Abstract
Hi-C experiments are used to infer the contact probabilities between loci separated by varying genome lengths. Contact probability should decrease as the spatial distance between two loci increases. However, studies comparing Hi-C and FISH data show that in some cases the distance between one pair of loci, with larger Hi-C readout, is paradoxically larger compared to another pair with a smaller value of the contact probability. Here, we show that the FISH-Hi-C paradox can be resolved using a theory based on a Generalized Rouse Model for Chromosomes (GRMC). The FISH-Hi-C paradox arises because the cell population is highly heterogeneous, which means that a given contact is present in only a fraction of cells. Insights from the GRMC is used to construct a theory, without any adjustable parameters, to extract the distribution of subpopulations from the FISH data, which quantitatively reproduces the Hi-C data. Our results show that heterogeneity is pervasive in genome organization at all length scales, reflecting large cell-to-cell variations.
Highlights
Hi-C experiments are used to infer the contact probabilities between loci separated by varying genome lengths
An outcome of our theory is that the discordance between fluorescence in situ hybridization (FISH) and Hi-C data arises because of extensive heterogeneity, which is embodied by the presence of a variety of conformations adopted by chromosomes in each cell
In order to combine the data from the two powerful techniques, it is crucial to establish a theoretical basis with potential a practical link, between the contact probability and average spatial distance
Summary
Hi-C experiments are used to infer the contact probabilities between loci separated by varying genome lengths. Because chromosome lengths are extremely large, ranging from tens of million base pairs in yeast to billion base pairs in human cells, they have to fold into highly compact structures in order to be accommodated in the cell nucleus This requires that loci that are well separated along the one-dimensional genome sequence be close in threedimensional (3D) space, which is made possible by forming a large number of loops. Fudenberg and Imakaev[15] performed polymer simulations using a strong attractive energy between two labeled loci and a tenfold weaker interaction between two other loci that are separated by a similar genomic distance They reported simulations based on the loop extrusion model. They did not provide any solution to the paradox, which is the principal goal of this work
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