to 10% of the CNVs in this study were found to be significantly associated with the expression of at least one gene within their vicinity.As expected, we find that CNVs that directly overlap gene sequences have the largest effects on gene expression (compared with non-overlapping CNVRs located nearby), with positive correlation (except for a few exceptions) between estimated genomic dosage and expression level.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA [2] Department of Cellular and Structural Biology, UT Health Science Center San Antonio, San Antonio, TX, USA.

ABSTRACT
Only few systematic studies on the contribution of copy number variation to gene expression variation have been published to date. Here we identify effects of copy number variable regions (CNVRs) on nearby gene expression by investigating 909 CNVRs and expression levels of 12059 nearby genes in white blood cells from Mexican-American participants of the San Antonio Family Heart Study. We empirically evaluate our ability to detect the contribution of CNVs to proximal gene expression (presumably in cis) at various window sizes (up to a 10 Mb distance) between the gene and CNV. We found a ~1-Mb window size to be optimal for capturing cis effects of CNVs. Up to 10% of the CNVs in this study were found to be significantly associated with the expression of at least one gene within their vicinity. As expected, we find that CNVs that directly overlap gene sequences have the largest effects on gene expression (compared with non-overlapping CNVRs located nearby), with positive correlation (except for a few exceptions) between estimated genomic dosage and expression level. We find that genes whose expression level is significantly influenced by nearby CNVRs are enriched for immunity and autoimmunity related genes. These findings add to the currently limited catalog of CNVRs that are recognized as expression quantitative trait loci, and have implications for future study designs as well as for prioritizing candidate causal variants in genomic regions associated with disease.

No MeSH data available.


Related in: MedlinePlus

CNVR111 and GSTM1 expression. Quantitative values representative of copy number (horizontal axis of the main panel) for CNVR111 (a duplication) are significantly associated with mRNA expression of GSTM1 (vertical axis of the main panel). A density plot shows that these quantitative values cluster in two overlapping distributions, which represent underlying discrete genotypes. A density plot of the gene expression values reveals that expression closely mirrors the underlying genotypes.
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fig1: CNVR111 and GSTM1 expression. Quantitative values representative of copy number (horizontal axis of the main panel) for CNVR111 (a duplication) are significantly associated with mRNA expression of GSTM1 (vertical axis of the main panel). A density plot shows that these quantitative values cluster in two overlapping distributions, which represent underlying discrete genotypes. A density plot of the gene expression values reveals that expression closely mirrors the underlying genotypes.

Mentions: The annotation for these 920 CNVRs was updated to hg19 using the liftOver utility from the UCSC genome browser.19 Eleven CNVRs do not map uniquely to hg19, resulting in a total of 909 CNVRs for use in this study. Figure 1 provides an example of the relationship between these quantitative values, their underlying discrete copy number state, and gene expression. A portion of these CNVRs represents known complex regions. However, most represent diallelic copy number polymorphisms (presence or absence of a deletion/duplication) as we previously observed reasonable concordance in size and location between these CNVRs and those identified to be polymorphisms by HapMap3.12, 15 We will refer to the total set as CNVs for the ease of communication.


Effects of copy number variable regions on local gene expression in white blood cells of Mexican Americans.

Blackburn A, Almeida M, Dean A, Curran JE, Johnson MP, Moses EK, Abraham LJ, Carless MA, Dyer TD, Kumar S, Almasy L, Mahaney MC, Comuzzie A, Williams-Blangero S, Blangero J, Lehman DM, Göring HH - Eur. J. Hum. Genet. (2015)

CNVR111 and GSTM1 expression. Quantitative values representative of copy number (horizontal axis of the main panel) for CNVR111 (a duplication) are significantly associated with mRNA expression of GSTM1 (vertical axis of the main panel). A density plot shows that these quantitative values cluster in two overlapping distributions, which represent underlying discrete genotypes. A density plot of the gene expression values reveals that expression closely mirrors the underlying genotypes.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4538210&req=5

fig1: CNVR111 and GSTM1 expression. Quantitative values representative of copy number (horizontal axis of the main panel) for CNVR111 (a duplication) are significantly associated with mRNA expression of GSTM1 (vertical axis of the main panel). A density plot shows that these quantitative values cluster in two overlapping distributions, which represent underlying discrete genotypes. A density plot of the gene expression values reveals that expression closely mirrors the underlying genotypes.
Mentions: The annotation for these 920 CNVRs was updated to hg19 using the liftOver utility from the UCSC genome browser.19 Eleven CNVRs do not map uniquely to hg19, resulting in a total of 909 CNVRs for use in this study. Figure 1 provides an example of the relationship between these quantitative values, their underlying discrete copy number state, and gene expression. A portion of these CNVRs represents known complex regions. However, most represent diallelic copy number polymorphisms (presence or absence of a deletion/duplication) as we previously observed reasonable concordance in size and location between these CNVRs and those identified to be polymorphisms by HapMap3.12, 15 We will refer to the total set as CNVs for the ease of communication.

Bottom Line: We found a ~1-Mb window size to be optimal for capturing cis effects of CNVs.Up to 10% of the CNVs in this study were found to be significantly associated with the expression of at least one gene within their vicinity.As expected, we find that CNVs that directly overlap gene sequences have the largest effects on gene expression (compared with non-overlapping CNVRs located nearby), with positive correlation (except for a few exceptions) between estimated genomic dosage and expression level.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA [2] Department of Cellular and Structural Biology, UT Health Science Center San Antonio, San Antonio, TX, USA.

ABSTRACT
Only few systematic studies on the contribution of copy number variation to gene expression variation have been published to date. Here we identify effects of copy number variable regions (CNVRs) on nearby gene expression by investigating 909 CNVRs and expression levels of 12059 nearby genes in white blood cells from Mexican-American participants of the San Antonio Family Heart Study. We empirically evaluate our ability to detect the contribution of CNVs to proximal gene expression (presumably in cis) at various window sizes (up to a 10 Mb distance) between the gene and CNV. We found a ~1-Mb window size to be optimal for capturing cis effects of CNVs. Up to 10% of the CNVs in this study were found to be significantly associated with the expression of at least one gene within their vicinity. As expected, we find that CNVs that directly overlap gene sequences have the largest effects on gene expression (compared with non-overlapping CNVRs located nearby), with positive correlation (except for a few exceptions) between estimated genomic dosage and expression level. We find that genes whose expression level is significantly influenced by nearby CNVRs are enriched for immunity and autoimmunity related genes. These findings add to the currently limited catalog of CNVRs that are recognized as expression quantitative trait loci, and have implications for future study designs as well as for prioritizing candidate causal variants in genomic regions associated with disease.

No MeSH data available.


Related in: MedlinePlus