期刊
SCIENCE
卷 359, 期 6375, 页码 555-558出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aao4426
关键词
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资金
- Harvard/MIT MD-PHD program
- Stuart H. Q. and Victoria Quan Fellowship in Neurobiology
- Paul G. Allen Family Foundation
- [K99 AG054749 01]
- [F30 MH102909]
- [1S10RR028832-01]
- [T32HG002295]
- [U01MH106883]
- [P50MH106933]
- [R01 NS032457 U01 MH106883]
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.
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