ShapeGTB: The role of local DNA shape in prioritization of functional variants in human promoters with machine learning

Motivation: The identification of functional sequence variations in regulatory DNA regions is one of the major challenges of modern genetics. Here, we report results of a combined multifactor analysis of properties characterizing functional sequence variants located in promoter regions of genes. Results: : We demonstrate that GC-content of the local sequence fragments and local DNA shape features play significant role in prioritization of functional variants and outscore features related to histone modifications, transcription factors binding sites, or evolutionary conservation descriptors. Those observations allowed us to build specialized machine learning classifier identifying functional SNPs within promoter regions – ShapeGTB. We compared our method with more general tools predicting pathogenicity of all non-coding variants. ShapeGTB outperformed them by a wide margin (AUC ROC 0.97 vs. 0.57-0.59). On the external validation set based on ClinVar database it displayed only slightly worse performance (AUC ROC 0.92 vs. 0.74-0.81). Such results suggest unique characteristics of mutations located within promoter regions and are a promising signal for the development of more accurate variant prioritization tools in the future. Availability and implementation: The datasets and source code are publicly available at: https://github.com/zubekj/ShapeGTB .