Relating CNVs to transcriptome data at fine resolution: Assessment of the effect of variant size, type, and overlap with functional regions

Schlattl, Andreas; Anders, Simon; Waszak, Sebastian M.; Huber, Wolfgang; Korbel, Jan O.

doi:10.1101/gr.122614.111

Cited by 107 publications

(109 citation statements)

References 48 publications

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“…However, this assumption cannot be used to explain the negative correlations between gene copy number and expression level. Schlattl et al (2011) found that $20% of associations of CNVs displayed the unexpected negative correlations, including several instances that had been previously observed (Stranger et al 2007a;Henrichsen et al 2009). …”

Section: Roles Of Cnv and Natural Selectionmentioning

confidence: 52%

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Genetic Variants Contribute to Gene Expression Variability in Humans

2013

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Expression quantitative trait loci (eQTL) studies have established convincing relationships between genetic variants and gene expression. Most of these studies focused on the mean of gene expression level, but not the variance of gene expression level (i.e., gene expression variability). In the present study, we systematically explore genome-wide association between genetic variants and gene expression variability in humans. We adapt the double generalized linear model (dglm) to simultaneously fit the means and the variances of gene expression among the three possible genotypes of a biallelic SNP. The genomic loci showing significant association between the variances of gene expression and the genotypes are termed expression variability QTL (evQTL). Using a data set of gene expression in lymphoblastoid cell lines (LCLs) derived from 210 HapMap individuals, we identify cis-acting evQTL involving 218 distinct genes, among which 8 genes, ADCY1, CTNNA2, DAAM2, FERMT2, IL6, PLOD2, SNX7, and TNFRSF11B, are cross-validated using an extra expression data set of the same LCLs. We also identify $300 trans-acting evQTL between .13,000 common SNPs and 500 randomly selected representative genes. We employ two distinct scenarios, emphasizing single-SNP and multiple-SNP effects on expression variability, to explain the formation of evQTL. We argue that detecting evQTL may represent a novel method for effectively screening for genetic interactions, especially when the multiple-SNP influence on expression variability is implied. The implication of our results for revealing genetic mechanisms of gene expression variability is discussed.Q UANTITATIVE genetic analysis has long focused on detecting genetic variants that affect organismal phenotypes. This is often done by contrasting mean differences in phenotypes among genotypes. Despite increasing evidence across several species for genetic control of phenotypic variance (Ansel et al. 2008;Hill and Mulder 2010; JimenezGomez et al. 2011), variance differences in phenotypes have been largely ignored. Recently, however, the fact that variance of phenotypes is genotype dependent has inspired the detection of genetic variants associated with phenotypic variability (Pare et al. 2010;Sudmant et al. 2010;Yang et al. 2012).When gene expression level is considered as a heritable, quantitative trait, statistical associations between mean gene expression and genotype can be established to identify those genomic loci associated with or linked to gene expression level (i.e., expression QTL, eQTL) (Montgomery and Dermitzakis 2011). The difference in mean gene expression and its genetic control have been extensively examined in humans (Stranger et al. 2005(Stranger et al. , 2007bPickrell et al. 2010). The difference in variance of gene expression (i.e., gene expression variability) is genetically controlled and likely to be selectable (Raser and O'Shea 2005;Blake et al. 2006;Maheshri and O'Shea 2007;Cheung and Spielman 2009;Zhang et al. 2009). A small number of initial efforts have been m...

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Section: Roles Of Cnv and Natural Selectionmentioning

confidence: 52%

“…Schlattl et al (2011) identified CNVs associated with the expression of 110 genes in CEU and YRI populations. These included a CNV downstream of HLA-DQB1, which is associated with HLA-DQB1 gene expression.…”

Section: Roles Of Cnv and Natural Selectionmentioning

confidence: 99%

Genetic Variants Contribute to Gene Expression Variability in Humans

2013

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“…This risk CNV in the intronic region of MGAT4C likely overlaps a repressor/insulator element, such that a deletion in this region leads to transcript overexpression, a scenario seen in several other instances (32)(33)(34). Two recent studies (34,35) identified several deletion CNVs that were associated with increased transcript expression, similar to our observations with MGAT4C. To evaluate the effect of changes in transcript expression, we carried out in vitro experiments using prostate cell lines (SI Methods).…”

Section: Replication Of Prostate Cancer Risk Variants In Independent Psamentioning

confidence: 99%

Identification of functionally active, low frequency copy number variants at 15q21.3 and 12q21.31 associated with prostate cancer risk

Demichelis

Setlur

Banerjee³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Copy number variants (CNVs) are a recently recognized class of human germ line polymorphisms and are associated with a variety of human diseases, including cancer. Because of the strong genetic influence on prostate cancer, we sought to identify functionally active CNVs associated with susceptibility of this cancer type. We queried low-frequency biallelic CNVs from 1,903 men of Caucasian origin enrolled in the Tyrol Prostate Specific Antigen Screening Cohort and discovered two CNVs strongly associated with prostate cancer risk. The first risk locus (P = 7.7 × 10 −4 , odds ratio = 2.78) maps to 15q21.3 and overlaps a noncoding enhancer element that contains multiple activator protein 1 (AP-1) transcription factor binding sites. Chromosome conformation capture (Hi-C) data suggested direct cis-interactions with distant genes. The second risk locus (P = 2.6 × 10 −3 , odds ratio = 4.8) maps to the α-1,3-mannosyl-glycoprotein 4-β-N-acetylglucosaminyltransferase C (MGAT4C) gene on 12q21.31. In vitro cell-line assays found this gene to significantly modulate cell proliferation and migration in both benign and cancer prostate cells. Furthermore, MGAT4C was significantly overexpressed in metastatic versus localized prostate cancer. These two risk associations were replicated in an independent PSA-screened cohort of 800 men (15q21.3, combined P = 0.006; 12q21.31, combined P = 0.026). These findings establish noncoding and coding germ line CNVs as significant risk factors for prostate cancer susceptibility and implicate their role in disease development and progression.cancer genetics | functionally active DNA loci | cancer predisposition | metabolism | chromosome looping

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“…Inherited copy number variations are known to modulate the expression of individual genes (Schlattl et al, 2011). In this study, we analyzed the expression of the DHRS4 gene cluster with copy number variations in the mouse liver cell line NCTC 1469, chimpanzee skin fibroblast cell line WES, and human hepatocyte (HL-7702) and neuroblastoma (BE(2)-M17 and SK-N-SH) cell lines.…”

Section: Three Homologous Copies Of the Dhrs4 Gene Cluster Have Diffementioning

confidence: 99%

CpG island evolution in the mammalian DHRS4 gene cluster and its role in the regulation of gene transcription

Liu

Song

et al. 2016

Genet. Mol. Res.

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ABSTRACT. The dehydrogenase/reductase (SDR family) member 4 (DHRS4) gene is copied during mammalian evolution; therefore, while only one DHRS4 gene is expressed in the mouse genome, the gene cluster consists of two (DHRS4 and DHRS4L1) and three (DHRS4, DHRS4L2, and DHRS4L1) copies in chimpanzees and humans, respectively. In this study, we explored the possible regulatory mechanism of the DHRS4 gene cluster in mammalian evolution by analyzing the promoter sequence, methylation of CpG islands, and RNA expression of the DHRS4 gene cluster in mice, chimpanzees, and humans by bioinformatics prediction, bisulfite sequencing PCR, and real-time reverse transcriptase-PCR. The results indicated that the DHRS4 gene was actively expressed in the three model species. The RNA level of DHRS4L1 was much lower than those of DHRS4 and DHRS4L2, and expressed lower homologous sequence identity to DHRS4 and DHRS4L2. DHRS4L2, the latest evolutionary copy of the DHRS4 gene in mammals, received a high promoter prediction score, and was the only copy of the DHRS4 gene cluster presenting hypermethylated CpG islands in the promoter region. An analysis of the relationship between the promoter characteristics and RNA expression of the DHRS4 gene cluster indicated that the development of CpG islands, in addition to the promoter sequence, during mammalian evolution could modulate the dose compensatory regulation of the copy number-varied DHRS4 gene cluster.

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Relating CNVs to transcriptome data at fine resolution: Assessment of the effect of variant size, type, and overlap with functional regions

Cited by 107 publications

References 48 publications

Genetic Variants Contribute to Gene Expression Variability in Humans

Genetic Variants Contribute to Gene Expression Variability in Humans

Identification of functionally active, low frequency copy number variants at 15q21.3 and 12q21.31 associated with prostate cancer risk

CpG island evolution in the mammalian DHRS4 gene cluster and its role in the regulation of gene transcription

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