HyenaCircle: a HyenaDNA-based pretrained large language model for long eccDNA prediction

Fuyu LiWenxiang LuYunfei Bai^*

• Southeast University, Nanjing, China

Introduction: Extrachromosomal circular DNA (eccDNA) represents a class of circular DNA molecules derived from chromosomes with diverse roles in disease. Long eccDNAs (typically 1-5 kb) pose detection challenges due to their large size, hindering functional studies. We propose HyenaCircle, a novel deep learning model leveraging large language model and third-generation sequencing data to predict long eccDNA formation.Methods: Full-length eccDNAs within 1-5 kb were identified by FLED algorithm for Nanopore sequencing data, extended by 100-bp flanking sequences, and paired with 20,000 length-matched negative controls from eccDNA-depleted genomic regions. HyenaCircle was built by adapting the pretrained HyenaDNA model with a designed classifier head. The strategies of data augmentation, regularization and class imbalance weighting were applied to increase model robustness.Results: HyenaCircle achieved comparable performance with a validation AUROC of 0.715 and recall of 0.776. It surpassed DNABERT by 5.9% in AUROC and demonstrated stable convergence. Hyperparameter optimization confirmed batch size 16 and learning rate 5×10⁻⁵ as optimal. The ablation studies revealed flanking sequences are important, as their removal reduced model stability. The model also showed superior stability over the baseline HyenaDNA architecture.HyenaCircle integrated third-generation sequencing data and large language model for long eccDNA prediction, which outperformed the existing model. Our work demonstrates that the HyenaDNA architecture enables effective long-sequence genomic modeling and provides a new insight for eccDNA prediction and identification.