RT Journal
A1 Murillo, Marina
A1 Salvadores, Marina
A1 Vaquer Picó, Aina
A1 Tsapanou, Lina
A1 Torres, Adrian Gabriel
A1 Supek, Fran
A1 Ribas de Pouplana, Lluis
T1 Age-dependent mutational loads in human tRNA genes are tumor-specific and result in chimeric tRNA sequences that could disrupt the genetic code
JF Genome Research 
JO Genome Research 
YR 2026 
FD April 15 
DO 10.1101/gr.281022.125 
SP gr.281022.125 
UL http://genome.cshlp.org/content/early/2026/04/15/gr.281022.125.abstract 
AB Transfer RNA genes (tDNAs) are essential genomic elements that safeguard translational fidelity. Using the T2T version of the human genome we have mapped the position of human tDNAs and analyzed their individual transcriptional activities. Then we have characterized, at single base resolution, the impact of somatic mutations in human tDNAs and its relationship to the transcriptional status of each gene. We confirm that tDNAs are hotspots for somatic mutagenesis, and show that they display mutational loads that are directly proportional to their transcription rates. Highly transcribed tDNAs in tumors or healthy tissues accumulate mutations at rates up to nine-fold higher than highly transcribed protein-coding genes. Mutational loads at tDNAs are tumor-specific, and increase with patient age. Mutations at structurally conserved tRNA positions appear to be under negative selection. Anticodon nucleotides crucial for decoding frequently acquire somatic mutations, readily generating chimeric tRNA species capable of systematically introducing amino acid substitutions across the proteome. Our results reveal a previously unrecognized source of somatic heterogeneity in human cancer and aging tissues that may directly impact upon translation efficiency and fidelity, and cause cell-specific proteostasis degeneration.