BOTH DNA STRANDS OF ANTIBODY GENES ARE HYPERMUTATION TARGETS

During the maturation of the immune response, antibody genes are subje cted to localized hypermutation. Mutations are not evenly distributed along the V gene; intrinsic hot spots exist that are correlated with p rimary sequence motifs. Although the mechanism of hypermutation remain s unknown, it has been proposed to exhibit DNA strand polarity because purine residues on the coding strand are more frequently targeted for mutation than pyrimidines. However, this polarity may not be an intri nsic property of the hypermutation mechanism but a consequence of evol utionary-selected peculiarities of V gene sequences. Furthermore, the possibility that both strands are hypermutation targets has received l ittle attention. To discriminate between these possibilities, we have analyzed the average frequency of mutations of each of the three bases of all nucleotide triplets by using large databases taken from both V and non-V mutation targets, We also have reassessed the sequence moti fs associated with hot spots, We find that even in non-Ig sequences, A mutates more than T, consistent with a strand-dependent component to targeting. However, the mutation biases of triplets and of their inver ted complements are correlated, demonstrating that there is a sequence -specific but strand-independent component to mutational targeting, Th us, there are two aspects of the hypermutation process that are sensit ive to local DNA sequences, one that is DNA strand-dependent and the o ther that is not.