Distinct responses to rare codons in select Drosophila tissues

Abstract

Codon usage bias has long been appreciated to influence protein production. Yet, relatively few studies have analyzed the impacts of codon usage on tissue-specific mRNA and protein expression. Here, we use codon-modified reporters to perform an organism-wide screen in Drosophila melanogaster for distinct tissue responses to codon usage bias. These reporters reveal a cliff-like decline of protein expression near the limit of rare codon usage in endogenously expressed Drosophila genes. Near the edge of this limit, however, we find the testis and brain are uniquely capable of expressing rare codon-enriched reporters. We define a new metric of tissue-specific codon usage, the tissue-apparent Codon Adaptation Index, to reveal a conserved enrichment for rare codon usage in the endogenously expressed genes of both Drosophila and human testis. We further demonstrate a role for rare codons in an evolutionarily young testis-specific gene, RpL10Aa. Optimizing RpL10Aa codons disrupts female fertility. Our work highlights distinct responses to rarely used codons in select tissues, revealing a critical role for codon bias in tissue biology.

Cellular energy regulates mRNA translation and degradation in a codon-specific manner

“…This is explained by a nonuniform effect of the abundance of energy-carrier molecules on codon decoding, which occurs independently of tRNA abundance regulation. Our results provide furthermore a mechanistic basis for previous observations of attenuated effects of codon optimality in brain and testis of the fruit fly [6,9], and, as ATP concentration is maximal at the G2/M phase [30], on attenuated effects of codon usage in proliferative cells in absence of tRNA regulation [7].…”

“…In light of such an explanation, regulation of the tRNA pool composition between cell types and conditions could differentially affect mRNA translation and degradation. Consistent with this hypothesis, associations between codon usage and differential expression between tissues and conditions have been reported across eukaryotes [5][6][7][8][9]. However, whether regulation of the tRNA pool is generally causing these associations is debated.…”

tRNA modifications inform tissue specific mRNA translation and codon optimization

“…Such findings made it more likely that tissue-specific codon optimality can regulate mRNA translation and local proteostasis. Such idea was challenged previously in Drosophila tissues by Allen et al (Allen et al, 2022). In their work, Allen et al (Allen et al, 2022) used codon mutated probes to evaluate the expression of rare codons in various tissues.…”

Human tissues exhibit diverse composition of translation machinery

“…It should also be noted that the brain and testis are immunologically privileged organs and this may bring some bias in transcriptomic and proteomic analysis of their content. It was also shown recently that testis and brain express genes that are enriched in rare codons both in humans and flies [104].…”