Genome-wide translocation sequencing reveals mechanisms of chromosome breaks and rearrangements in B cells

Cell. 2011 Sep 30;147(1):107-19. doi: 10.1016/j.cell.2011.07.049.


Whereas chromosomal translocations are common pathogenetic events in cancer, mechanisms that promote them are poorly understood. To elucidate translocation mechanisms in mammalian cells, we developed high-throughput, genome-wide translocation sequencing (HTGTS). We employed HTGTS to identify tens of thousands of independent translocation junctions involving fixed I-SceI meganuclease-generated DNA double-strand breaks (DSBs) within the c-myc oncogene or IgH locus of B lymphocytes induced for activation-induced cytidine deaminase (AID)-dependent IgH class switching. DSBs translocated widely across the genome but were preferentially targeted to transcribed chromosomal regions. Additionally, numerous AID-dependent and AID-independent hot spots were targeted, with the latter comprising mainly cryptic I-SceI targets. Comparison of translocation junctions with genome-wide nuclear run-ons revealed a marked association between transcription start sites and translocation targeting. The majority of translocation junctions were formed via end-joining with short microhomologies. Our findings have implications for diverse fields, including gene therapy and cancer genomics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / metabolism*
  • Cells, Cultured
  • Chromosome Breakage*
  • DNA Breaks, Double-Stranded
  • Genes, myc
  • Genome*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunoglobulin Heavy Chains / genetics
  • Mice
  • Mutagenesis*
  • Neoplasms / genetics
  • Spleen / cytology
  • Translocation, Genetic*


  • Immunoglobulin Heavy Chains