Many disease-related genotype variations (GVs) reside in non-gene coding regions and the mechanisms of their association with diseases are largely unknown. A possible impact of GVs on disease formation is to alter the spatial organization of chromosome. However, the relationship between GVs and 3D genome structure has not been studied at the chromosome scale. The kilobase resolution of chromosomal structures measured by Hi-C have provided an unprecedented opportunity to tackle this problem. Here we proposed a network-based method to capture global properties of the chromosomal structure. We uncovered that genome organization is scale free and the genomic loci interacting with many other loci in space, termed as hubs, are critical for stabilizing local chromosomal structure. Importantly, we found that cancer-specific GVs target hubs to drastically alter the local chromosomal interactions. These analyses revealed the general principles of 3D genome organization and provided a new direction to pinpoint genotype variations in non-coding regions that are critical for disease formation.

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