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Nucleic Acids Research
Article . 2026 . Peer-reviewed
License: CC BY
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https://doi.org/10.1101/2025.0...
Article . 2025 . Peer-reviewed
License: CC BY
Data sources: Crossref
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PubMed Central
Article . 2026
License: CC BY
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Advancing codon language modeling with synonymous codon constrained masking

Authors: James Heuschkel; Laura Kingsley; Noah Pefaur; Andrew Nixon; Steven Cramer;

Advancing codon language modeling with synonymous codon constrained masking

Abstract

Abstract Codon language models offer a promising framework for modeling protein-coding DNA sequences, yet current approaches often conflate codon usage with amino acid semantics, limiting their ability to capture DNA-level biology. We introduce SynCodonLM, a codon language model that enforces a biologically grounded constraint: masked codons are only predicted from synonymous options, guided by the known protein sequence. This design disentangles codon-level from protein-level semantics, enabling the model to learn nucleotide-specific patterns. The constraint is implemented by masking non-synonymous codons from the prediction space prior to softmax. Unlike existing models, which cluster codons by amino acid identity, SynCodonLM clusters by nucleotide properties, revealing structure aligned with DNA-level biology. Furthermore, SynCodonLM outperforms existing models on six of seven benchmarks sensitive to DNA-level features, including messenger RNA and protein expression. Our approach advances domain-specific representation learning and opens avenues for sequence design in synthetic biology, as well as deeper insights into diverse bioprocesses.

Keywords

Models, Genetic, Computational Biology, RNA, Messenger, Codon, Codon Usage, Algorithms

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selected citations
These citations are derived from selected sources.
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
3
Top 10%
Average
Average
Green
gold