Abstract
DNA duplications that overlap topologically associated domain (TAD) boundaries can create new TADs.
Major finding: DNA duplications that overlap topologically associated domain (TAD) boundaries can create new TADs.
Concept: Noncoding DNA duplications have different phenotypic effects based on how the TAD structure is altered.
Impact: TADs influence the phenotypic effects of copy-number variations.
The genome is divided into regulatory units called topologically associated domains (TAD) that are separated by boundary regions that prevent enhancers from interacting with target genes in neighboring domains. As copy-number variations are frequently present in cancer, Franke, Ibrahim, and colleagues used chromosome conformation capture at the SOX9 locus to determine how genomic duplications affect TAD formation. This locus contains two TADs, one of which includes the SOX9 gene and one that includes the potassium channel genes KCNJ2 and KCNJ16. SOX9 is a developmental transcription factor, and duplications within the SOX9 TAD lead to female-to-male sex reversals, whereas duplications affecting the same region and also extending into KCNJ2 and KCNJ16 cause Cooks syndrome, characterized by limb malformation, without disrupting sexual development. A third duplication affecting SOX9 and an upstream gene desert, but not KCNJ2 and KCNJ16, has no phenotypic effect. The sex-reversal duplications were located within the SOX9 TAD (intra-TAD) and increased intra-TAD interactions with the duplicated regions, but did not change the overall TAD architecture. In contrast, the duplications associated with no phenotype or Cooks syndrome spanned both the SOX9 and KCJN TADs (inter-TAD) and thereby created a new chromatin domain (neo-TAD). The neo-TAD that was not associated with a phenotype was insulated from the neighboring genes, preventing the duplicated regions from interacting with SOX9, KCNJ2, and KCNJ16. However, the Cooks syndrome duplication created a neo-TAD containing part of KCNJ2, which promoted KCNJ2 activation by regulatory elements normally located in the SOX9 TAD, and resulted in limb malformation and other traits associated with Cooks syndrome. Taken together, these results provide a mechanism by which overlapping noncoding DNA duplications can have different phenotypic effects depending on how the TAD structure is altered and suggest that copy-number variations need to be considered in the context of the overall chromatin architecture.