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Science. 2018 Feb 2;359(6375):555-559. doi: 10.1126/science.aao4426. Epub 2017 Dec 7.

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

Author information

1
Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA.
2
Departments of Neurology and Pediatrics, Harvard Medical School, Boston, MA, USA.
3
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
4
Program in Neuroscience and Harvard/MIT MD-PHD Program, Harvard Medical School, Boston, MA, USA.
5
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
6
Computational Statistics and Bioinformatics Group, Advanced Artificial Intelligence Research Laboratory, WuXi NextCODE, Cambridge, MA, USA.
7
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
8
Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
9
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. peter_park@hms.harvard.edu christopher.walsh@childrens.harvard.edu.
10
Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA.
11
Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA. peter_park@hms.harvard.edu christopher.walsh@childrens.harvard.edu.

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.

Comment in

PMID:
29217584
PMCID:
PMC5831169
DOI:
10.1126/science.aao4426
[Indexed for MEDLINE]
Free PMC Article

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