Sterile DJH Rearrangements Reveal that Distance Between Gene Segments on the Human Ig H Chain Locus Influences Their Ability To Rearrange

Rearrangement of the Ig locus occurs in two steps. First, a J(H) gene is rearranged to a D gene followed by a V-H gene rearranging to the DJ(H) rearrangement. By next generation sequencing, we analyzed 9969 unique DJ(H) rearrangements and 5919 unique V(H)DJ(H) rearrangements obtained from peripheral blood B cells from 110 healthy adult donors. We found that DJ(H) rearrangements and nonproductive V(H)DJ(H) rearrangements share many features but differ significantly in their use of D genes and propensity for somatic hypermutation. In D to J(H) gene rearrangements, the D genes proximal to the J(H) locus are used more frequently than J(H) locus distal D genes, whereas V-H locus proximal D genes were observed more frequently in nonproductive V(H)DJ(H) rearrangements. We further demonstrate that the distance between V-H, D, and J(H) gene segments influence their ability to rearrange within the human Ig locus.