Manifold Based Optimization for Single-Cell 3D Genome Reconstruction

PLoS Comput Biol. 2015 Aug 11;11(8):e1004396. doi: 10.1371/journal.pcbi.1004396. eCollection 2015 Aug.

Abstract

The three-dimensional (3D) structure of the genome is important for orchestration of gene expression and cell differentiation. While mapping genomes in 3D has for a long time been elusive, recent adaptations of high-throughput sequencing to chromosome conformation capture (3C) techniques, allows for genome-wide structural characterization for the first time. However, reconstruction of "consensus" 3D genomes from 3C-based data is a challenging problem, since the data are aggregated over millions of cells. Recent single-cell adaptations to the 3C-technique, however, allow for non-aggregated structural assessment of genome structure, but data suffer from sparse and noisy interaction sampling. We present a manifold based optimization (MBO) approach for the reconstruction of 3D genome structure from chromosomal contact data. We show that MBO is able to reconstruct 3D structures based on the chromosomal contacts, imposing fewer structural violations than comparable methods. Additionally, MBO is suitable for efficient high-throughput reconstruction of large systems, such as entire genomes, allowing for comparative studies of genomic structure across cell-lines and different species.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Animals
  • Chromosome Mapping / methods*
  • Chromosomes / chemistry
  • Chromosomes / genetics
  • Computational Biology / methods*
  • Genome / genetics*
  • Imaging, Three-Dimensional / methods*
  • Mice

Associated data

  • GEO/GSE48262

Grant support

This work was supported by the Research Council of Norway (JP) and the Molecular Life Science Program of the University of Oslo (OG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.