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

Science
Authors
Keywords
Abstract

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.

Year of Publication
2018
Journal
Science
Volume
359
Issue
6375
Pages
555-559
Date Published
2018 02 02
ISSN
1095-9203
DOI
10.1126/science.aao4426
PubMed ID
29217584
PubMed Central ID
PMC5831169
Links
Grant list
S10 RR028832 / RR / NCRR NIH HHS / United States
R01 NS032457 / NS / NINDS NIH HHS / United States
U01 MH106883 / MH / NIMH NIH HHS / United States
K99 AG054748 / AG / NIA NIH HHS / United States
K99 AG050749 / AG / NIA NIH HHS / United States
T32 HG002295 / HG / NHGRI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
Howard Hughes Medical Institute / United States
F30 MH102909 / MH / NIMH NIH HHS / United States
U54 HD090255 / HD / NICHD NIH HHS / United States
P50 MH106933 / MH / NIMH NIH HHS / United States