Disease-associated protein states accessible to 8-oxoguanine transcriptional miscoding without genomic mutation

8-Oxoguanine (8-oxoG) is a prevalent oxidative DNA lesion that can influence coding output during transcription without altering the original DNA sequence. When located on the template strand, 8-oxoG can prompt RNA polymerase II to insert adenine, creating a temporary coding-sense C A error that is limited by the genetic code to 18 possible directional amino-acid substitutions.

By mapping these substitutions onto ClinVar, researchers identified 3,910 disease-associated protein states across 1,333 genes, accounting for 5.7% of all evaluable pathogenic or likely pathogenic missense states. In 211 instances, transcriptional miscoding and the associated genomic disease variant impact distinct nucleotides within the same codon but ultimately result in the same amino acid substitution, enabling the disease-associated protein state to emerge while the affected genomic nucleotide remains unmutated.

These accessible states were found to be more common among genes with post-mitotic expression and neurological disease associations, particularly in neuronal signaling pathways. According to published oxidized-guanine maps, there are 2,146 accessible genomic coordinates, while human proteogenomic data contains 78 exact codon-compatible protein states that cannot be explained by sample-specific transcript sequences.

In summary, this study outlines a chemically restricted group of disease-associated protein states that can be reached through 8-oxoG transcriptional miscoding without causing a permanent genomic mutation.