Widespread RNA and DNA Sequence Differences in the

The transmission of information from DNA to RNA is a critical process. We compared RNA sequences from human B cells of 27 individuals to the corresponding DNA sequences from the same individuals and uncovered more than 10,000 exonic sites where the RNA sequences do not match that of the DNA. All 12 possible categories of discordances were observed. These differences were nonrandom as many sites were found in multiple individuals and in different cell types, including primary skin cells and brain tissues. Using mass spectrometry, we detected peptides that are translated from the discordant RNA sequences and thus do not correspond exactly to the DNA sequences. These widespread RNA-DNA differences in the human transcriptome provide a yet unexplored aspect of genome variation. DNA carries genetic information that ispassed onto mRNA and proteins thatperform cellular functions, and it is as-sumed that the sequence of mRNA reflects that of the DNA. This assumed precision is important because mRNA serves as the template for protein synthesis. Hence, genetic studies have mostly fo-cused on DNA sequence polymorphism as the basis of individual differences in disease suscep-tibility. Studies of mRNA and proteins analyze their expression and not sequence differences among individuals. There are, however, known exceptions to the one-to-one relationship betweenDNAandmRNA sequences. These include errors in transcription (1, 2) and RNA-DNA differences that result from RNA editing (3–7). Errors are rare because proof-reading and repair mechanisms ensure the fidel-ity of transcription (8–10). RNA editing is carried out by enzymes that target mRNA posttranscrip-tionally: ADARs (adenosine deaminases that act on RNA) that deaminate adenosine to inosine, which is then recognized by the translation ma-chineries as a guanosine (A-to-G), and APOBECs (apolipoprotein B mRNA editing enzymes, cat-alytic polypeptide-like), which edit cytidine to uri-dine (C-to-U). Previously, sequence comparisons and computational predictions have identified many A-to-G editing sites (6, 7, 11–13). By con-trast, C-to-U changes are rare; apolipoprotein B is one of the few known target genes of huma