Dissecting the cosegregation probability from genome architecture mapping

Genome architecture mapping (GAM) is a recently developed methodology that offers the cosegregation probability of two genomic segments from an ensemble of thinly sliced nuclear profiles, enabling us to probe and decipher three-dimensional chromatin organization. The cosegregation probability from GAM binned at 1 Mb, which thus probes the length scale associated with the genomic separation greater than 1 Mb, is, however, not identical to the contact probability obtained from Hi-C, and its correlation with interlocus distance measured with fluorescence in situ hybridization is not so good as the contact probability. In this study, by using a polymer-based model of chromatins, we derive a theoretical expression of the cosegregation probability as well as that of the contact probability and carry out quantitative analyses of how they differ from each other. The results from our study, validated with in silico GAM analysis on three-dimensional genome structures from fluorescence in situ hybridization, suggest that to attain strong correlation with the interlocus distance, a properly normalized version of cosegregation probability needs to be calculated based on a large number of nuclear slices ($n>{10}^3$).