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Such presumed selection is described as optimal codon choice. Non-optimal codons, defined as those least commonly used in highly transcribed genes, may in principle also play important roles, but the dynamics of their use remain understudied. Here, we examine non-optimal codon use using sex-biased genes expressed in the gonads of Drosophila melanogaster as a case study. We show that genes with sex-biased expression exhibit a preference for non-optimal codon use, especially testis-biased genes. Further, we show that the use of non-optimal codons is not random. Instead, specific non-optimal codons are favored, again especially in testis-biased genes. Non-optimal codon use is positively linked to elevated disorder of the encoded proteins. Remarkably, all 18 degenerate amino acids were associated with higher disorder when encoded by the identified primary non-optimal codon, than when encoded by its sister optimal codon. We hypothesize that selection may have promoted non-optimal codon choice for a subset of favored non-optimal codons to regulate translation. We discuss the putative roles of tRNA gene copy numbers, pleiotropy, and sex-biased expression in the evolution of this level of gene regulation.<\/jats:p>","DOI":"10.1093\/gbe\/evag093","type":"journal-article","created":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T11:39:35Z","timestamp":1775907575000},"source":"Crossref","is-referenced-by-count":0,"title":["Evidence for Non-optimal Codon Choice in Highly Transcribed Sex-Biased Genes of\n                    <i>Drosophila melanogaster<\/i>"],"prefix":"10.1093","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9331-0520","authenticated-orcid":false,"given":"Carrie A","family":"Whittle","sequence":"first","affiliation":[{"name":"Department of Organismic and Evolutionary Biology, Harvard University , Cambridge, MA 02138 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2922-5855","authenticated-orcid":false,"given":"Cassandra G","family":"Extavour","sequence":"additional","affiliation":[{"name":"Department of Organismic and Evolutionary Biology, Harvard University , Cambridge, MA 02138 ,","place":["USA"]},{"name":"Department of Molecular and Cellular Biology, Harvard University , Cambridge, MA 02138 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2026,4,13]]},"reference":[{"key":"2026050614220692100_evag093-B1","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1016\/S0959-437X(00)00250-1","article-title":"Gene expression and molecular evolution","volume":"11","author":"Akashi","year":"2001","journal-title":"Curr Opin Genet Dev."},{"key":"2026050614220692100_evag093-B2","doi-asserted-by":"publisher","first-page":"1291","DOI":"10.1093\/genetics\/164.4.1291","article-title":"Translational selection and yeast proteome 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