Ganz Javier, Luquette Lovelace J, Bizzotto Sara, Bohrson Craig L, Jin Hu, Miller Michael B, Zhou Zinan, Galor Alon, Park Peter J, Walsh Christopher A
Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Department of Pediatrics, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.
Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA.
bioRxiv. 2023 Jan 14:2023.01.14.523958. doi: 10.1101/2023.01.14.523958.
Characterizing the mechanisms of somatic mutations in the brain is important for understanding aging and disease, but little is known about the mutational patterns of different cell types. We performed whole-genome sequencing of 71 oligodendrocytes and 51 neurons from neurotypical individuals (0.4 to 104 years old) and identified >67,000 somatic single nucleotide variants (sSNVs) and small insertions and deletions (indels). While both cell types accumulate mutations with age, oligodendrocytes accumulate sSNVs 69% faster than neurons (27/year versus 16/year) whereas indels accumulate 42% slower (1.8/year versus 3.1/year). Correlation with single-cell RNA and chromatin accessibility from the same brains revealed that oligodendrocyte mutations are enriched in inactive genomic regions and are distributed similarly to mutations in brain cancers. In contrast, neuronal mutations are enriched in open, transcriptionally active chromatin. These patterns highlight differences in the mutagenic processes in glia and neurons and suggest cell type-specific, age-related contributions to neurodegeneration and oncogenesis.
了解大脑中体细胞突变的机制对于理解衰老和疾病很重要，但对于不同细胞类型的突变模式却知之甚少。我们对来自神经典型个体（0.4至104岁）的71个少突胶质细胞和51个神经元进行了全基因组测序，鉴定出超过67,000个体细胞单核苷酸变体（sSNV）以及小插入和缺失（indel）。虽然这两种细胞类型都会随着年龄增长而积累突变，但少突胶质细胞积累sSNV的速度比神经元快69%（每年27个与每年16个），而indel积累速度则慢42%（每年1.8个与每年3.1个）。与来自同一大脑的单细胞RNA和染色质可及性的相关性表明，少突胶质细胞突变在非活性基因组区域富集，并且其分布与脑癌中的突变相似。相比之下，神经元突变在开放的、转录活跃的染色质中富集。这些模式突出了神经胶质细胞和神经元诱变过程的差异，并表明细胞类型特异性的、与年龄相关的因素对神经退行性变和肿瘤发生有影响。
