CodonMoE: DNA Language Models for Codon-Dependent mRNA Prediction

MOTIVATION: Genomic language models (gLMs) face a fundamental efficiency challenge: one must either maintain separate specialized models for each biological modality (DNA and RNA) or develop large multi-modal architectures. Both approaches impose significant computational burdens-modality-specific models require redundant infrastructure despite inherent biological connections, while multi-modal architectures demand increased parameter counts and extensive cross-modality pretraining. RESULTS: To address this limitation, we introduce CodonMoE (Adaptive Mixture of Codon Reformative Experts), a lightweight adapter that transforms DNA language models into effective RNA analyzers without RNA-specific pretraining. Our theoretical analysis establishes CodonMoE as a universal approximator at the codon level, capable of mapping arbitrary functions from codon sequences to codon-dependent RNA properties given sufficient expert capacity. Across four RNA prediction tasks spanning stability, expression, and regulation, DNA models augmented with CodonMoE significantly outperform their unmodified counterparts, with the HyenaDNA+CodonMoE series achieving state-of-the-art results using 80% fewer parameters than specialized RNA models. By maintaining sub-quadratic complexity while achieving superior performance, our approach provides a principled path toward unifying genomic language modeling, leveraging more abundant DNA data and reducing computational overhead while preserving modality-specific performance advantages. AVAILABILITY: Source code for the method and to reproduce the results is available at https://github.com/Kingsford-Group/CodonMoE. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.