The Extent and Nature Of Chromosomal Rearrangements in B Lymphocytes

Chromosomal rearrangements, including translocations, require formation and joining of DNA double strand breaks (DSBs). These events disrupt the integrity of the genome and are frequently involved in producing leukemias, lymphomas and sarcomas. Mature B cell lymphomas are unique among tumors in that they frequently carry clonal recurrent translocations. This may be the result of Activation Induced Cytidine Deaminase (AID) expression, which introduces a heretofore uncharacterized array of rearrangements. Despite the importance of these events, current understanding of their genesis is limited. To examine the origins of chromosomal rearrangements we developed Translocation Capture Sequencing (TC-Seq), a method to document chromosomal rearrangements to a fixed DSB genome-wide, in primary cells. We examined over 180,000 rearrangements obtained from 400 million activated B lymphocytes to two loci, IgH and c-myc. Our data and analysis reveal that proximity between DSBs, transcriptional activity and chromosome territories are key determinants of genome rearrangement. Specifically, rearrangements tend to occur in cis and to transcribed genes. We also find that AID induces rearrangement in specific hotspots. Hotspots are predominantly genic, transcribed, and are found as translocation partners in mature B cell lymphoma.