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. 2017 Feb 17;45(3):1049-1058.
doi: 10.1093/nar/gkw1155.

3D genome structure modeling by Lorentzian objective function

Tuan Trieu  1 , Jianlin Cheng  1   2
Affiliations

3D genome structure modeling by Lorentzian objective function

Tuan Trieu et al. Nucleic Acids Res. .

Abstract

The 3D structure of the genome plays a vital role in biological processes such as gene interaction, gene regulation, DNA replication and genome methylation. Advanced chromosomal conformation capture techniques, such as Hi-C and tethered conformation capture, can generate chromosomal contact data that can be used to computationally reconstruct 3D structures of the genome. We developed a novel restraint-based method that is capable of reconstructing 3D genome structures utilizing both intra-and inter-chromosomal contact data. Our method was robust to noise and performed well in comparison with a panel of existing methods on a controlled simulated data set. On a real Hi-C data set of the human genome, our method produced chromosome and genome structures that are consistent with 3D FISH data and known knowledge about the human chromosome and genome, such as, chromosome territories and the cluster of small chromosomes in the nucleus center with the exception of the chromosome 18. The tool and experimental data are available at https://missouri.box.com/v/LorDG.

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Figures

Figure 1.
Figure 1.
Lorentzian function. When x = d (the contact distance is satisfied), the function is maximized; when x is very far from d (the contact is violated seriously), it becomes flat and its value is very small.
Figure 2.
Figure 2.
Signal to noise ratio of data sets generated with different value of formula image
Figure 3.
Figure 3.
Correlation between reconstructed distances in models with different value of formula image and wish distances. The correlation was peaked at 1.1.
Figure 4.
Figure 4.
Correlation of models generated with different values of formula image and the true model. The model generated by formula image is the second most similar model to the true model after the model reconstructed with formula image.
Figure 5.
Figure 5.
Spearman's correlation of reconstructed model and the true model on the synthetic data with respect to different levels of noise.
Figure 6.
Figure 6.
Root mean square error (RMSE) between reconstructed models and the true model of the five methods on the synthetic data with different levels of noise.
Figure 7.
Figure 7.
The superposition of the structures of chromosome 1 at 1 Mb and 500 Kb resolution.
Figure 8.
Figure 8.
Distances between four fluorescence in situ hybridization (FISH) probes in the model of chromosome 14 reconstructed by LorDG. L1, L2, L3 and L4 denote four probes. The distances between probes are labeled along the virtual line segments connected them.
Figure 9.
Figure 9.
Loop and peak loci (L1, L2) on fragments of (A) Chr. 17, (B) Chr. 14 (C) Chr. 11 and (D) Chr.13.
Figure 10.
Figure 10.
A genome structure with chromosome in different colors demonstrating the existence of chromosome territories.
Figure 11.
Figure 11.
Distances between centers of the mass of chromosomes and of the genome. The intensity of red is proportional to proximity. Small chromosomes (17, 19, 20, 21 and 22), except chromosome 18, cluster near the center of the genome, as shown by their close proximity to the center of the genome.
Figure 12.
Figure 12.
Telomeres and/or elongated regions of large chromosomes intrude into the nucleus center (the red circle), where small chromosomes are located, but not shown for the purpose of clarity.
See this image and copyright information in PMC

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