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Figure 3.

Figure 3. From: Allele-specific DNA methylation: beyond imprinting.

Allele-specific mapping for maximizing information from GWAS. This figure is adapted from Tycko (42). It shows the general strategy for overlaying information from genome-wide maps of allelic asymmetries with data from GWAS. Mapping ASE, ASTF and ASM can help to pinpoint bona fide regulatory polymorphisms, which reveal their presence by conferring the allelic asymmetries in the relevant disease target tissue. Supra-threshold and sub-threshold GWAS peaks that co-localize with these regulatory polymorphisms warrant attention as true-positive signals.

Benjamin Tycko. Hum Mol Genet. 2010 October 15;19(R2):R210-R220.
Figure 2.

Figure 2. From: Allele-specific DNA methylation: beyond imprinting.

Possible mechanisms of cis-regulated ASE and ASM. The cis-acting effects of sequence polymorphisms can be either short-range (A and B) or long-range (C). Details of each model are discussed in the text. Working out the relevance of each mechanism will depend on developing efficient methods for high-resolution mapping of allelic asymmetries and for determining long-range haplotypes in large collections of primary tissues. Black circles, methylated CpG dinucleotides; white circles, unmethylated CpGs; dark gray rectangle and arrow, first exon of the gene.

Benjamin Tycko. Hum Mol Genet. 2010 October 15;19(R2):R210-R220.
Figure 1.

Figure 1. From: Allele-specific DNA methylation: beyond imprinting.

Example of primary data and validations showing non-imprinted ASM. (A) Primary data from MSNP on Affymetrix 6.0 arrays. Pre-digestion of the genomic DNA (PBL sample) with the methylation-sensitive restriction enzyme HpaII prior to linker ligation and PCR for probe synthesis leads to a dropout of the B-allele, suggesting that this allele is relatively hypomethylated. (B) Validation by bisulfite conversion of genomic DNA followed by PCR, cloning and sequencing of multiple clones. Black circles are methylated CpG dinucleotides; white circles are unmethylated CpGs; the dash indicates a CpG SNP in one individual. The two alleles are distinguished in the group of clones by an SNP (rs2302902) that is not destroyed by the bisulfite conversion. Using pre-digestion/PCR assays, the hypermethylated allele was the A-allele at rs4762138 in each of 11 informative PBL samples, consistent with cis-regulation of DNA methylation. (C) Map of the ELK3 gene, containing the intragenic index SNP on the microarrays (rs4762138) and the nearby SNP (rs2302902) that was utilized for distinguishing the alleles in the bisulfite sequencing. The region with ASM subjected to sequencing (gray bar) is CG-rich but is not a CpG island; two CpG islands are near the gene promoter (green bars). Black rectangles are exons 1 and 2. The functional role of the allelic asymmetry at this position in the ELK3 gene is under investigation. Unpublished data are from K. Kerkel and B.T.

Benjamin Tycko. Hum Mol Genet. 2010 October 15;19(R2):R210-R220.

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