Exome-based Variant Detection in Core Promoters.

Yeong C Kim,San Ming Wang,Bradley Downs,Jiangtao Luo,Jian Cui,Fengxia Xiao

doi:10.1038/srep30716

Abstract

Core promoter controls the initiation of transcription. Core promoter sequence change can disrupt transcriptional regulation, lead to impairment of gene expression and ultimately diseases. Therefore, comprehensive characterization of core promoters is essential to understand normal and abnormal gene expression in biomedical studies. Here we report the development of EVDC (Exome-based Variant Detection in Core promoters) method for genome-scale analysis of core-promoter sequence variation. This method is based on the fact that exome sequences contain the sequences not only from coding exons but also from non-coding region including core promoters generated by random fragmentation in exome sequencing process. Using exome data from three cell types of CD4+ T cells, CD19+ B cells and neutrophils of a single individual, we characterized the features of core promoter-mapped exome sequences, and analysed core-promoter variation in this individual genome. We also compared the core promoters between YRI (Yoruba in Ibadan, Nigeria) and the CEU (Utah residents of European decedent) populations using the exome data generated by the 1000 Genome project, and observed much higher variation in YRI population than in CEU population. Our study demonstrates that the EVDC method provides a simple but powerful means for genome-wile de novo characterization of core promoter sequence variation.

Highlights

Core promoter controls the initiation of transcription
ChIP-sequencing (e.g., ChIP-exo) can only analyse a given type of trans-element binding sites in one assay[12]; promoter-array[13] has low specificity to provide gene-specific probes due to the highly conserved core promoter sequences among different genes, and has inherited deficiency to detect altered core-promoters as the probes designed for the array are based on normal reference genome sequences; Cap Analysis Gene Expression (CAGE) can locate promoters precisely but it does not analyse core promoter contents[14]; and whole-genome sequencing is not cost-effective as core promoters account for only a tiny portion of the entire genome
As the promoter sequences are collected indirectly through probes targeting coding exons, they preserve the native information of the core promoter sequences; (2) It detects the variants in core promoters at genome level

Summary

Introduction

Core promoter controls the initiation of transcription. Core promoter sequence change can disrupt transcriptional regulation, lead to impairment of gene expression and diseases. We report the development of EVDC (Exome-based Variant Detection in Core promoters) method for genome-scale analysis of core-promoter sequence variation. Our study demonstrates that the EVDC method provides a simple but powerful means for genome-wile de novo characterization of core promoter sequence variation. Transcription initiation is regulated through highly specific spatial interaction between cis- and trans-elements in the core promoter[1,2,3]. It has been observed that over half of exome sequences are routinely originated outside of coding exons[16,17] This is caused by the random fragmentation of genomic DNA used in exome library preparation[18], which generates both coding-exon templates and coding-exon connected non-coding templates including core promoters. Sequencing the isolated DNA templates will generate the sequences derived from core promoters (Fig. 1)

Methods

Results

Conclusion