Current theoretical models fail to predict the topological complexity of the human genome.
Understanding the folding of the human genome is a key challenge of modern structural biology. The emergence of chromatin conformation capture assays (e.g., Hi-C) has revolutionized chromosome biology and provided new insights into the three dimensional structure of the genome. The experimental data are highly complex and need to be analyzed with quantitative tools. It has been argued that the data obtained from Hi-C assays are consistent with a fractal organization of the genome. A key characteristic of the fractal globule is the lack of topological complexity (knotting or inter-linking). However, the absence of topological complexity contradicts results from polymer physics showing that the entanglement of long linear polymers in a confined volume increases rapidly with the length and with decreasing volume. In vivo and in vitro assays support this claim in some biological systems. We simulate knotted lattice polygons confined inside a sphere and demonstrate that their contact frequencies agree with the human Hi-C data. We conclude that the topological complexity of the human genome cannot be inferred from current Hi-C data.
Department of Mathematics, University of California, Davis Davis, CA, USA ; Department of Molecular and Cellular Biology, University of California, Davis Davis, CA, USA.
Javier
J
Arsuaga
Division of Biology and Biomedical Sciences, Department of Medicine, Department of Genetics, The Genome Institute at Washington University in St. Louis St. Louis, MO, USA.
Reyka G
RG
Jayasinghe
Hypnagogic Software Vancouver, BC, Canada.
Robert G
RG
Scharein
Department of Epidemiology and Biostatistics, University of California, San Francisco San Francisco, CA, USA.
Mark R
MR
Segal
Department of Microbiology and Molecular Genetics, University of California, Davis Davis, CA, USA.
Robert H
RH
Stolz
Department of Mathematics, University of California, Davis Davis, CA, USA ; Department of Microbiology and Molecular Genetics, University of California, Davis Davis, CA, USA.
Mariel
M
Vazquez
BFACF; DNA knotting; Hi-C; chromosome organization; equilibrium globule; lattice models