Universitat de Barcelona, Gran Via de les Corts Catalanes, Barcelona, Spain.
Universitat de Barcelona Institute of Complex Systems, Martı́ Franquès, Barcelona, Spain.
BMC Genomics. 2020 Apr 16;21(1):304. doi: 10.1186/s12864-020-6706-x.
Recent paleogenomic studies have highlighted a very small set of proteins carrying modern human-specific missense changes in comparison to our closest extinct relatives. Despite being frequently alluded to as highly relevant, species-specific differences in regulatory regions remain understudied. Here, we integrate data from paleogenomics, chromatin modification and physical interaction, and single-cell gene expression of neural progenitor cells to identify derived regulatory changes in the modern human lineage in comparison to Neanderthals/Denisovans. We report a set of genes whose enhancers and/or promoters harbor modern human single nucleotide changes and are active at early stages of cortical development.
We identified 212 genes controlled by regulatory regions harboring modern human changes where Neanderthals/Denisovans carry the ancestral allele. These regulatory regions significantly overlap with putative modern human positively-selected regions and schizophrenia-related genetic loci. Among the 212 genes, we identified a substantial proportion of genes related to transcriptional regulation and, specifically, an enrichment for the SETD1A histone methyltransferase complex, known to regulate WNT signaling for the generation and proliferation of intermediate progenitor cells.
This study complements previous research focused on protein-coding changes distinguishing our species from Neanderthals/Denisovans and highlights chromatin regulation as a functional category so far overlooked in modern human evolution studies. We present a set of candidates that will help to illuminate the investigation of modern human-specific ontogenetic trajectories.
最近的古基因组研究强调了一小部分蛋白质，与我们最近灭绝的亲属相比，这些蛋白质携带现代人类特异性的错义变化。尽管经常被提及具有高度相关性，但调节区域的种间差异仍未得到充分研究。在这里，我们整合了古基因组学、染色质修饰和物理相互作用以及神经祖细胞的单细胞基因表达的数据，以确定与尼安德特人和丹尼索万人相比，现代人类谱系中的衍生调节变化。我们报告了一组基因，其增强子和/或启动子具有现代人类单核苷酸变化，并且在皮质发育的早期阶段具有活性。
我们鉴定了 212 个基因，这些基因的调控区域携带有现代人类的变化，而尼安德特人和丹尼索万人则携带祖先等位基因。这些调控区域与假定的现代人类正选择区域和与精神分裂症相关的遗传基因座显著重叠。在这 212 个基因中，我们鉴定出了相当一部分与转录调控相关的基因，特别是富含 SETD1A 组蛋白甲基转移酶复合物，该复合物已知可调节 WNT 信号通路，从而促进中间祖细胞的产生和增殖。
这项研究补充了以前专注于区分我们的物种与尼安德特人和丹尼索万人的蛋白质编码变化的研究，并强调了染色质调节作为一个迄今为止在现代人类进化研究中被忽视的功能类别。我们提出了一组候选基因，这将有助于阐明对现代人类特定个体发生轨迹的研究。
