Evolutionary stability of topologically associating domains is associated with conserved gene regulation

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.Electronic supplementary materialThe online version of this article (10.1186/s12915-018-0556-x) contains supplementary material, which is available to authorized users.

Most regulatory interactions are not in linkage disequilibrium

“…The fact that haplotype breakpoints do not align with chromatin boundaries may indicate that recombination is deleterious at these functional elements, perhaps due to the mutagenic effects of recombination. These findings are different from observations regarding fixed structural differences between genomes of different mammals, which tend to preserve TADs with breakpoints enriched at TAD boundaries [31,32]. We therefore conclude that while chromatin domains are functional genomic entities maintained as syntenic units over evolutionary time, recombination is independent of chromatin structure.…”

Most chromatin interactions are not in linkage disequilibrium

“…The fact that haplotype breakpoints do not align with chromatin boundaries may indicate that recombination is deleterious at these functional elements. These findings are different from observations regarding fixed structural differences between genomes of various mammals, which tend to preserve TADs with breakpoints enriched at TAD boundaries (Krefting et al 2018;Lazar et al 2018). We therefore conclude that, while chromatin domains are functional genomic entities maintained as syntenic units over evolutionary time, recombination is largely independent of interphase chromatin structure.…”

Evolution of gene regulation in ruminants differs between evolutionary breakpoint regions and homologous synteny blocks

“…Indirect effects include the suppression of recombination within the rearranged region (Navarro and Barton 2003;Joron et al 2011;Farré et al 2013) due to incomplete pairing during meiosis, which could lead to the accumulation of genetic incompatibilities and, in some cases, speciation (Brown and O'Neill 2010). EBRs can disrupt coding sequences or alter gene expression of adjacent genes by separating them from their regulatory elements, bringing new regulatory sequences, moving the genes to different regulatory domains, or reconfiguring chromatin interactions by rearranging topologically associating domains (TADs) (Cande et al 2009;Puig et al 2015;Krefting et al 2018;Lazar et al 2018). Although the relationship between chromosome rearrangements and changes in gene expression has been demonstrated in some species (Marquès-Bonet et al 2004;Giannuzzi et al 2014;Fuller et al 2016), these studies analyzed the genomic and epigenomic features in a reference genome framework, and assumed that they might be representative of ancestral states, without attempting any explicit ancestral reconstruction or inferring the origin of the genomic or epigenomic features.…”