{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T20:10:22Z","timestamp":1777320622252,"version":"3.51.4"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000},"content-version":"vor","delay-in-days":56,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100011859","name":"Algoma University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011859","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Algoma University Research Fund","award":["40370-71-AURF"],"award-info":[{"award-number":["40370-71-AURF"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Although the genetic code is degenerate, codon selection is nonrandom and reflects significant functional constraints. Codon-usage bias (CUB) acts as a layer of post\u2013transcriptional regulation, influencing messenger RNA (mRNA) stability, translation kinetics, and co-translational protein folding. While CUB is well-characterized in unicellular organisms, its regulatory scope and functional consequences in humans remain complex and less defined. Our study offers a comprehensive evaluation of human codon usage. We report that genes exhibiting the strongest codon bias are enriched in high-stoichiometry biological processes, such as skin development and oxygen\/carbon dioxide transport, and harbor significantly fewer synonymous variants than expected (\u03c1 = \u22120.24,\u00a0P\u00a0&amp;lt;\u00a02.2\u00a0\u00d7\u00a010\u221216). Furthermore, we find that codon optimization is structurally distinct: it is significantly more pronounced in structured protein domains compared to intrinsically disordered regions (IDRs) (Cliff\u2019s \u0394= 0.26, P\u00a0&amp;lt;\u00a02.2\u00a0\u00d7\u00a010\u221216). Consistent with translational selection, the most frequently used codons are supported by higher transfer RNA (tRNA) gene copy numbers (\u03c1 = 0.49, P\u00a0&amp;lt;\u00a06.4\u00a0\u00d7\u00a010\u22124). Finally, by correcting for GC3 content, we reveal that the apparent correlation between effective number of codon and adaptation indices (CAI\/tAI) vanishes, allowing us to disentangle mutational pressure from translational selection. Collectively, our findings position CUB as a central, evolutionarily conserved regulator of translation and protein folding in humans. Our results provide a comprehensive and integrated view of intergenic and intragenic CUB in humans, reinforcing the biological relevance of synonymous codon choice in shaping translational dynamics and protein biogenesis. This provides a refined framework for interpreting synonymous variation and guiding functional genomics.<\/jats:p>","DOI":"10.1093\/nargab\/lqag024","type":"journal-article","created":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T12:55:25Z","timestamp":1772283325000},"source":"Crossref","is-referenced-by-count":1,"title":["Mapping the inter- and intra-genic codon-usage landscape in\n                    <i>Homo sapiens<\/i>"],"prefix":"10.1093","volume":"8","author":[{"given":"Maahil","family":"Arshad","sequence":"first","affiliation":[{"name":"Program in Molecular Medicine, Hospital for Sick Children , Toronto, ON, M5G 1X8 ,","place":["Canada"]},{"name":"Department of Molecular Genetics, University of Toronto , Toronto, ON, M5S 1A8 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew","family":"Uchmanowicz","sequence":"additional","affiliation":[{"name":"Department of Biology, Algoma University , Sault Ste Marie, ON, P6A 2G4 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vanshika","family":"Rana","sequence":"additional","affiliation":[{"name":"Department of Biology, Algoma University , Sault Ste Marie, ON, P6A 2G4 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4863-7273","authenticated-orcid":false,"given":"Brett","family":"Trost","sequence":"additional","affiliation":[{"name":"Program in Molecular Medicine, Hospital for Sick Children , Toronto, ON, M5G 1X8 ,","place":["Canada"]},{"name":"Department of Molecular Genetics, University of Toronto , Toronto, ON, M5S 1A8 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8326-1999","authenticated-orcid":false,"given":"Stephen\u00a0W","family":"Scherer","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, University of Toronto , Toronto, ON, M5S 1A8 ,","place":["Canada"]},{"name":"The Centre for Applied Genomics, The Hospital for Sick Children , Toronto, ON M5G 0A4 ,","place":["Canada"]},{"name":"The Hospital for Sick Children , Toronto, ON M5G 0A4 ,","place":["Canada"]},{"name":"McLaughlin Centre , Toronto, ON M5G 0A4 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5333-6691","authenticated-orcid":false,"given":"Muhammad Arshad","family":"Rafiq","sequence":"additional","affiliation":[{"name":"Department of Biology, Algoma University , Sault Ste Marie, ON, P6A 2G4 ,","place":["Canada"]},{"name":"The Centre for Applied Genomics, The Hospital for Sick Children , Toronto, ON M5G 0A4 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2026,3,3]]},"reference":[{"key":"2026030303143972400_B1","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1186\/s12859-017-1793-7","article-title":"A 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