# Conformational Heterogeneity in Human Interphase Chromosome Organization Reconciles the FISH and Hi-C Paradox

## TL;DR

This paper resolves the apparent contradiction between FISH and Hi-C data on chromosome organization by introducing a heterogeneity-based theory that explains contact probability and spatial distance variations across cell populations.

## Contribution

It presents a novel, parameter-free theoretical framework based on the Generalized Rouse Model to interpret FISH and Hi-C data considering cell heterogeneity.

## Key findings

- Heterogeneity explains FISH-Hi-C paradox.
- The model accurately reproduces Hi-C data from FISH distributions.
- Genome organization varies significantly across cells.

## 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.