To study inherent properties of somatic hypermutation of human immunoglobulin genes in the absence of antigen selection, mutations of human non-productive VH6 rearrangements enriched by subtractive hybridization were characterized. Ten unique clones arising from nine non-productive rearrangements were isolated. The frequency of mutation was 3.0%. Analysis of these mutations showed intrinsic bias for transitions and cytosine (C) to guanine (G) and G to C transversions. Bias for the strand of DNA targeted by mutation was not evident. Replacement mutations in the complementarity-determining region (CDR) occurred more frequently than expected based on the primary DNA sequence. This targeting of replacement mutations to the CDR may explain the conservation of the VH6 sequence in primates.
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