Fig. 1: Schematic of HiDENSEC pipeline.
Pipeline (left to right) begins from formalin-fixed paraffin-embedded tumor samples subjected to Hi-C. FFPE samples may be microdissected; the green outline in the example outlines the nevus and the red curve the melanoma area. When aligned to the human reference genome Hi-C reveals large-scale structural variants as off-diagonal enrichments in contact maps. HiDENSEC first corrects the on-diagonal intensities of contact maps for covariates such as chromatin compartments, mappability, GC content, and restriction site density. These corrected intensities provide absolute copy numbers for every genomic region. Copy numbers for large-scale structural variants inferred from the Hi-C contact maps can also be assigned. Hi-C reads can also be used to compute the regional allele frequency spectrum of germline mutations, which aid in providing higher resolution inference. Combining the output of HiDENSEC on multiple samples from a single patient allows inferences on the temporal order in which structural and copy number alterations during tumor evolution.
