Kim, JunhoHuang, August YueJohnson, Shelby LLai, JennyIsacco, LauraJeffries, Ailsa MMiller, Michael BLodato, Michael AWalsh, Christopher ALee, Eunjung Alice2024-03-112024-03-112022-10-07Kim J, Huang AY, Johnson SL, Lai J, Isacco L, Jeffries AM, Miller MB, Lodato MA, Walsh CA, Lee EA. Prevalence and mechanisms of somatic deletions in single human neurons during normal aging and in DNA repair disorders. Nat Commun. 2022 Oct 7;13(1):5918. doi: 10.1038/s41467-022-33642-w. PMID: 36207339; PMCID: PMC9546902.2041-172310.1038/s41467-022-33642-w36207339https://hdl.handle.net/20.500.14038/53161Replication errors and various genotoxins cause DNA double-strand breaks (DSBs) where error-prone repair creates genomic mutations, most frequently focal deletions, and defective repair may lead to neurodegeneration. Despite its pathophysiological importance, the extent to which faulty DSB repair alters the genome, and the mechanisms by which mutations arise, have not been systematically examined reflecting ineffective methods. Here, we develop PhaseDel, a computational method to detect focal deletions and characterize underlying mechanisms in single-cell whole genome sequences (scWGS). We analyzed high-coverage scWGS of 107 single neurons from 18 neurotypical individuals of various ages, and found that somatic deletions increased with age and in highly expressed genes in human brain. Our analysis of 50 single neurons from DNA repair-deficient diseases with progressive neurodegeneration (Cockayne syndrome, Xeroderma pigmentosum, and Ataxia telangiectasia) reveals elevated somatic deletions compared to age-matched controls. Distinctive mechanistic signatures and transcriptional associations suggest roles for somatic deletions in neurodegeneration.enOpen Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/. © The Author(s) 2022Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/Genome informaticsNeural ageingNeurodegenerationStructural variationJournal ArticleNature communications