Highly diversified core promoters in the human genome and their effects on gene expression and disease predisposition
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RESEARCH ARTICLE
Open Access
Highly diversified core promoters in the human genome and their effects on gene expression and disease predisposition Hemant Gupta1†, Khyati Chandratre1†, Siddharth Sinha1†, Teng Huang1†, Xiaobing Wu1, Jian Cui2, Michael Q. Zhang3 and San Ming Wang1*
Abstract Background: Core promoter controls transcription initiation. However, little is known for core promoter diversity in the human genome and its relationship with diseases. We hypothesized that as a functional important component in the genome, the core promoter in the human genome could be under evolutionary selection, as reflected by its highly diversification in order to adjust gene expression for better adaptation to the different environment. Results: Applying the “Exome-based Variant Detection in Core-promoters” method, we analyzed human corepromoter diversity by using the 2682 exome data sets of 25 worldwide human populations sequenced by the 1000 Genome Project. Collectively, we identified 31,996 variants in the core promoter region (− 100 to + 100) of 12,509 human genes (https://dbhcpd.fhs.um.edu.mo). Analyzing the rich variation data identified highly ethnic-specific patterns of core promoter variation between different ethnic populations, the genes with highly variable core promoters, the motifs affected by the variants, and their involved functional pathways. eQTL test revealed that 12% of core promoter variants can significantly alter gene expression level. Comparison with GWAS data we located 163 variants as the GWAS identified traits associated with multiple diseases, half of these variants can alter gene expression. Conclusion: Data from our study reals the highly diversified nature of core promoter in the human genome, and highlights that core promoter variation could play important roles not only in gene expression regulation but also in disease predisposition. Keywords: Core promoter, Variation, 1000 genomes, Exome, eQTL, GWAS
Background Transcription initiation is the gateway for gene expression. In eukaryotic cells, RNA polymerase II-mediated transcriptional initiation is regulated by the basal transcriptional machinery of cis- and trans-elements in the core promoter region surrounding the transcriptional start site (TSS). The well-known core cis-elements * Correspondence: [email protected] † Hemant Gupta, Khyati Chandratre, Siddharth Sinha and Teng Huang contributed equally to this work. 1 Cancer Centre and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau, SAR, China Full list of author information is available at the end of the article
consist of TFIIB recognition element (BRE), TATA box, Initiator element (Inr), downstream promoter element (DPE) etc. and their flanking sequences. The trans-elements of the preinitiation complex (PIC) consist of RNA polymerase II and six general transcription factors TFIIA, TFIIB, TFIID, TFIIE, TFIIF and TFIIH [1–10]. Variation in cis sequences can interfere cis-trans interaction and therefore modulate gene expression in physiol
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