近日，美国加州大学圣迭戈Joseph G. Gleeson及其课题组发现，细胞类型分辨率的镶嵌揭示人类前脑的克隆动态。相关论文于2024年4月10日在线发表于国际学术期刊《自然》。

研究人员利用特定细胞类型内的大脑镶嵌变异作为克隆动态的独特指标，称为细胞类型特异性镶嵌变异条形码分析。从四个半球和两个不同的人类神经典型供体中，研究人员分别鉴定出了287和780个镶嵌变体，并将其用于克隆动态去卷积。大脑内的克隆扩散和等位基因比例显示，与常驻的新皮层兴奋神经元或常驻的基底节GABA能抑制神经元相比，本地海马兴奋神经元的谱系限制性更强。

此外，在细胞类型特异性和单细胞水平上同时进行的基因组转录组分析表明，DLX1⁺抑制性神经元亚群起源于背侧新皮层，这些神经元从与兴奋性神经元共享的起源地呈放射状扩散。最后，顶叶内17个位置的镶嵌变体分布显示，对于兴奋性神经元和抑制性神经元来说，前后轴的克隆扩散限制先于背腹轴的限制。因此，细胞类型分辨率的体细胞镶嵌可以揭示人类前脑发育的谱系关系。

据悉，关于人类前脑中特定脑细胞亚型的解剖起源和系谱关系仍存在争议。因此，直接观察成熟人脑对于全面了解其结构组织和细胞起源至关重要。

附：英文原文

Title: Cell-type-resolved mosaicism reveals clonal dynamics of the human forebrain

Author: Chung, Changuk, Yang, Xiaoxu, Hevner, Robert F., Kennedy, Katie, Vong, Keng Ioi, Liu, Yang, Patel, Arzoo, Nedunuri, Rahul, Barton, Scott T., Noel, Geoffroy, Barrows, Chelsea, Stanley, Valentina, Mittal, Swapnil, Breuss, Martin W., Schlachetzki, Johannes C. M., Kingsmore, Stephen F., Gleeson, Joseph G.

Issue&Volume: 2024-04-10

Abstract: Debate remains around the anatomical origins of specific brain cell subtypes and lineage relationships within the human forebrain1,2,3,4,5,6,7. Thus, direct observation in the mature human brain is critical for a complete understanding of its structural organization and cellular origins. Here we utilize brain mosaic variation within specific cell types as distinct indicators for clonal dynamics, denoted as cell-type-specific mosaic variant barcode analysis. From four hemispheres and two different human neurotypical donors, we identified 287 and 780 mosaic variants, respectively, that were used to deconvolve clonal dynamics. Clonal spread and allele fractions within the brain reveal that local hippocampal excitatory neurons are more lineage-restricted than resident neocortical excitatory neurons or resident basal ganglia GABAergic inhibitory neurons. Furthermore, simultaneous genome transcriptome analysis at both a cell-type-specific and a single-cell level suggests a dorsal neocortical origin for a subgroup of DLX1+ inhibitory neurons that disperse radially from an origin shared with excitatory neurons. Finally, the distribution of mosaic variants across 17 locations within one parietal lobe reveals that restriction of clonal spread in the anterior–posterior axis precedes restriction in the dorsal–ventral axis for both excitatory and inhibitory neurons. Thus, cell-type-resolved somatic mosaicism can uncover lineage relationships governing the development of the human forebrain.

DOI: 10.1038/s41586-024-07292-5

Source: https://www.nature.com/articles/s41586-024-07292-5