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.
bioRxiv. 2023 Sep 17:2023.09.14.557820. doi: 10.1101/2023.09.14.557820.
DNA-based evolutionary comparisons of regulatory genomic elements enable insight into functional changes, 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 factor targets in human-hominin lineages, and MEF2 factor targets in the ape lineage. Finally, conserved features were more enriched in brain disease variants, whereas there was no distinct enrichment on the human lineage compared to its ancestral lineages. Our study identifies major evolutionary patterns in the human brain epigenome at cellular resolution.
基于DNA的调控基因组元件进化比较能够洞察功能变化，克服组织难以获取的问题。在此，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进化上存在差异，而其他细胞类型则是保守的。使用多组学数据集，我们进一步确定了与多个谱系分化的基因调控元件相关的基因，并牵连到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，并确定了人亚科谱系中bHLH-PAS因子靶标的扩展，以及猿类谱系中MEF2因子靶标的扩展。最后，保守特征在脑部疾病变体中更为富集，而与祖先谱系相比，人类谱系中没有明显的富集。我们的研究在细胞分辨率上确定了人类大脑表观基因组中的主要进化模式。
