We further show that specific tissues, namely the testis and brain, are distinct in the ability to robustly express proteins encoded by rare codons. We find that reporter protein expression declines drastically over a narrow range of rare codon usage in a gene. Using a library of codon-altered reporters, we conduct an organism-wide screen during Drosophila development. Here, we leverage the genetic and cell biological strengths of Drosophila melanogaster to reveal tissue-specific impacts of codon bias. For example, codon usage frequencies differ between tissue-specific gene sets in numerous plant species ( Camiolo et al., 2012 Liu, 2012), Drosophila ( Payne et al., 2019), and potentially humans ( Plotkin et al., 2004 Sémon et al., 2006), hinting that codon usage could play a fundamental role in tissue and cellular identity. Studies analyzing gene expression datasets cross-referenced with codon usage also suggest that the impact of codon bias on protein expression may differ between tissues. In humans, tRNA levels have been shown to differ between tissues and cell types, impacting the translation efficiency of rare codon-enriched transcripts ( Dittmar et al., 2006 Gingold et al., 2014), and RAS isoforms that differ in codon usage have different transcription/translation kinetics based on cellular context ( Fu et al., 2018). Further, while rare codons generally destabilize mRNAs in Drosophila whole embryos, this effect is attenuated within the embryonic central nervous system, where codon bias has little impact on mRNA stability ( Burow et al., 2018). For example, codon bias underlies differences between maternal and zygotic mRNAs in developing zebrafish, Xenopus, mouse, and Drosophila ( Bazzini et al., 2016). Codon bias impacts expression and structure of clock proteins that underlie the in vivo circadian clock function in Neurospora, cyanobacteria, and Drosophila ( Fu et al., 2016 Xu et al., 2013 Zhou et al., 2013), protein secretion in yeast ( Pechmann et al., 2014), and virus/host interactions (including in COVID-19, Alonso and Diambra, 2020 Shin et al., 2015).Įmerging studies suggest codon bias plays an important role in fundamental tissue-level processes. Conversely, a high frequency of rare codons in an mRNA can cause ribosomal stalling and trigger RNA degradation or premature translation termination ( Buschauer et al., 2020 Radhakrishnan et al., 2016 Yang et al., 2019). In general, mRNAs enriched in codons commonly used in a given species are more stable and are more robustly translated ( Presnyak et al., 2015 Sorensen and Pedersen, 1991 Yan et al., 2016 Yu et al., 2015 Zhao et al., 2017). This disproportionate usage frequency among synonymous codons is termed codon usage bias (hereafter: codon bias).Ĭodon bias is governed by several biochemical mechanisms and has diverse biological consequences. Synonymous codons are used at varying frequencies throughout a given genome ( Grantham et al., 1980 Ikemura, 1985 Sharp and Li, 1986). It was initially thought that synonymous substitutions, those leading to changes in nucleotide sequence but resulting in an identical protein sequence, were functionally ‘silent.’ However, it is now clear that this is not the case. The genetic code is redundant, with 61 codons encoding only 20 amino acids ( Crick, 1968 Zuckerkandl and Pauling, 1965). Our work highlights distinct responses to rarely used codons in select tissues, revealing a critical role for codon bias in tissue biology. Optimizing RpL10Aa codons disrupts female fertility. We further demonstrate a role for rare codons in an evolutionarily young testis-specific gene, RpL10Aa. We define a new metric of tissue-specific codon usage, the tissue-apparent Codon Adaptation Index (taCAI), to reveal a conserved enrichment for rare codon usage in the endogenously expressed genes of both Drosophila and human testis. Near the edge of this limit, however, we find the testis and brain are uniquely capable of expressing rare codon-enriched reporters. These reporters reveal a cliff-like decline of protein expression near the limit of rare codon usage in endogenously expressed Drosophila genes. Here, we use codon-modified reporters to perform an organism-wide screen in Drosophila melanogaster for distinct tissue responses to codon usage bias. Yet, relatively few studies have analyzed the impacts of codon usage on tissue-specific mRNA and protein expression. Codon usage bias has long been appreciated to influence protein production.
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