Abstract
AbstractReplication 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.
Funder
National Research Foundation of Korea
United States Department of Defense | United States Army | Army Medical Command | Congressionally Directed Medical Research Programs
U.S. Department of Health & Human Services | National Institutes of Health
Brigham and Women's Hospital
U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke
U.S. Department of Health & Human Services | NIH | National Institute of Mental Health
Paul G. Allen Family Foundation
Howard Hughes Medical Institute
A-T Children's Project
The Suh Kyungbae Science Foundation
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Cited by
8 articles.
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