Imputation-free reconstructions of three-dimensional chromosome architectures in human diploid single-cells using allele-specified contacts

Abstract

Abstract Single-cell Hi-C analysis of diploid human cells is difficult because of the lack of dense chromosome contact information and the presence of homologous chromosomes with very similar nucleotide sequences. Thus here, we propose a new algorithm to reconstruct the three-dimensional (3D) chromosomal architectures from the Hi-C dataset of single diploid human cells using allele-specific single-nucleotide variations (SNVs). We modified our recurrence plot-based algorithm, which is suitable for the estimation of the 3D chromosome structure from sparse Hi-C datasets, by newly incorporating a function of discriminating SNVs specific to each homologous chromosome. Here, we eventually regard a contact map as a recurrence plot. Importantly, the proposed method does not require any imputation for ambiguous segment information, but could efficiently reconstruct 3D chromosomal structures in single human diploid cells at a 1-Mb resolution. Datasets of segments without allele-specific SNVs, which were considered to be of little value, can also be used to validate the estimated chromosome structure. Introducing an additional mathematical measure called a refinement further improved the resolution to 40-kb or 100-kb. The reconstruction data supported the notion that human chromosomes form chromosomal territories and take fractal structures where the dimension for the underlying chromosome structure is a non-integer value.