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Probing the limits of genetic recoding using multi-omics-guided evolution
Akos Nyerges1, Anush Chiappino-Pepe2, Bogdan Budnik3
1Department of Genetics, Harvard Medical School, Boston, MA, USA. akos_nyerges@hms.harvard.edu.
Nature Communications
|June 22, 2026
Summary
Synthetic biology enables engineering the genetic code for virus resistance and novel biosynthesis. However, synonymous codon replacement (recoding) can be lethal, impacting organism fitness, which this study investigates.
Area of Science:
- Synthetic biology
- Genomics
- Molecular biology
Background:
- Engineering the genetic code via synonymous codon replacement (recoding) offers potential for virus resistance and unnatural biopolymer synthesis.
- Recoding is often lethal, and its impact on organism fitness is not well understood.
Purpose of the Study:
- To investigate the fitness consequences of recoding the genetic code in synthetic Escherichia coli genomes.
- To explore the effects of recoding on genome stability, gene expression, and overall organism fitness.
Main Methods:
- Genome synthesis and construction of partially recoded *Escherichia coli* strains.
- Multi-omics analyses (genome, transcriptome, translatome, proteome) for comprehensive profiling.
- Directed evolution and multi-omics-guided strategies to restore fitness.
Main Results:
- Construction of synthetic *E. coli* with up to 45.8% recoded genome using a 57-codon code.
- Identification of widespread defects, including unassigned codons, due to recoding.
- Multi-omics data revealed recoding-induced transcriptional and translational changes causing fitness defects across numerous conditions.
Conclusions:
- Recoding the genetic code significantly impacts cellular processes and organism fitness.
- Multi-omics profiling is crucial for understanding and mitigating recoding-induced defects.
- A multi-omics-guided evolution strategy can rapidly restore fitness in recoded organisms, enabling radical genome engineering.
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