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Background  The regulatory effect of inherited or  de novo  genetic variants occurring in promoters as well as in transcribed or even coding gene regions is gaining greater recognition as a contributing factor to disease processes in addition to mutations affecting protein functionality. Thousands of such regulatory mutations are already recorded in HGMD, OMIM, ClinVar and other databases containing published disease causing and associated mutations. It is therefore important to properly annotate genetic variants occurring in experimentally verified and predicted transcription factor binding sites (TFBS) that could thus influence the factor binding event. Selection of the promoter sequence used is an important factor in the analysis as it directly influences the composition of the sequence available for transcription factor binding analysis.    Results  In this study we first establish genomic regions likely to be involved in regulation of gene expression. TRANSFAC uses a method of virtual transcription start sites (vTSS) calculation to define the best supported promoter for a gene. We have performed a comparison of the virtually calculated promoters between the best supported and secondary promoters in hg19 and hg38 reference genomes to test and validate the approach. Next we create and utilize a workflow for systematic analysis of casual disease associated variants in TFBS using Genome Trax and TRANSFAC databases. A total of 841 and 736 experimentally verified TFBSs within best supported promoters were mapped over HGMD and ClinVar mutation sites respectively. Tens of thousands of predicted ChIP-Seq derived TFBSs were mapped over mutations as well. We have further analyzed some of these mutations for potential gain or loss in transcription factor binding.    Conclusions  We have confirmed the validity of TRANSFAC’s approach to define the best supported promoters and established a workflow of their use in annotation of regulatory genetic variants.

Establishing and validating regulatory regions for variant annotation and expression analysis