Analysis of the structural variability of topologically associated domains as revealed by Hi-C

Three-dimensional chromosome structure plays an integral role in gene expression and regulation, replication timing, and other cellular processes. Topologically associating domains (TADs), one of the building blocks of chromosome structure, are genomic regions with higher contact frequencies within the region than outside the region. A central question is the degree to which TADs are conserved or vary between conditions. We analyze a set of 137 Hi-C samples from 9 different studies under 3 measures in order to quantify the effects of various sources of biological and experimental variation. We observe significant variation in TAD sets between both non-replicate and replicate samples, and show that this variability does not seem to come from genetic sequence differences. The effects of experimental protocol differences are also measured, demonstrating that samples can have protocol-specific structural changes, but that TADs are generally robust to lab-specific differences. This study represents a systematic quantification of the key factors influencing comparisons of chromosome structure.