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PreprintCited by 4Microbial Metabolic Engineering and BioproductionFungal and yeast genetics researchGene Regulatory Network Analysis

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AI-directed gene fusing prolongs the evolutionary half-life of synthetic gene circuits

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Menuhin-Gruman, Itamar, Arbel, Matan, Naki, Doron, Bergman, Shaked, Tuller, Tamir·2025·Science Advances
DOI 10.1101/2025.02.10.637495PMC PMC12487889

Preprint — published as 10.1126/sciadv.adx0796

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Abstract

Evolutionary instability is a persistent challenge in synthetic biology, often leading to the loss of heterologous gene expression over time. Here, we present STABLES, a novel gene fusion strategy that links a gene of interest (GOI) to an essential endogenous gene (EG), with a “leaky” stop codon in between. This ensures both selective pressure against deleterious mutations and high expression of the GOI. By leveraging a machine learning (ML) framework, we predict optimal GOI-EG pairs based on bioinformatic and biophysical features, identify linkers likely to minimize protein misfolding, and optimize DNA sequences for stability and expression. Experimental validation in Saccharomyces cerevisiae demonstrated significant improvements in stability and productivity for fluorescent proteins and human proinsulin. The results highlight a scalable, adaptable and organism-agnostic method to enhance the evolutionary stability of engineered strains, with broad implications for industrial biotechnology and synthetic biology.

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Metadata

Authors
Menuhin-Gruman, I., Arbel, M., Naki, D., Bergman, S., & Tuller, T.
Affiliations
Tel Aviv University (IL)
Corresponding author
Tuller, Tamir
ORCID
Venue
Science Advances
Publisher
openRxiv
Published
2025-02-12
Volume
11
Issue
40
Pages
eadx0796-eadx0796
ISSN
2375-2548 (ISSN-L)
DOI
10.1101/2025.02.10.637495
PMC
PMC12487889
OpenAlex
W4414694589
Cited by
4
References
1
Citations by year
2026: 3 · 2025: 1
FWCI
1.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Science Advances (publishedVersion, cc-by-nc)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc)
Funders
Tel Aviv University
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial Metabolic Engineering and Bioproduction
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
Keywords
gene fusion, evolutionary stability, synthetic gene circuits, heterologous expression, protein misfolding, Saccharomyces cerevisiae, fluorescent proteins, human proinsulin, stables
MeSH terms
Artificial Intelligence, Genes, Synthetic, Humans, Saccharomyces cerevisiae, Evolution, Molecular, Gene Regulatory Networks, Synthetic Biology

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