Genome aging: somatic mutation in the brain links age-related decline with disease and nominates pathogenic mechanisms
Open accessAbstract
Aging is a mysterious process, not only controlled genetically but also subject to random damage that can accumulate over time. While DNA damage and subsequent mutation in somatic cells were first proposed as drivers of aging more than 60 years ago, whether and to what degree these processes shape the neuronal genome in the human brain could not be tested until recent technological breakthroughs related to single-cell whole-genome sequencing. Indeed, somatic single-nucleotide variants (SNVs) increase with age in the human brain, in a somewhat stochastic process that may nonetheless be controlled by underlying genetic programs. Evidence from the literature suggests that in addition to demonstrated increases in somatic SNVs during aging in normal brains, somatic mutation may also play a role in late-onset, sporadic neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease. In this review, we will discuss somatic mutation in the human brain, mechanisms by which somatic mutations occur and can be controlled, and how this process can impact human health.
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Somatic mutations induced by erroneous DNA damage repair or transposable elements are a common feature of neural development, giving rise to neuron diversity through genomic mosaicism.
“somatic mutations induced by erroneous DNA damage repair or transposable elements are a common feature of neural development, giving rise to neuron diversity through genomic mosaicism”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Lodato & Walsh, 2019
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Self-citation
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- Authors
- Lodato, M. A., & Walsh, C. A.
- Affiliations
- Broad Institute (US)
- Corresponding author
- Walsh, Christopher A
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2019-09-06
- Volume
- 28
- Issue
- R2
- Pages
- R197-R206
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC7015843
- OpenAlex
- W2977413235
- Cited by
- 56
- References
- 91
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 5 · 2023: 6 · 2022: 11 · 2021: 9 · 2020: 12 · 2018: 1
- FWCI
- 2.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Human Molecular Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (K99 AG054749, R01 NS35129,, R01 NS032457)
- National Institute of Mental Health (U01MH106883)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- somatic mutations, brain aging, somatic single nucleotide variants, DNA damage, Alzheimer's disease, Parkinson's disease, neurodegenerative diseases, age-related decline, pathophysiological mechanisms, single-cell whole-genome sequencing
- MeSH terms
- Whole Genome Sequencing, Aging, Alzheimer Disease, Brain, Humans, Mutation, Neurons, Parkinson Disease, Polymorphism, Single Nucleotide, Single-Cell Analysis
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