DeepVRegulome: DNABERT-based deep-learning framework for predicting the functional impact of short genomic variants on the human regulome

Abstract

Whole-genome sequencing (WGS) has revealed numerous non-coding short variants whose functional impacts remain poorly understood. Despite recent advances in deep-learning genomic approaches, accurately predicting and prioritizing clinically relevant mutations in gene regulatory regions remains a major challenge. We developed DeepVRegulome, a computational framework integrating 464 fine-tuned DNABERT models (458 transcription factor, 4 histone mark, and 2 splice site models) trained on ENCODE and GENCODE datasets. The framework pairs these deep learning models with a suite of analytical tools: quantitative variant scoring via log-odds ratios to assess functional impact, attention-based motif analysis to identify disrupted sequence patterns, and survival analysis using Kaplan-Meier and Cox proportional hazards models to link high-impact variants with clinical outcomes. To ensure the framework accurately captures variant effects on baseline binding status, we benchmarked DeepVRegulome against an independent experimental assay of allele-specific transcription factor binding (SNP-SELEX) data and compared its performance to four established variant-effect predictors. The analysis identified 572 splice-disrupting and 9,837 transcription-factor binding site-altering mutations occurring in greater than 10 percentage of glioblastoma samples. Survival analysis linked 1352 mutations and 563 disrupted regulatory regions to patient outcomes, enabling stratification via non-coding mutation signatures. All the code, fine-tuned models, and an interactive data portal are publicly available.