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.

Spanish Ministerio de Economía y Competitividad [BFU2010–19310, BFU2013–47736-P to M.A.M.-R., BIO2007–61762 to L.S.]; European Research Council [609989 to M.A.M.-R., 232913 to L.S.]; Human Frontiers Science Program [RGP0044 to M.A.M.-R.]; Spanish Instituto de Salud Carlos III [PI10/01702 to L.S.]; Fundación Marcelino Botin (to L.S.). Funding for open access charge: ERC Synergy [609989].