Caglayan Emre, Konopka Genevieve
Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX, 75390, USA.
Peter O'Donnell Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX, 75390, USA.
Nat Commun. 2025 Jul 1;16(1):5625. doi: 10.1038/s41467-025-60665-w.
DNA-based evolutionary comparisons of regulatory genomic elements enable insight into functional changes driven in cis, partially overcoming tissue inaccessibility. Here, we harnessed adult and fetal cortex single-cell ATAC-seq datasets to uncover DNA substitutions specific to the human and human-ancestral lineages within apes. We found that fetal microglia identity is evolutionarily divergent in all lineages, whereas other cell types are conserved. Using multiomic datasets, we further identified genes linked to multiple lineage-divergent gene regulatory elements and implicated biological pathways associated with these divergent features. We also uncovered patterns of transcription factor binding site evolution across lineages and identified expansion of bHLH-PAS transcription factor targets in human-hominin lineages, and MEF2 transcription factor targets in the ape lineage. Finally, conserved features were more enriched in brain disease variants, whereas there was no distinct enrichment of brain disease variants on the human lineage compared to its ancestral lineages. Our study identifies ancestral evolutionary patterns of the human brain epigenome at cellular resolution.
基于DNA的调控基因组元件进化比较能够深入了解顺式驱动的功能变化，部分克服了组织难以获取的问题。在这里，我们利用成人和胎儿皮质单细胞ATAC-seq数据集，揭示了猿类中人类和人类祖先谱系特有的DNA替代。我们发现，胎儿小胶质细胞的身份在所有谱系中在进化上是不同的，而其他细胞类型是保守的。使用多组学数据集，我们进一步确定了与多个谱系分化基因调控元件相关的基因，并确定了与这些分化特征相关的生物学途径。我们还揭示了跨谱系转录因子结合位点的进化模式，并确定了bHLH-PAS转录因子靶点在人类-人亚科谱系中的扩展，以及MEF2转录因子靶点在猿类谱系中的扩展。最后，保守特征在脑部疾病变异中更为富集，而与祖先谱系相比，人类谱系中脑部疾病变异没有明显的富集。我们的研究在细胞分辨率上确定了人类大脑表观基因组的祖先进化模式。
