Assessing the limits of restraint-based 3D modeling of genomes and genomic domains

Trussart, Marie, 1985-; Serra, François; Baù, Davide; Junier, Ivan; Serrano Pubull, Luis, 1982-; Martí Renom, Marc A.

doi:http://dx.doi.org/10.1093/nar/gkv221

Assessing the limits of restraint-based 3D modeling of genomes and genomic domains

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Trussart M, Serra F, Baù D, Junier I, Serrano L, Marti-Renom MA. Assessing the limits of restraint-based 3D modeling of genomes and genomic domains. Nucleic acids research. 2015;43(7):3465-77. DOI: 10.1093/nar/gkv221

Abstract

Restraint-based modeling of genomes has been recently explored with the advent of Chromosome Conformation Capture (3C-based) experiments. We previously developed a reconstruction method to resolve the 3D architecture of both prokaryotic and eukaryotic genomes using 3C-based data. These models were congruent with fluorescent imaging validation. However, the limits of such methods have not systematically been assessed. Here we propose the first evaluation of a mean-field restraint-based reconstruction of genomes by considering diverse chromosome architectures and different levels of data noise and structural variability. The results show that: first, current scoring functions for 3D reconstruction correlate with the accuracy of the models; second, reconstructed models are robust to noise but sensitive to structural variability; third, the local structure organization of genomes, such as Topologically Associating Domains, results in more accurate models; fourth, to a certain extent, the models capture the intrinsic structural variability in the input matrices and fifth, the accuracy of the models can be a priori predicted by analyzing the properties of the interaction matrices. In summary, our work provides a systematic analysis of the limitations of a mean-field restrain-based method, which could be taken into consideration in further development of methods as well as their applications.