Abstract
BackgroundThe 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.ResultsHere, 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.ConclusionsTogether, 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.
Highlights
The human genome is highly organized in the three-dimensional nucleus
While topologically associating domains (TADs) were initially described for mammalian genomes, a similar domain organization was found in the genomes of non-mammalian species such as Drosophila [5], zebrafish [13], Caenorhabditis elegans [14], and yeast [15, 16]
Identification of evolutionary rearrangement breakpoints from whole-genome alignments To analyze the stability of TADs in evolution, we first identified evolutionary rearrangements by using wholegenome alignment data from the UCSC Genome Browser [19, 20] to compare the human genome to 12 other species
Summary
Chromosomes fold locally into topologically associating domains (TADs) defined by increased intra-domain chromatin contacts. Disruption of TADs can result in altered gene expression and is associated to genetic diseases and cancers. 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. The development of high-throughput experiments to measure pairwise chromatin-chromatin interactions, such as Hi-C [2], enabled the identification of genomic domains of several hundred kilo-bases with increased self-interaction frequencies, described as topologically associating domains (TADs) [3,4,5]. Loci within TADs contact each other more frequently and TAD boundaries insulate interactions of loci in different TADs. TADs have been shown to be important for gene regulation by restricting the interaction of cell-type specific enhancers with their target. Evolutionary conservation of TADs together with their spatio-temporal stability within organisms would collectively imply that TADs are robust structures
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