Aging and neurodegeneration are associated with increased mutations in single human neurons

• Published in: Science (American Association for the Advancement of Science) Vol. 359; no. 6375; pp. 555 - 559
• Main Authors: Lodato, Michael A, Rodin, Rachel E, Bohrson, Craig L, Coulter, Michael E, Barton, Alison R, Kwon, Minseok, Sherman, Maxwell A, Vitzthum, Carl M, Luquette, Lovelace J, Yandava, Chandri N, Yang, Pengwei, Chittenden, Thomas W, Hatem, Nicole E, Ryu, Steven C, Woodworth, Mollie B, Park, Peter J, Walsh, Christopher A
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 02-02-2018
• Subjects: Accumulation; Adolescent; Adult; Age; Age Factors; Aged; Aged, 80 and over; Aging; Aging - genetics; Brain; Child; Child, Preschool; Cockayne syndrome; Cockayne Syndrome - genetics; Deoxyribonucleic acid; Divergence; DNA; DNA Mutational Analysis; DNA repair; DNA Repair - genetics; DNA sequencing; Female; Gastrulation; Genetic disorders; Genomes; Hippocampus; Hippocampus - cytology; Hippocampus - embryology; Humans; Infant; Male; Middle Aged; Mutation; Mutation Rate; Neurodegeneration; Neurodegenerative Diseases - genetics; Neurogenesis; Neurogenesis - genetics; Neurons; Prefrontal cortex; Prefrontal Cortex - cytology; Prefrontal Cortex - embryology; Repair; Single-Cell Analysis; Whole Genome Sequencing; Xeroderma pigmentosum; Xeroderma Pigmentosum - genetics; Young Adult
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aao4426

It has long been hypothesized that aging and neurodegeneration are associated with somatic mutation in neurons; however, methodological hurdles have prevented testing this hypothesis directly. We used single-cell whole-genome sequencing to perform genome-wide somatic single-nucleotide variant (sSNV) identification on DNA from 161 single neurons from the prefrontal cortex and hippocampus of 15 normal individuals (aged 4 months to 82 years), as well as 9 individuals affected by early-onset neurodegeneration due to genetic disorders of DNA repair (Cockayne syndrome and xeroderma pigmentosum). sSNVs increased approximately linearly with age in both areas (with a higher rate in hippocampus) and were more abundant in neurodegenerative disease. The accumulation of somatic mutations with age-which we term genosenium-shows age-related, region-related, and disease-related molecular signatures and may be important in other human age-associated conditions.