Prevalence and mechanisms of somatic deletions in single human neurons during normal aging and in DNA repair disorders
Year: 2022
Type: article
Study design: Observational Study
Abstract: Replication 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.
Source: Nature Communications
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,890
Funders: U.S. Department of Defense, Howard Hughes Medical Institute, U.S. Department of Health and Human Services, Doris Duke Charitable Foundation, Paul G. Allen Family Foundation, A-T Children's Project, Brigham and Women's Hospital, BrightFocus Foundation, National Research Foundation, National Research Foundation of Korea, Ministry of Education, India, National Institutes of Health, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Congressionally Directed Medical Research Programs
Awards: Genome-Wide Somatic Mutation in Alzheimer's Disease Pathogenesis Using Single Neuron Analysis, Mechanism for endogenous retroelements to mimic ancient exogenous identities in aging and diseased human tissue, G1388908201, G1424521977, Vascular, Pulmonary and Renal Injury, G2218992114, Genome-Wide Somatic Mutations in Alzheimer’s Disease During Pathologic Progression, G2373339882, G262780762, G2776647444, G2929379768, G2947081175, G3002166866, Medical Scientist Training Program, G3529731519, G3549828030, G3687241855, G4019737058, The role of somatic mutation in neurodegenerative disease, 1/2-Somatic mosaicism and autism spectrum disorder, SINGLE-CELL ANALYSIS OF SOMATIC MUTATION IN AGING ANO NEUROOEGENERATIVE DISEASE IN THE HUMAN BRAIN, G6064773490, G617146100, G7651559264, G7962882732, G8849234563, G8867845400, Boston Children's Hospital/HMS Intellectual and Developmental Disabilities Research Center, Cell Identity Determination in Human Brain: Somatic Mutation and Cell Lineage, Rates and mechanisms of age-related somatic mutation in normal and Alzheimer brain, Medical Scientist Training Program
OpenAlex ID: W4303423645