Single-cell damagenome profiling unveils vulnerable genes and functional pathways in human genome toward DNA damage
Single-cell damagenome profiling unveils vulnerable genes and functional pathways in human genome toward DNA damage
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DOI：
10.1126/sciadv.abf3329
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发表时间：
2021-07
期刊：
影响因子：
13.6
通讯作者：
Qiangyuan Zhu;Yichi Niu;Michael C. Gundry;Chenghang Zong
中科院分区：
文献类型：
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作者：
Qiangyuan Zhu;Yichi Niu;Michael C. Gundry;Chenghang Zong
一种新的单细胞全基因组扩增方法允许对DNA损伤和基因脆弱性进行全基因组表征。我们报道了一种新的单细胞全基因组扩增方法（LCS-WGA），可以有效地捕获存在于单细胞中的自发DNA损伤。我们将这些损伤相关的单核苷酸变异称为“damSNV”，并将damSNV的全基因组分布称为损伤基因组。我们观察到，在单个人类神经元中，损伤基因组分布与三维基因组结构显著相关。这种不均匀分布表明不同基因的DNA损伤程度不同。接下来，我们确定了在高损伤基因中显著富集的功能。在阿尔茨海默病（AD）和自闭症谱系障碍（ASD）的单细胞转录组检测到的差异表达基因（DEG）中也富集了类似的功能。这一结果可以通过AD和ASD神经元DEG中高损伤基因的显著富集来解释。高损伤基因的发现为DNA损伤在人类疾病和病症中的重要作用提供了新的线索。
A new single-cell whole-genome amplification method allows the genome-wide characterization of DNA damage and gene vulnerability. We report a novel single-cell whole-genome amplification method (LCS-WGA) that can efficiently capture spontaneous DNA damage existing in single cells. We refer to these damage-associated single-nucleotide variants as “damSNVs,” and the whole-genome distribution of damSNVs as the damagenome. We observed that in single human neurons, the damagenome distribution was significantly correlated with three-dimensional genome structures. This nonuniform distribution indicates different degrees of DNA damage effects on different genes. Next, we identified the functionals that were significantly enriched in the high-damage genes. Similar functionals were also enriched in the differentially expressed genes (DEGs) detected by single-cell transcriptome of both Alzheimer’s disease (AD) and autism spectrum disorder (ASD). This result can be explained by the significant enrichment of high-damage genes in the DEGs of neurons for both AD and ASD. The discovery of high-damage genes sheds new lights on the important roles of DNA damage in human diseases and disorders.