解析人类和黑猩猩神经发育过程中人类加速区域的三维相互作用组。
Resolving the three-dimensional interactome of human accelerated regions during human and chimpanzee neurodevelopment.
作者信息
Pal Atreyo, Noble Mark A, Morales Matheo, Pal Richik, Baumgartner Marybeth, Yang Je Won, Yim Kristina M, Uebbing Severin, Noonan James P
机构信息
Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA.
College of Computing, Data Science, and Society, University of California, Berkeley, Berkeley, CA 94720, USA.
出版信息
Cell. 2025 Mar 20;188(6):1504-1523.e27. doi: 10.1016/j.cell.2025.01.007. Epub 2025 Jan 30.
Human accelerated regions (HARs) have been implicated in human brain evolution. However, insight into the genes and pathways they control is lacking, hindering the understanding of their function. Here, we identify 2,963 conserved gene targets for 1,590 HARs and their orthologs in human and chimpanzee neural stem cells (NSCs). Conserved gene targets are enriched for neurodevelopmental functions and are overrepresented among differentially expressed genes (DEGs) identified in human NSCs (hNSCs) and chimpanzee NSCs (cNSCs) as well as in human versus non-human primate brains. Species-specific gene targets do not converge on any function and are not enriched among DEGs. HAR targets also show cell-type-specific expression in the human fetal brain, including in outer radial glia, which are linked to cortical expansion. Our findings support that HARs influence brain evolution by altering the expression of ancestral gene targets shared between human and chimpanzee rather than by gaining new targets in human and facilitate hypothesis-directed studies of HAR biology.
人类加速区（HARs）与人类大脑进化有关。然而，目前尚缺乏对它们所控制的基因和通路的深入了解，这阻碍了对其功能的认识。在此，我们确定了1590个HARs及其在人类和黑猩猩神经干细胞（NSCs）中的直系同源基因的2963个保守基因靶点。保守基因靶点在神经发育功能方面富集，并且在人类神经干细胞（hNSCs）、黑猩猩神经干细胞（cNSCs）以及人类与非人类灵长类动物大脑中鉴定出的差异表达基因（DEGs）中过度代表。物种特异性基因靶点没有集中在任何功能上，也没有在DEGs中富集。HAR靶点在人类胎儿大脑中也表现出细胞类型特异性表达，包括在外放射状胶质细胞中，这些细胞与皮质扩张有关。我们的研究结果支持，HARs通过改变人类和黑猩猩之间共享的祖先基因靶点的表达来影响大脑进化，而不是通过在人类中获得新的靶点，并促进了针对HAR生物学的假设导向研究。
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