Abstract
Topologically associating domains, or TADs, are functional units that organize chromosomes into 3D structures of interacting chromatin. TADs play an important role in regulating gene expression by constraining enhancer-promoter contacts and there is evidence that deletion of TAD boundaries leads to aberrant expression of neighboring genes. While the mechanisms of TAD formation have been well-studied, current knowledge on the patterns of TAD evolution across species is limited. Due to the integral role TADs play in gene regulation, their structure and organization is expected to be conserved during evolution. However, more recent research suggests that TAD structures diverge relatively rapidly. We use Hi-C chromosome conformation capture to measure evolutionary conservation of whole TADs and TAD boundary elements between D. melanogaster and D. triauraria, two early-branching species from the melanogaster species group which diverged ∼15 million years ago. We find that the majority of TADs have been reorganized since the common ancestor of D. melanogaster and D. triauraria, via a combination of chromosomal rearrangements and gain/loss of TAD boundaries. TAD reorganization between these two species is associated with a localized effect on gene expression, near the site of disruption. By separating TADs into subtypes based on their chromatin state, we find that different subtypes are evolving under different evolutionary forces. TADs enriched for broadly expressed, transcriptionally active genes are evolving rapidly, potentially due to positive selection, whereas TADs enriched for developmentally-regulated genes remain conserved, presumably due to their importance in restricting gene-regulatory element interactions. These results provide novel insight into the evolutionary dynamics of TADs and help to reconcile contradictory reports related to the evolutionary conservation of TADs and whether changes in TAD structure affect gene expression.
Highlights
The recent development of Hi-C sequencing techniques has allowed for inference of threedimensional chromosome conformation through identification of inter- and intra-chromosomal interactions at high-resolution across the entire genome
We considered boundaries to be orthologous when high confidence boundary regions lifted-over from D. melanogaster to D. triauraria overlapped either a high or low confidence boundary that was independently identified in D. triauraria
We found a similar pattern for D. melanogaster and D. triauraria, where the median size of synteny blocks is significantly lower for the X chromosome compared to the autosomes (S6 Fig, Wilcoxon test p = 1.35e–12)
Summary
The recent development of Hi-C sequencing techniques has allowed for inference of threedimensional chromosome conformation through identification of inter- and intra-chromosomal interactions at high-resolution across the entire genome. TADs are regions of highly-interacting chromatin that contain genes with similar expression patterns and epigenetic states, and their location is conserved throughout development and across tissue types in both mammals and Drosophila [2,3,4]. Domains are demarcated by boundaries which are regions of decompacted chromatin bound by insulator proteins [5]. Other insulator proteins, including BEAF-32, Chromator, CP190, and M1BP are more frequently found at TAD boundaries [3, 10,11,12,13] and depletion of M1BP has been shown to disrupt 3D genome organization in the Drosophila Kc167 cell line [10]
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