Predicting the Evolutionary and Functional Landscapes of Viruses with a Unified Nucleotide-Protein Language Model: LucaVirus

Pan, Y.-F.; He, Y.; Liu, Y.-Q.; Shan, Y.-T.; Liu, S.-N.; Liu, X.; Pan, X.; Bai, Y.; Xu, Z.; Wang, Z.; Ye, J.; Holmes, E. C.; Li, B.; Chen, Y.-Q.; Li, Z.-R.; Shi, M.

doi:10.1101/2025.06.14.659722

bioRxiv · 10.1101/2025.06.14.659722

Predicting the Evolutionary and Functional Landscapes of Viruses with a Unified Nucleotide-Protein Language Model: LucaVirus

Pan, Y.-F.·He, Y.·Liu, Y.-Q.·Shan, Y.-T.·Liu, S.-N.·Liu, X.·Pan, X.·Bai, Y.·Xu, Z.·Wang, Z.·Ye, J.·Holmes, E. C.·Li, B.·Chen, Y.-Q.·Li, Z.-R.·Shi, M.

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Abstract

Predicting viral evolution and function remains a central challenge in biology, hindered by high sequence divergence and limited knowledge compared to cellular organisms. Here, we introduce LucaVirus, a multi-modal foundation model for viruses, trained on 25.4 billion nucleotide and amino acid tokens covering nearly all known viruses. LucaVirus learns biologically meaningful representations capturing relationships between sequences, protein/gene homology, and evolutionary divergence. Using these embeddings, we developed downstream models that address key virology tasks: identifying hidden viruses in genomic "dark matter", annotating enzymatic activities of uncharacterized proteins, predicting viral evolvability, and identifying antibody candidates for emerging viruses. LucaVirus achieves state-of-the-art results in three tasks and matches leading models in the fourth with one-third the parameters. Together, these findings demonstrate the power of a unified foundation model to comprehensively decode the viral world and establish LucaVirus as an efficient and versatile platform for AI-driven virology, from virus discovery to functional and therapeutic predictions.

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Pan, Y.-F., He, Y., Liu, Y.-Q., Shan, Y.-T., Liu, S.-N., Liu, X., Pan, X., Bai, Y., Xu, Z., Wang, Z., Ye, J., Holmes, E. C., Li, B., Chen, Y.-Q., Li, Z.-R., Shi, M.. 2025-06-20. Predicting the Evolutionary and Functional Landscapes of Viruses with a Unified Nucleotide-Protein Language Model: LucaVirus. https://doi.org/10.1101/2025.06.14.659722

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