The strand bias paradox of somatic hypermutation at immunoglobulin loci

Somatic hypermutation has two phases: phase 1 affects cytosine-guanine (C/G) pairs and is triggered by the deamination of cytosine residues in DNA to uracil; phase 2 affects mostly adenine-thymine (A/T) pairs and is induced by the detection of uracil lesions in DNA. It is not known how, at V(D)J genes in mice, hypermutations accumulate at A/T pairs with strand bias without perturbing the strand unbiased accumulation of hypermutations at C/G pairs. Additionally, it is not known why, in contrast, at switch regions in mice, both C/G-targeted and A/T-targeted hypermutations accumulate in a strand unbiased manner. To explain the strand bias paradox, we propose that phase 1 and phase 2 hypermutations are generated at different stages of the cell cycle.