DamageFormer: a damage-aware multimodal deep learning framework for DNA lesion identification from nanopore sequencing.

Background: DNA lesions arise from endogenous metabolism and environmental exposure and are the major drivers of mutagenesis, aging, and cancer development. However, mapping DNA damage at nucleotide resolution remains a technically challenging task. Nanopore sequencing enables direct detection of chemical perturbations through alterations in ionic current signals. Despite this potential, existing computational approaches remain limited in their capacity to generalize across diverse lesion types and to effectively integrate nucleotide sequence context with raw signal information for accurate detection and localization. Results: We presented DamageFormer, a multimodal deep learning framework for detection and localization of DNA lesions using native nanopore sequencing data. Central to this framework is LesionBERT, a damage-aware genomic foundation model built upon DNABERT-2 and enhanced with lesion-focused reconstruction objectives to improve representation of chemically modified bases. DamageFormer integrated LesionBERT with a neural signal model through an adaptive gating mechanism, enabling dynamic weighting of sequence context and nanopore signal evidence. The model was trained using a joint objective that combines prediction, localization, and contrastive alignment losses to promote cross-modal coherence and spatial precision. On an oxidative DNA damage benchmark comprising paired sequence and signal data, DamageFormer achieved an AUROC of 0.99997 for lesion detection and a mean absolute localization error of 0.00439, consistently outperforming state-of-the-art baselines. Model interpretation analyses revealed context-dependent modality weighting that adapts to variation in signal quality and sequence ambiguity. The proposed framework further generalizes to chemically distinct guanine lesions not observed during the training process, demonstrating its robustness and transferability to unseen damage types. Conclusions: Damage-aware biological language modeling combined with adaptive multimodal fusion enables accurate and interpretable identification of DNA lesions from nanopore sequencing data. This framework provides a scalable approach for characterizing genome-wide damage landscapes and illustrates how chemical DNA information can be systematically incorporated into genomic language models. The source code and pretrained models of this work are available at: https://github.com/UF-HOBIYin-Lab/DamageFormer.