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ARCADE: Controllable Codon Design from Foundation Models via Activation Engineering.

作者信息

Li Jiayi, Liang Litian, Du Shiyi, Tang Shijie, Lai Hong-Sheng, Kingsford Carl

机构信息

Ray and Stephanie Lane Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA, 15217, US.

出版信息

bioRxiv. 2025 Aug 23:2025.08.19.668819. doi: 10.1101/2025.08.19.668819.


DOI:10.1101/2025.08.19.668819
PMID:40894773
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12393422/
Abstract

Codon sequence design is crucial for generating mRNA sequences with desired functional properties for tasks such as creating novel mRNA vaccines or gene editing therapies. Yet existing methods lack flexibility and controllability to adapt to various design objectives. We propose a novel framework, ARCADE, that enables flexible control over generated codon sequences. ARCADE is based on activation engineering and leverages inherent knowledge from pretrained genomic foundation models. Our approach extends activation engineering techniques beyond discrete feature manipulation to continuous biological metrics. Specifically, we define biologically meaningful semantic steering vectors in the model's activation space, which directly modulate continuous-valued properties such as the codon adaptation index, minimum free energy, and GC content without retraining. Experimental results demonstrate the superior performance and far greater flexibility of ARCADE compared to existing codon optimization approaches, underscoring its potential for advancing programmable biological sequence design.

摘要

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本文引用的文献

[1]
Genomic language models: opportunities and challenges.

Trends Genet. 2025-4

[2]
Nucleotide Transformer: building and evaluating robust foundation models for human genomics.

Nat Methods. 2025-2

[3]
Sequence modeling and design from molecular to genome scale with Evo.

Science. 2024-11-15

[4]
CodonBERT large language model for mRNA vaccines.

Genome Res. 2024-8-20

[5]
CodonBERT: a BERT-based architecture tailored for codon optimization using the cross-attention mechanism.

Bioinformatics. 2024-7-1

[6]
CpG dinucleotide enrichment in the influenza A virus genome as a live attenuated vaccine development strategy.

PLoS Pathog. 2023-5

[7]
Algorithm for optimized mRNA design improves stability and immunogenicity.

Nature. 2023-9

[8]
Revealing determinants of translation efficiency via whole-gene codon randomization and machine learning.

Nucleic Acids Res. 2023-3-21

[9]
The Codon Statistics Database: A Database of Codon Usage Bias.

Mol Biol Evol. 2022-8-3

[10]
Informative RNA base embedding for RNA structural alignment and clustering by deep representation learning.

NAR Genom Bioinform. 2022-2-22

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