Abstract
Three-dimensional chromosome structure plays an integral role in gene expression and regulation, replication timing, and other cellular processes. Topologically associated domains (TADs), 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 137 Hi-C samples from 9 studies under 3 measures 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 provide initial evidence that this variability does not 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 key factors influencing comparisons of chromosome structure, suggesting significant variability and the potential for cell-type-specific structural features, which has previously not been systematically explored. The lack of observed influence of heredity and genetic differences on chromosome structure suggests that factors other than the genetic sequence are driving this structure, which plays an important role in human disease and cellular functioning.
Highlights
While it is recognized that the three-dimensional structure of the chromosome is an integral part of many key genomic functions, we lack a full understanding of the variability of this structure across biological sources or experimental conditions
The Jaccard Index (JI) quantifies the similarity between two sets, in this case defined as sets of topologically associated domains (TADs) boundaries, returning a value that represents the fraction of TAD boundaries shared between the two samples
TADsim is a measure adapted from a method that identifies structurally similar regions between two TAD sets [38]; it quantifies the fraction of the genome covered by similar TAD structures using the variation of information (VI) metric [27]
Summary
While it is recognized that the three-dimensional structure of the chromosome is an integral part of many key genomic functions, we lack a full understanding of the variability of this structure across biological sources or experimental conditions. The experiment involves cross-linking and ligating spatially close genomic segments, aligning them back to the genome to find their genomic positions. The output of this experiment is a matrix in which the rows and columns represent segments of the genome along a chromosome, and each matrix entry records the pairwise interaction frequency of the genome fragments of the associated row and column. These values reflect 3D proximity, quantifying the frequency of contact between every pair of genomic segments
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