BACKGROUND: The human genome is highly organized in the three-dimensional 
nucleus. Chromosomes fold locally into topologically associating domains (TADs) 
defined by increased intra-domain chromatin contacts. TADs contribute to gene 
regulation by restricting chromatin interactions of regulatory sequences, such 
as enhancers, with their target genes. Disruption of TADs can result in altered 
gene expression and is associated to genetic diseases and cancers. However, it 
is not clear to which extent TAD regions are conserved in evolution and whether 
disruption of TADs by evolutionary rearrangements can alter gene expression.
RESULTS: Here, we hypothesize that TADs represent essential functional units of 
genomes, which are stable against rearrangements during evolution. We 
investigate this using whole-genome alignments to identify evolutionary 
rearrangement breakpoints of different vertebrate species. Rearrangement 
breakpoints are strongly enriched at TAD boundaries and depleted within TADs 
across species. Furthermore, using gene expression data across many tissues in 
mouse and human, we show that genes within TADs have more conserved expression 
patterns. Disruption of TADs by evolutionary rearrangements is associated with 
changes in gene expression profiles, consistent with a functional role of TADs 
in gene expression regulation.
CONCLUSIONS: Together, these results indicate that TADs are conserved building 
blocks of genomes with regulatory functions that are often reshuffled as a whole 
instead of being disrupted by rearrangements.