A transfer RNA modification drives genome-wide synonymous recoding across human commensal bacterial families

Inosine modification on tRNA anticodon (I34) is universally conserved in three kingdoms of life and critical to tRNA decoding capabilities. We found that tRNALeu(IAG) in commensal human bacterial families in Lactobaccilales is concurrent with genome-wide synonymous leucine codon reprogramming. Pathway analysis reveals drastic synonymous Leu codon shifts in metabolism proteins, where many genome-wide dominant UUA in families without tRNALeu(IAG) is reprogrammed to CUU, CUC and UUG in families with tRNALeu(IAG). We provide biochemical and phenotypic results to support mechanisms that enable synonymous Leu codon substitutions to confer greater translation equivalency and growth fitness. The appearance of a single tRNA modification can propel the genome-wide evolution of synonymous codons.