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Analysis of 6912 Unselected Somatic Hypermutations in Human VDJ Rearrangements Reveals Lack of Strand Specificity and Correlation between Phase II Substitution Rates and Distance to the Nearest 3′ Activation-Induced Cytidine Deaminase Target1

The initial event of somatic hypermutation (SHM) is the deamination of cytidine residues by activation-induced cytidine deaminase (AID). Deamination is followed by the replication over uracil and/or different error-prone repair events. We sequenced 659 nonproductive human IgH rearrangements (IGHV3-23*01) from blood B lymphocytes enriched for CD27-positive memory cells. Analyses of 6,912 unique, unselected substitutions showed that in vivo hot and cold spots for the SHM of C and G residues corresponded closely to the target preferences reported for AID in vitro. A detailed analysis of all possible four-nucleotide motifs present on both strands of the VH gene showed significant correlations between the substitution frequencies in reverse complementary motifs, suggesting that the SHM machinery targets both strands equally well. An analysis of individual JH and D gene segments showed that the substitution frequencies in the individual motifs were comparable to the frequencies found in the VH gene. Interestingly, JH6-carrying sequences were less likely to undergo SHM (average 15.2 substitutions per VH region) than sequences using JH4 (18.1 substitutions, p = 0.03). We also found that the substitution rates in G and T residues correlated inversely with the distance to the nearest 3′ WRC AID hot spot motif on both the nontranscribed and transcribed strands. This suggests that phase II SHM takes place 5′ of the initial AID deamination target and primarily targets T and G residues or, alternatively, the corresponding A and C residues on the opposite strand.