UGM: Unified Multi-scale Genomic Event Modeling with Site-level Joint Prediction

Genomic events span multiple spatial scales, from single-nucleotide substitutions to large structural variants, yet existing foundation models process only reference DNA sequences, leaving methylation, short variants, and structural-variant boundaries as downstream labels or auxiliary inputs. We propose the Unified Genomic Model (UGM), an encoder-only genomic foundation model that learns multi-scale genomic events as native tokens within a unified 43-token vocabulary. UGM introduces three algorithmic components: (i) a unified event tokenizer that maps reference bases, SNPs, CpG methylation, short INDELs, and structural-variant boundaries into a single event-state space; (ii) event-balanced pretraining, which promotes adequate gradient coverage for rare but biologically important events; and (iii) Site-Level Joint Prediction (SJP), a masked-language-modeling objective that recovers the complete genomic state at a masked position as a single token rather than predicting base, methylation, and variant labels independently. We evaluate UGM against specialized and generalist baselines across functional variant classification, regulatory benchmarks (NT and GUE), structural-variant detection, and cross-event attention analysis. UGM achieves competitive performance, particularly on tasks where explicit event-state information is central. It obtains the highest score on all seven functional variant tasks, reaches competitive splicing prediction on NT, and notably outperforms DNA-only baselines on SV breakpoint detection. These results suggest that native multi-scale event pretraining is a promising direction for genomic representation learning.