美国波士顿儿童医院Christopher A. Walsh和美国哈佛医学院Peter J. Park共同合作，近期取得重要工作进展。他们研究对比了衰老人类神经元和少突胶质细胞体细胞突变模式。相关研究成果2024年3月18日在线发表于《细胞》杂志上。

据介绍，表征大脑中的体细胞突变对于解开衰老的复杂机制很重要，但对不同脑细胞类型的突变模式知之甚少。

研究人员对来自0.4–104岁的神经正常个体的86个单个少突胶质细胞、20个混合胶质细胞和56个单个神经元进行了全基因组测序（WGS），并鉴定了超过92000个体细胞单核苷酸变体（sSNV）和小插入/缺失（indel）。尽管这两种细胞类型的体细胞突变都随着年龄的增长而线性积累，但少突胶质细胞的sSNV积累速度比神经元快81%，比神经元慢28%。突变与同一大脑的单核RNA图谱和染色质可及性的相关性表明，少突胶质细胞突变富集在不活跃的基因组区域，并在整个基因组中分布，类似于脑癌中的突变。相反，神经元突变在开放的、转录活跃的染色质中富集。

总之，这些明显的差异表明少突胶质细胞和神经元中存在各种活跃的诱导突变过程。

附：英文原文

Title: Contrasting somatic mutation patterns in aging human neurons and oligodendrocytes

Author: Javier Ganz, Lovelace J. Luquette, Sara Bizzotto, Michael B. Miller, Zinan Zhou, Craig L. Bohrson, Hu Jin, Antuan V. Tran, Vinayak V. Viswanadham, Gannon McDonough, Katherine Brown, Yasmine Chahine, Brian Chhouk, Alon Galor, Peter J. Park, Christopher A. Walsh

Issue&Volume: 2024-03-18

Abstract: Characterizing somatic mutations in the brain is important for disentangling the complex mechanisms of aging, yet little is known about mutational patterns in different brain cell types. Here, we performed whole-genome sequencing (WGS) of 86 single oligodendrocytes, 20 mixed glia, and 56 single neurons from neurotypical individuals spanning 0.4–104 years of age and identified >92,000 somatic single-nucleotide variants (sSNVs) and small insertions/deletions (indels). Although both cell types accumulate somatic mutations linearly with age, oligodendrocytes accumulated sSNVs 81% faster than neurons and indels 28% slower than neurons. Correlation of mutations with single-nucleus RNA profiles and chromatin accessibility from the same brains revealed that oligodendrocyte mutations are enriched in inactive genomic regions and are distributed across the genome similarly to mutations in brain cancers. In contrast, neuronal mutations are enriched in open, transcriptionally active chromatin. These stark differences suggest an assortment of active mutagenic processes in oligodendrocytes and neurons.

DOI: 10.1016/j.cell.2024.02.025

Source: https://www.cell.com/cell/fulltext/S0092-8674(24)00227-7