Cell type-specific enrichment of somatic aneuploidy in the mammalian brain.
Cell type-specific enrichment of somatic aneuploidy in the mammalian brain.
复制标题
哺乳动物大脑中体细胞非整倍性的细胞类型特异性富集。
DOI：
10.1101/2023.12.18.572285
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Ecker,JosephR
中科院分区：
文献类型：
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作者：
Mukamel,EranA;Liu,Hanqing;Behrens,MMargarita;Ecker,JosephR
体细胞突变改变个体脑细胞1-3子集的基因组，影响基因调控并导致疾病过程4，5。镶嵌单核苷酸变体的特征是在大脑2，3中具有单细胞分辨率，但我们对大规模结构变异的信息有限，包括全染色体复制或丢失1，6，7。我们使用了成年小鼠大脑中超过415,000个单细胞DNA甲基化和染色质构象的数据集来全面鉴定非整倍体细胞。1%的细胞发生全染色体丢失或复制，在非神经细胞类型中，包括少突胶质前体细胞和周细胞，染色体丢失或复制的比例高达1.8%。在所有非整倍体中，我们观察到16号染色体上三体的强烈丰富，该三体与人类21号染色体同线，在唐氏综合征中构成三体。16号染色体三体出现在多种细胞类型和跨脑区域，表明不分离是大脑中体细胞变异的反复特征。
Somatic mutations alter the genomes of a subset of an individual’s brain cells1–3, impacting gene regulation and contributing to disease processes4,5. Mosaic single nucleotide variants have been characterized with single-cell resolution in the brain2,3, but we have limited information about large-scale structural variation, including whole-chromosome duplication or loss1,6,7. We used a dataset of over 415,000 single-cell DNA methylation and chromatin conformation profiles across the adult mouse brain to identify aneuploid cells comprehensively. Whole-chromosome loss or duplication occurred in <1% of cells, with rates up to 1.8% in non-neuronal cell types, including oligodendrocyte precursors and pericytes. Among all aneuploidies, we observed a strong enrichment of trisomy on chromosome 16, which is syntenic with human chromosome 21 and constitutively trisomic in Down syndrome. Chromosome 16 trisomy occurred in multiple cell types and across brain regions, suggesting that nondisjunction is a recurrent feature of somatic variation in the brain.