Very Few RNA and DNA Sequence Differences in the Human Transcriptome

RNA editing is an important cellular process by which the nucleotides in a mature RNA transcript are altered to cause them to differ from the corresponding DNA sequence. While this process yields essential transcripts in humans and other organisms, it is believed to occur at a relatively small number of loci. The rarity of RNA editing has been challenged by a recent comparison of human RNA and DNA sequence data from 27 individuals, which revealed that over 10,000 human exonic sites appear to exhibit RNA-DNA differences (RDDs). Many of these differences could not have been caused by either of the two previously known human RNA editing mechanisms—ADAR-mediated A→G substitutions or APOBEC1-mediated C→U switches—suggesting that a previously unknown mechanism of RNA editing may be active in humans. Here, we reanalyze these data and demonstrate that genomic sequences exist in these same individuals or in the human genome that match the majority of RDDs. Our results suggest that the majority of these RDD events were observed due to accurate transcription of sequences paralogous to the apparently edited gene but differing at the edited site. In light of our results it seems prudent to conclude that if indeed an unknown mechanism is causing RDD events in humans, such events occur at a much lower frequency than originally proposed.