Single-cell damagenome profiling unveils vulnerable genes and functional pathways in human genome toward DNA damage

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.

Automated summary

A novel single-cell whole-genome amplification method was reported in this study, which efficiently captures spontaneous DNA damage in single cells. The study identified high-damage genes and found significant enrichment of these genes in differentially expressed genes (DEGs) detected in both Alzheimer's disease (AD) and autism spectrum disorder (ASD) single-cell transcriptomes. This discovery shed new lights on the role of DNA damage in human diseases and disorders.