Figure 1.
Schematic diagram of our approach.
Figure 2.
Hi-C detects interaction between known translocation partners BCR-ABL and MYC-IGH.
(A) Chromosomes 9 and 22 are physically joined in K562 (left), but not in GM06990 (right). (B) Hi-C contact map of chromosomes 9 and 22 in K562 cells. Inset shows the chromosomal bands containing BCR (22q11) and ABL (9q34). High read counts identify the site of the BCR-ABL translocation. (C) Hi-C contact maps of chromosomes 9 and 22 in GM06990 cells, which show a relatively low read count in the BCR-ABL megabase bin compared to K562. (D) Normalized Hi-C contact map for chromosomes 9 and 22 in GM06990 shows elevated signal in the chromosomal bands containing BCR and ABL. (E) Centered interaction scores for the chromosomal bands containing the translocation partners MYC-IGH as well as the control partners MYC-TGFBR2 and IGH-TGFBR2, compared to the background distribution of scores on the same chromosome pairs. Error bars represent the 5th and 95th percentiles.
Table 1.
Translocation datasets and permutation results.
Figure 3.
Many translocation partners exhibit high contact frequencies in the normal nucleus.
Permutation test results for blood translocations from the Mitelman (A and B, n = 577) and multiple myeloma datasets (C and D, n = 89). Histograms (A and C) represent the distribution of the mean proximity score within each of 1,000 permuted sets of n translocations that preserve the characteristics of the true set (Permutation Method 1, see Methods). Red arrow indicates the mean of the proximity scores for n real translocations. Cumulative distribution plots (B and D) compare the distribution of the n scores for real translocations versus the distribution of the 1000n scores for permuted translocations. Heatmaps show Hi-C contact maps in GM06990 cells for two significant individual translocations: t(12;19)(q13;p13) (E) in the Mitelman Database and t(4;14)(p16.3;q32.33) (F) in the multiple myeloma dataset. Black boxes indicate the chromosomal bands containing the translocation breakpoints.
Figure 4.
Features of translocation breakpoints.
Comparison of average (A) gene content (% bases spanned by transcripts; includes both exons and introns) and (B) chromatin compartment score for Mitelman database translocations (red) and 1,000 permuted sets, each of size n = 571, that preserve the characteristics of the true set. Chromatin compartment scores are calculated using the first eigenvector of the Tanay-normalized correlation matrix (see Methods). Positive and negative scores indicate open and closed chromatin compartments, respectively. (C) Mean Hi-C interaction scores for Mitelman blood translocations (red dots) compared to sets of permuted regions selected from the same chromatin compartments (gray boxplots).