Implications of Codon Usage, tRNA Gene Redundancy and tRNA Gene Clustering in Experimental Models of Mistranslation

The genetic code converts information transcribed in messenger-RNA (mRNA) into the amino acid sequences that build proteins. Transfer-RNAs (tRNAs) are the adaptors for this conversion from nucleic acids to proteins as they discriminate mRNA codons via anticodon-codon base pairing and recruit cognate amino acids to the ribosome for faithful protein biosynthesis. Although the genetic code is identical among many common model organisms and humans, there are profound differences in genomic codon usage, tRNA gene redundancy and genomic organization of tRNA genes that may change the accuracy and efficiency by which the genetic code is translated. Furthermore, these factors may influence how organisms tolerate tRNA variants that induce translation errors. Such tRNA variants are common in human populations, yet their contribution to human disease remains mostly unclear. Thus, tRNA variants have been studied in several model organisms and induce different rates of mistranslation and toxicity. To understand why mistranslating tRNA variants affect model organisms differently, we compare codon frequency, tRNA gene abundance and the genomic organization of tRNA genes in these commonly used model organisms (yeast, roundworms, fruit flies, mice and rats) and humans. We describe unique translation biases across model systems that influence tolerance of mistranslating tRNA variants, efficiency of protein biosynthesis, and co-translational protein quality control. Our review serves as a practical resource for researchers studying tRNA biology and the regulation of protein biosynthesis in these model organisms to guide experimental design and data interpretation.