{
  "abstract": "Engineering the genetic code of an organism provides the basis for (i) making any organism safely resistant to natural viruses and (ii) preventing genetic information flow into and out of genetically modified organisms while (iii) allowing the biosynthesis of genetically encoded unnatural polymers 1–4 . Achieving these three goals requires the reassignment of multiple of the 64 codons nature uses to encode proteins. However, synonymous codon replacement—recoding—is frequently lethal, and how recoding impacts fitness remains poorly explored. Here, we explore these effects using whole-genome synthesis, multiplexed directed evolution, and genome-transcriptome-translatome-proteome co-profiling on multiple recoded genomes. Using this information, we assemble a synthetic Escherichia coli genome in seven sections using only 57 codons to encode proteins. By discovering the rules responsible for the lethality of synonymous recoding and developing a data-driven multi-omics-based genome construction workflow that troubleshoots synthetic genomes, we overcome the lethal effects of 62,007 synonymous codon swaps and 11,108 additional genomic edits. We show that synonymous recoding induces transcriptional noise including new antisense RNAs, leading to drastic transcriptome and proteome perturbation. As the elimination of select codons from an organism’s genetic code results in the widespread appearance of cryptic promoters, we show that synonymous codon choice may naturally evolve to minimize transcriptional noise. Our work provides the first genome-scale description of how synonymous codon changes influence organismal fitness and paves the way for the construction of functional genomes that provide genetic firewalls from natural ecosystems and safely produce biopolymers, drugs, and enzymes with an expanded chemistry.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Genetics, Harvard Medical School, Boston, MA, USA. akos_nyerges@hms.harvard.edu",
    "Department of Genetics, Harvard Medical School, Boston, MA, USA",
    "Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA",
    "BGI Research, Shenzhen, China",
    "GenScript USA Inc., Piscataway, NJ, USA",
    "DOE Joint Genome Institute (JGI), Lawrence Berkeley National Laboratory, Berkeley, CA, USA",
    "Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA, USA",
    "Institute of Biochemistry, HUN-REN Biological Research Centre, Szeged, Hungary",
    "BGI Research, Changzhou, China",
    "Guangdong Provincial Key Laboratory of Genome Read and Write, BGI Research, Shenzhen, China",
    "Department of Genetics, Harvard Medical School, Boston, MA, USA. gchurch@genetics.med.harvard.edu",
    "Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA. gchurch@genetics.med.harvard.edu"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 31,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Ákos Nyerges",
      "orcid": "0000-0002-1581-490X"
    },
    {
      "affs": [
        1
      ],
      "name": "Anush Chiappino-Pepe",
      "orcid": "0000-0002-3993-907X"
    },
    {
      "affs": [
        2
      ],
      "name": "Bogdan Budnik",
      "orcid": "0000-0003-3622-2003"
    },
    {
      "affs": [
        1
      ],
      "name": "Maximilien S. Baas-Thomas",
      "orcid": "0000-0001-9821-9585"
    },
    {
      "affs": [
        1
      ],
      "name": "Elissa Rhuby",
      "orcid": "0000-0001-8189-6029"
    },
    {
      "affs": [
        1
      ],
      "name": "Regan Flynn"
    },
    {
      "affs": [
        3,
        1
      ],
      "name": "Shirui Yan",
      "orcid": "0009-0004-7081-2677"
    },
    {
      "affs": [
        1
      ],
      "name": "Nili Ostrov",
      "orcid": "0000-0002-2157-587X"
    },
    {
      "affs": [
        4
      ],
      "name": "Min Liu",
      "orcid": "0000-0001-7672-7482"
    },
    {
      "affs": [
        4
      ],
      "name": "Meizhou Wang"
    },
    {
      "affs": [
        4
      ],
      "name": "Qingmei Zheng"
    },
    {
      "affs": [
        4
      ],
      "name": "Fangxiang Hu",
      "orcid": "0000-0002-7641-9882"
    },
    {
      "affs": [
        4
      ],
      "name": "Kangming Chen"
    },
    {
      "affs": [
        1
      ],
      "name": "Alexandra Rudolph"
    },
    {
      "affs": [
        1
      ],
      "name": "Xi Dawn Chen",
      "orcid": "0000-0001-8127-6014"
    },
    {
      "affs": [
        1
      ],
      "name": "Jenny J. Ahn",
      "orcid": "0009-0000-3912-7162"
    },
    {
      "affs": [
        1
      ],
      "name": "Owen Spencer"
    },
    {
      "affs": [
        1
      ],
      "name": "Venkat Ayalavarapu"
    },
    {
      "affs": [
        5
      ],
      "name": "Angela Tarver",
      "orcid": "0000-0002-5564-5653"
    },
    {
      "affs": [
        5
      ],
      "name": "Miranda Harmon‐Smith",
      "orcid": "0000-0002-3980-1820"
    },
    {
      "affs": [
        5
      ],
      "name": "Matthew Hamilton"
    },
    {
      "affs": [
        5
      ],
      "name": "Ian K. Blaby",
      "orcid": "0000-0002-1631-3154"
    },
    {
      "affs": [
        5
      ],
      "name": "Yasuo Yoshikuni",
      "orcid": "0000-0002-8372-640X"
    },
    {
      "affs": [
        6
      ],
      "name": "Behnoush Hajian"
    },
    {
      "affs": [
        4
      ],
      "name": "Adeline Jin"
    },
    {
      "affs": [
        7
      ],
      "name": "Bálint Kintses",
      "orcid": "0000-0003-0844-0310"
    },
    {
      "affs": [
        7
      ],
      "name": "Mónika Számel"
    },
    {
      "affs": [
        7
      ],
      "name": "Viktória Seregi"
    },
    {
      "affs": [
        8,
        3,
        9
      ],
      "name": "Yue Shen",
      "orcid": "0000-0002-3276-7295"
    },
    {
      "affs": [
        4
      ],
      "name": "Zilong Li",
      "orcid": "0000-0002-5134-7026"
    },
    {
      "affs": [
        10,
        11
      ],
      "name": "George McDonald Church",
      "orcid": "0000-0003-3535-2076"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/7t61sjsf1zv97.bib",
  "cited_by": 19,
  "doi": "10.1038/s41467-026-74300-9",
  "fulltext_url": null,
  "id": "7t61sjsf1zv97",
  "issns": [
    "2041-1723"
  ],
  "landing_url": "https://doi.org/10.1038/s41467-026-74300-9",
  "language": "en",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|RNA and protein synthesis mechanisms"
    ]
  ],
  "openalex": "W7165566122",
  "pdf_url": "https://www.nature.com/articles/s41467-026-74300-9.pdf",
  "pmcid": "PMC11195188",
  "pmid": "38915524",
  "published": "2026-06-22",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/7t61sjsf1zv97.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T13:21:05Z",
      "native_id": "W7165566122",
      "source": "openalex",
      "url": "https://doi.org/10.1038/s41467-026-74300-9"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|RNA and protein synthesis mechanisms",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Probing the limits of genetic recoding using multi-omics-guided evolution",
  "title_text": "Probing the limits of genetic recoding using multi-omics-guided evolution",
  "type": "peer-reviewed",
  "updated_at": "2026-11-08T13:20:41Z",
  "url": "https://research.draconitic.com/paper/7t61sjsf1zv97",
  "venue": "Nature Communications",
  "versions": []
}