Chromosomal translocations are guided by the spatial organization of the genome

The extent to which the three-dimensional organization of the genome contributes to chromosomal translocations is an important question in cancer genomics. We now have generated a high-resolution Hi-C spatial organization map of the G1-arrested mouse pro-B cell genome and mapped translocations from target DNA double-strand breaks (DSBs) within it via high-throughput genome-wide translocation sequencing. RAG endonuclease-cleaved antigen-receptor loci are dominant translocation partners for target DSBs regardless of genomic position, reflecting high frequency DSBs at these loci and their co-localization in a fraction of cells. To directly assess spatial proximity contributions, we normalized genomic DSBs via ionizing-radiation. Under these conditions, translocations were highly enriched in cis along single chromosomes containing target DSBs and within other chromosomes and sub-chromosomal domains in a manner directly related to pre-existing spatial proximity. Our studies reveal the power of combining two high-throughput genomic methods to address long-standing questions in cancer biology. Hi-C interaction maps for WT and ATM -/- G1-arrested AMuLV-transformed pro-B cell lines.