Krebswissenschaft und -therapie

Synonymous Mutations that Increase the tRNA Adaptation Index (tAI) are Generally Suppressed in Human Oncogenes

Abstract

Duan Chu and Lai Wei

Background: Different synonymous codons are decoded at distinct rates during translation elongation due to the difference in tRNA availability, term tRNA adaptation index (tAI). Codons with higher tAI values are translated faster. Synonymous mutations do not change the amino acid (AA) but do sometimes change the tAI. That means synonymous mutations are able to alter the translation efficiency of host genes. In the cancer field, synonymous mutations are often automatically ignored. However, the increased translation of oncogenes or the decreased translation of tumor suppressor genes (TSG) might also lead to oncogenesis even when the protein sequences are unchanged. These changes in translation level could be induced by synonymous mutations.

Results and Discussion: We downloaded the single nucleotide polymorphisms (SNPs) in human populations. The ancestral state is parsed according to genomic alignments between human, macaque and mouse. We found that in the normal human populations, derived synonymous mutations that increase tAI are strongly suppressed in oncogenes but slightly favored in TSG. In oncogenes, mutation sites with higher conservation levels are more likely to decrease the tAI.

Conclusion: Our results indicate that the synonymous mutations in the human genome are not strictly neutral. The potentially increased translation of oncogenes and the decreased translation of TSG caused by synonymous mutations are suppressed in normal human populations. This is an indirect evidence that the synonymous-induced translational changes might be related to oncogenesis and should not be ignored in the cancer studies.