Department of Genetics, Human Genetics Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, New Jersey, United States.
PLoS Genet. 2020 Dec 7;16(12):e1009229. doi: 10.1371/journal.pgen.1009229. eCollection 2020 Dec.
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.
拓扑关联域（TADs）是将染色体组织成相互作用染色质的 3D 结构的功能单元。TADs 通过约束增强子-启动子接触在调节基因表达中发挥重要作用，有证据表明 TAD 边界的缺失会导致相邻基因的异常表达。虽然 TAD 形成的机制已经得到了很好的研究，但目前对物种间 TAD 进化模式的了解是有限的。由于 TAD 在基因调控中起着不可或缺的作用，它们的结构和组织预计在进化过程中是保守的。然而，最近的研究表明，TAD 结构相对较快地发生分歧。我们使用 Hi-C 染色体构象捕获来测量 D. melanogaster 和 D. triauraria 之间整个 TAD 和 TAD 边界元件的进化保守性，这两个物种是来自 melanogaster 物种组的早期分支物种，它们在大约 1500 万年前就已经分化。我们发现，自 D. melanogaster 和 D. triauraria 的共同祖先以来，大多数 TAD 已经通过染色体重排和 TAD 边界的获得/丢失进行了重组。这两个物种之间的 TAD 重组与基因表达的局部效应有关，即在破坏位点附近。通过根据染色质状态将 TAD 分为亚型，我们发现不同的亚型在不同的进化力量下进化。富含广泛表达、转录活性基因的 TAD 进化迅速，可能是由于正选择，而富含发育调节基因的 TAD 保持保守，可能是因为它们在限制基因调节元件相互作用方面的重要性。这些结果为 TAD 的进化动态提供了新的见解，并有助于调和与 TAD 的进化保守性以及 TAD 结构的变化是否影响基因表达有关的矛盾报告。
