Identifying Functional Promoter SNPs. Using Allelic Imbalance. High-throughput sequencing is becoming increasingly impor- tant in the identification of genetic ...
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Human Mutation OFFICIAL JOURNAL
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& Identifying Functional Promoter SNPs Using Allelic Imbalance High-throughput sequencing is becoming increasingly important in the identification of genetic variation associated with disease or disease predisposition. There has been much success in the identification and classification of disease-associated genetic variation within the coding region of genes. For the most part, such causative variants encode amino acid substitutions that affect the catalytic activity or stability of the associated gene product. Causative SNPs can also occur within the promoter of genes affecting the level of transcription, but the identification of these functional SNPs has been problematic. Allelic imbalance (AI) is a method that reveals differences in expression between alleles due to cis-regulatory variation. By using a SNP in the coding region of UGT2B15 (rs1902023:G>T) to differentiate expression levels between the two alleles, Sun and
colleagues (Hum Mutat 31:99–107, 2010) observed that the G allele had higher levels of transcript (11–36% higher) than the T allele in liver tissue but not breast tissue. Seven SNPs in the promoter region were found to be in near-perfect linkage disequilibrium with the rs1902023 variant and each SNP, along with both haplotypes, were tested with a reporter gene assay. Two of these SNPs were shown to alter reporter gene activity in liver cells but not breast cells. ChIP analysis identified an NRF2 transcription factor binding site in the region surrounding one of the two SNPs. AI is a powerful technique for identifying functional promoter variants that affect transcriptional activity and should help in classifying potential phenotype altering variants in the promoter region. –William S. Oetting, University of Minnesota DOI 10.1002/humu.21174
