A Novel Mistranslating tRNA Model in Drosophila melanogaster has Diverse, Sexually Dimorphic Effects

Transfer RNAs (tRNAs) are the adaptor molecules required for reading of the genetic code and the accurate production of proteins. tRNA variants can lead to genome-wide mistranslation, the misincorporation of amino acids not specified by the standard genetic code into nascent proteins. While genome sequencing has identified putative mistranslating tRNA variants in human populations, little is known regarding how mistranslation affects multicellular organisms. Here, we create a Drosophila melanogaster model for mistranslation by integrating a serine tRNA variant that mistranslates serine for proline (tRNASerUGG, G26A) into the fly genome. Using mass spectrometry, we find that tRNASerUGG, G26A misincorporates serine for proline at a frequency of [~] 0.6% per codon. We find that mistranslation extends development time and decreases the number of flies that reach adulthood. Adult flies containing tRNASerUGG, G26A present with more morphological deformities and worse climbing performance than flies expressing only wild type tRNA. Female flies with the serine tRNA variant have more deformities and experience a faster decline in climbing performance than males, suggesting sex-specific effects. This model will enable studies into the synergistic effects of mistranslating tRNA variants and disease-causing alleles.