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<p>Engineering the genetic code—by reassigning multiple of the 64 natural codons—enables making organisms resistant to all viruses, preventing genetic information exchange, and allowing the biosynthesis of genetically encoded unnatural polymers. However, synonymous codon replacement—recoding—is frequently lethal, and how recoding impacts fitness remains poorly explored. Here, we explore these effects using genome synthesis, directed evolution, and genome-transcriptome-translatome-proteome co-profiling on multiple synthetic <i>Escherichia coli</i> genomes. We construct six partially recoded <i>E. coli</i> strains bearing up to 45.8% of a synthetic genome with a deleterious 57-codon genetic code. As our analyses revealed widespread defects—including unassigned codons in Syn61 and Syn57—we apply multi-omics to revise our genome design and mitigate defects. Using multi-omics, we show that recoding induces transcriptional and translational changes leading to fitness defects under hundreds of conditions. Finally, we develop a multi-omics-guided evolution strategy that rapidly restores fitness, enabling genome synthesis with radical changes.</p>

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Probing the limits of genetic recoding using multi-omics-guided evolution

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月22日

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  • Akos Nyerges,
  • Anush Chiappino-Pepe,
  • Bogdan Budnik,
  • Maximilien Baas-Thomas,
  • Elissa Rhuby,
  • Regan Flynn,
  • Shirui Yan,
  • Nili Ostrov,
  • Min Liu,
  • Meizhou Wang,
  • Qingmei Zheng,
  • Fangxiang Hu,
  • Kangming Chen,
  • Alexandra Rudolph,
  • Dawn Chen,
  • Jenny Ahn,
  • Owen Spencer,
  • Venkat Ayalavarapu,
  • Angela Tarver,
  • Miranda Harmon-Smith,
  • Matthew Hamilton,
  • Ian Blaby,
  • Yasuo Yoshikuni,
  • Behnoush Hajian,
  • Adeline Jin,
  • Balint Kintses,
  • Monika Szamel,
  • Viktoria Seregi,
  • Yue Shen,
  • Zilong Li,
  • George M. Church

摘要

Engineering the genetic code—by reassigning multiple of the 64 natural codons—enables making organisms resistant to all viruses, preventing genetic information exchange, and allowing the biosynthesis of genetically encoded unnatural polymers. However, synonymous codon replacement—recoding—is frequently lethal, and how recoding impacts fitness remains poorly explored. Here, we explore these effects using genome synthesis, directed evolution, and genome-transcriptome-translatome-proteome co-profiling on multiple synthetic Escherichia coli genomes. We construct six partially recoded E. coli strains bearing up to 45.8% of a synthetic genome with a deleterious 57-codon genetic code. As our analyses revealed widespread defects—including unassigned codons in Syn61 and Syn57—we apply multi-omics to revise our genome design and mitigate defects. Using multi-omics, we show that recoding induces transcriptional and translational changes leading to fitness defects under hundreds of conditions. Finally, we develop a multi-omics-guided evolution strategy that rapidly restores fitness, enabling genome synthesis with radical changes.