Department of Genetics, Rutgers University, Piscataway, NJ 08854, USA.
LifeCell, Kelambakkam Main Road, Keelakottaiyur, Chennai 600127, Tamil Nadu, India.
Mol Biol Evol. 2022 Nov 3;39(11). doi: 10.1093/molbev/msac216.
Topologically associating domains (TADs) are thought to play an important role in preventing gene misexpression by spatially constraining enhancer-promoter contacts. The deleterious nature of gene misexpression implies that TADs should, therefore, be conserved among related species. Several early studies comparing chromosome conformation between species reported high levels of TAD conservation; however, more recent studies have questioned these results. Furthermore, recent work suggests that TAD reorganization is not associated with extensive changes in gene expression. Here, we investigate the evolutionary conservation of TADs among 11 species of Drosophila. We use Hi-C data to identify TADs in each species and employ a comparative phylogenetic approach to derive empirical estimates of the rate of TAD evolution. Surprisingly, we find that TADs evolve rapidly. However, we also find that the rate of evolution depends on the chromatin state of the TAD, with TADs enriched for developmentally regulated chromatin evolving significantly slower than TADs enriched for broadly expressed, active chromatin. We also find that, after controlling for differences in chromatin state, highly conserved TADs do not exhibit higher levels of gene expression constraint. These results suggest that, in general, most TADs evolve rapidly and their divergence is not associated with widespread changes in gene expression. However, higher levels of evolutionary conservation and gene expression constraints in TADs enriched for developmentally regulated chromatin suggest that these TAD subtypes may be more important for regulating gene expression, likely due to the larger number of long-distance enhancer-promoter contacts associated with developmental genes.
拓扑关联域（TADs）被认为通过空间限制增强子-启动子接触来防止基因表达错误。基因表达错误的有害性质意味着 TADs 应该在相关物种中保守。几项早期的比较物种间染色体构象的研究报告了 TAD 保守性的高水平；然而，最近的研究对这些结果提出了质疑。此外，最近的研究表明，TAD 重组与广泛的基因表达变化无关。在这里，我们研究了 11 种果蝇中 TADs 的进化保守性。我们使用 Hi-C 数据在每个物种中识别 TAD，并采用比较系统发育的方法得出 TAD 进化的经验估计率。令人惊讶的是，我们发现 TADs 进化得很快。然而，我们也发现进化的速度取决于 TAD 的染色质状态，与发育调控染色质富集的 TAD 相比，广泛表达、活跃染色质富集的 TAD 进化速度显著较慢。我们还发现，在控制染色质状态差异后，高度保守的 TADs 并没有表现出更高水平的基因表达约束。这些结果表明，一般来说，大多数 TADs 进化迅速，它们的分化与基因表达的广泛变化无关。然而，发育调控染色质富集的 TADs 具有更高的进化保守性和基因表达约束水平，这表明这些 TAD 亚型可能对调节基因表达更为重要，可能是因为与发育基因相关的长距离增强子-启动子接触较多。
