High prevalence of focal and multi-focal somatic genetic variants in the human brain
Open accessAbstract
Somatic mutations during stem cell division are responsible for several cancers. In principle, a similar process could occur during the intense cell proliferation accompanying human brain development, leading to the accumulation of regionally distributed foci of mutations. Using dual platform >5000-fold depth sequencing of 102 genes in 173 adult human brain samples, we detect and validate somatic mutations in 27 of 54 brains. Using a mathematical model of neurodevelopment and approximate Bayesian inference, we predict that macroscopic islands of pathologically mutated neurons are likely to be common in the general population. The detected mutation spectrum also includes DNMT3A and TET2 which are likely to have originated from blood cell lineages. Together, these findings establish developmental mutagenesis as a potential mechanism for neurodegenerative disorders, and provide a novel mechanism for the regional onset and focal pathology in sporadic cases.
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A few small studies of primary brain samples have hinted that cancer-associated variants and clonal overgrowth might occur in brain microglia.
“A few small studies of primary brain samples have hinted that cancer-associated variants and clonal overgrowth might occur in brain microglia, which proliferate throughout life25,27,28.”
From Somatic cancer variants enriched in Alzheimer’s disease microglia-like cells drive inflammatory and proliferative states (2026) · cites this paper as [27]
The Results and Discussion sections on multiple regional mutations and brains with more than one mutation report cancer-associated variants in human brain samples and discuss possible clonal origins or subclone evolution. They do not identify the affected brain cells as microglia or show clonal overgrowth of microglia; some variants are instead attributed to blood-cell lineages. The paper also does not establish that microglia proliferate throughout life. (LLM, conf=0.85)
Experimental — accuracy not yet measuredMutations consistent with CHIP were found in 17 brain samples from 1,776 persons in ADSP.
“Similar to a prior study22, we found mutations consistent with CHIP in 17 brain samples (Fig. 4a and Supplementary Table 13), although paired blood samples were not available for this set.”
From Clonal hematopoiesis is associated with protection from Alzheimer’s disease (2023) · cites this paper as [22]
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“Targeted ultra-deep sequencing has been widely used as a costefficient strategy to increase sequencing depth and thus improve sensitivity in detecting somatic mutations, especially for screening mutations in cancer-related genes (Martincorena et al., 2015; Keogh et al., 2018).”
MethodMason, D. M., Wang, Y., Bhatia, T. N., Miner, K. M., Trbojevic, S., Stolz, J. F., Luk, K. C., & Leak, R. K. (2019) · Brain Pathology · doi:10.1111/bpa.12718 · Cited by 22 · see citing works
“An alternative view is that there is no obligatory trigger or induction site or Lewy body disorders (9, 89, 90, 131), or even directional movement of α-synucleinopathy; instead, pathology might arise simultaneously in many parts of the central and peripheral nervous systems caused by spontaneous mutations, which are q…”
BackgroundA microglia clonal inflammatory disorder in Alzheimer’s disease
Vicario, R., Fragkogianni, S., Weber, L., Lazarov, T., Hu, Y., Hayashi, S. Y., Craddock, B., Socci, N. D., Alberdi, A., Baako, A., et al. (2025) · eLife · doi:10.7554/elife.96519.3 · Cited by 21 · see citing works
“Mosaicism has been documented in the brain tissue of AD patients in several deep-sequencing studies ( Keogh et al., 2018 ; Wei et al., 2019 ; Park et al., 2019 ), showing that the enrichment of putative pathogenic somatic mutations in the PI3K-AKT, MAPK, and AMPK pathway do occur in the brain of…”
Construction and imaging of a neurovascular unit model
Dong, T.-W., Li, M., Gao, F., Wei, P., & Wang, J. (2022) · Neural Regeneration Research · doi:10.4103/1673-5374.332131 · Cited by 21 · see citing works
“PET can be combined with computed tomography (CT) and MRI for more reliable detection of various diseases in different parts of the nervous system, and can be used to quantitatively analyze certain endogenous substances and metabolic activities in the brain (Keogh et al., 2018).”
BackgroundMethodEpigenetic regulation in the pathophysiology of Lewy body dementia
Chouliaras, L., Kumar, G. S., Thomas, A. J., Lunnon, K., Chinnery, P. F., & O'Brien, J. T. (2020) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2020.101822 · Cited by 23 · see citing works
Self-citationHeteroplasmic mitochondrial DNA mutations in frontotemporal lobar degeneration
Nie, Y.-Z., Murley, A., Golder, Z., Rowe, J., Allinson, K., & Chinnery, P. (2022) · Acta Neuropathologica · doi:10.1007/s00401-022-02423-6 · Cited by 16 · see citing works
“Genetic factors play a prominent role in the pathogenesis of FTLD, with single high-penetrance variants in MAPT, GRN, C9ORF72 found in ~ 20% of affected individuals; other autosomal dominant genes in 10–20%, and multiple risk loci identified through genome wide association studies [5].”
BackgroundSelf-citationTracing brain genotoxic stress in Parkinson’s disease with a novel single-cell genetic sensor
El-Saadi, M. W., Tian, X., Grames, M. S., Ren, M., Keys, K., Li, H., Knott, E. L., Yin, H., Huang, S., & Lu, X. (2022) · Science Advances · doi:10.1126/sciadv.abd1700 · Cited by 18 · see citing works
“Brain somatic mutations could arise in the developing embryo in the progenitor cells of neurons or glia through replication errors during S phase, which has been speculated to contribute to the origin of neurodevelopmental disorders ( 18 , 19 ).”
Huang, A. Y., Zhou, Z., Talukdar, M., Miller, M. B., Chhouk, B., Enyenihi, L., Rosen, I., Stronge, E., Zhao, B., Kim, D., et al. (2024) · doi:10.1101/2024.01.03.574078 · Cited by 16 · see citing works
“Although gene panel sequencing of 20 AD brains 27 and whole exome sequencing of DNA from micro-dissected neuronal nuclei of 52 AD brains 28 found no consistent excess of clonal somatic mutations in AD, these studies were extremely limited in their ability to detect clonal somatic mutations by small…”
Huang, A. Y., Zhou, Z., Talukdar, M., Enyenihi, L., Miller, M. B., Chhouk, B., Rosen, I., Zheng, M., Zhou, M., Yang, A., et al. (2026) · Cell · doi:10.1016/j.cell.2026.03.040 · Cited by 15 · see citing works
“27 The current consensus in the literature suggests that no progenitor capable of giving rise to both yolk sac-derived microglia and hematopoietic stem cells is known or believed to exist during embryonic development, 58 indicating that the shared somatic variants between brain and blood and the…”
An Epigenetic LINE-1-Based Mechanism in Cancer
Lavia, P., Sciamanna, I., & Spadafora, C. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232314610 · Cited by 20 · see citing works
Parkinson’s disease is associated with clonal hematopoiesis with TET2 mutation
Woo, K. A., Kim, H., Lee, C. Y., Shin, J. H., Sun, C.-H., Im, H., An, H., Lim, J., Choi, S., Koh, Y., et al. (2024) · npj Parkinson s Disease · doi:10.1038/s41531-024-00784-1 · Cited by 16 · see citing works
“The presence of mutations in DNMT3A and TET2 , the two most frequently mutated genes in CHIP 5 , in the whole-brain DNA of elderly individuals 12 raises the possibility of CNS involvement in CHIP.”
Basu, S., Song, M., Adams, L., Jeong, I., Je, G., Guhathakurta, S., Jiang, J. B., Boparai, N., Dai, W., Cardozo‐Pelaez, F., et al. (2023) · Acta Neuropathologica · doi:10.1007/s00401-023-02632-7 · Cited by 16 · see citing works
“Accumulating evidence indicates that somatic mutations in the brain can arise during brain development [35] and aging with brain-region specificity [44].”
BackgroundVery large hidden genetic diversity in one single tumor: evidence for tumors-in-tumor
Chen, B., Wu, X.-R., Ruan, Y.-S., Zhang, Y., Cai, Q., Zapata, L., Wu, C.-I., Lan, P., & Wen, H.-J. (2022) · National Science Review · doi:10.1093/nsr/nwac250 · Cited by 13 · see citing works
Nie, Y.-Z., Szebényi, K., Wenger, L., Lakatos, A., & Chinnery, P. (2025) · Science Advances · doi:10.1126/sciadv.adr0690 · Cited by 12 · see citing works
Self-citationThe Landscape of Mutational Mosaicism in Autistic and Normal Human Cerebral CortexPreprint
Rodin, R. E., Dou, Y.-M., Kwon, M., Sherman, M. A., D'Gama, A. M., Doan, R. N., Rento, L., Girskis, K. M., Bohrson, C. L., Kim, S., et al. (2020) · bioRxiv · doi:10.1101/2020.02.11.944413 · Cited by 12 · see citing works
Cacic, A. M., Schulz, F. I., Germing, U., Dietrich, S., & Gattermann, N. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1303785 · Cited by 10 · see citing works
“CHIP-associated mutations were found in brain samples (156, 157), presumably due to in fi ltration of the brain by marrow-derived mutant myeloid cells that have adopted a microglial-like phenotype (156).”
BackgroundMin, S., Li, Z.-C., Shieh, A. W., Giase, G., Bao, R., Zhang, C., Kuney, L., Kopp, R., Asif, H., Alliey-Rodriguez, N., et al. (2021) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2021.07.010 · Cited by 11 · see citing works
Leija-Salazar, M., Pittman, A., Mokretar, K., Morris, H., Schapira, A., & Proukakis, C. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.570424 · Cited by 11 · see citing works
“When using molecular barcodes, two brain somatic SNVs were found in AD-associated genes of 98 patients (29), whereas no somatic SNVs in familial ADgenes were found in 20 patients (19).”
BackgroundMethodThe genetic landscape of early‐onset Alzheimer's disease in China
Qin, W. D., Li, F., Liu, W., Li, Y., Cao, S., Wei, Y., Li, Y., Wang, Y., Wang, Q., & Jia, J. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.14486 · Cited by 9 · see citing works
“20,35 Although the individuals with EOAD were younger thancontrols,mutationsignatureanalysesshowedthatEOADpatients had a 61.4% prevalence of SBS5 (notable for C > T variants), which was much higher than the control group.”
InfluentialClonal haematopoiesis of emerging significance
Hammond, D. E., & Loghavi, S. (2021) · Pathology · doi:10.1016/j.pathol.2021.02.005 · Cited by 10 · see citing works
Monocyte-derived microglia with Dnmt3a mutation cause motor pathology in aging mice
Kim, J.-S., Trzebanski, S., Shin, S.-H., Ilani, N., Kaushansky, N., Scheller, M., Solomon, A., Liu, Z.-Y., Aust, O., Boura-Halfon, S., et al. (2023) · bioRxiv · doi:10.1101/2023.11.16.567402 · Cited by 7
“Of note, the available reports of monocyte-derived microglia in humans, as defined by CH mutations, so far refer to brain regions that overlap with the areas in which we observe MoMg accumulation in the aging mice, including the occipital cortex, medulla and putamen 28,66 .”
BackgroundA Synopsis Clonal Hematopoiesis of Indeterminate Potential in Hematology
Zerdan, M. B., Nasr, L., Saba, L., Meouchy, P., Safi, N., Allam, S., Bhandari, J., & Chaulagain, C. P. (2022) · Cancers · doi:10.3390/cancers14153663 · Cited by 6 · see citing works
A Quantitative Model of Sporadic Axonal Degeneration in the Drosophila Visual System
Richard, M., Doubková, K., Nitta, Y., Kawai, H., Sugie, A., & Tavosanis, G. (2022) · Journal of Neuroscience · doi:10.1523/jneurosci.2115-21.2022 · Cited by 15 · see citing works
Koss, D. J., Todd, O., Menon, H., Anderson, Z., Yang, T., Findlay, L., Graham, B., Palmowski, P., Porter, A., Morrice, N., et al. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00813-4 · Cited by 7 · see citing works
“Consequently, aging neurons exhibit an increased number of individual genomic errors, leading to the accumulation of somatic mutations within the brain, compromising optimal neuronal function and increasing the risk for disease [5, 6].”
Self-citationVerheijen, B. M. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00277 · Cited by 5 · see citing works
RetractedObrębski, T., Maleszewska, M., Dunin-Horkawicz, S., & Malik, A. R. (2026) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2026.111267 · Cited by 5 · see citing works
“Cells bearing CHIP-associated mutations, presumably originating from circulating blood cells, are found in the brains of aged patients (111, 120), supporting the possibility that CHIP cells may have a direct impact on neuro-degeneration.”
Huang, A. Y., Cheng, Y., Ku, J., Zhao, B., Park, J., Kim, D., Choi, J., & Lee, E. A. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf1450 · Cited by 4 · see citing works
“These AD somatic variants were specifically enriched in genes that regulate cell cycle and proliferation, aligning with previous reports that such proliferation-related somatic variants, particularly in microglia, may contribute to the pathogenesis of neurodegeneration [ 11 , 77 –79 ].”
Somatic mutations reveal hypermutable brains and are associated with neuropsychiatric disordersPreprint
Bae, T., Fasching, L., Wang, Y., Shin, J. H., Šuvakov, M., Jang, Y., Norton, S., Dias, C., Mariani, J., Jourdon, A., et al. (2022) · medRxiv · doi:10.1101/2022.02.09.22269114 · Cited by 4 · see citing works
McDonough, G. A., Cheng, Y., Morillo, K. S., Doan, R. N., Zhou, Z., Kenny, C. J., Foutz, A., Kim, C., Cohen, M. L., Appleby, B. S., et al. (2024) · Acta Neuropathologica · doi:10.1007/s00401-024-02774-2 · Cited by 5 · see citing works
“Studies in AD have also not identified significant pathogenic brain somatic mutations in genes linked to causative germline disease, namely APP, PSEN1, and PSEN2 [38, 68, 79] apart from a single reported case with a 14% VAF variant in PSEN1 [9].”
Paterson, C., Bozic, I., Smith, M., Hoad, X., & Evans, D. (2021) · bioRxiv · doi:10.1038/s41416-022-01955-8 · Cited by 3
Gateways for myeloid cell entry into the central nervous system
Amann, L., & Prinz, M. (2026) · Neuron · doi:10.1016/j.neuron.2026.04.001 · Cited by 2 · see citing works
Clonal hematopoiesis: linking hematopoietic stem cell aging with age-related diseases
Li, Z., Zhou, Z., You, W., Xiao, F., Ju, Z., & Chen, Z. (2025) · Oral Science and Homeostatic Medicine · doi:10.26599/oshm.2025.9610016 · Cited by 1 · see citing works
The phenomenon of clonal hematopoiesis: etiology, classification and its prognostic role
Kunevich, E. O., Mikhaleva, M., Крысюк, О. Б., Bogdanov, A. N., Zherniakova, A., & Волошин, С. В. (2025) · Oncohematology · doi:10.17650/1818-8346-2025-20-1-28-54 · Cited by 2 · see citing works
High-Depth PRNP Sequencing in Brains With Sporadic Creutzfeldt-Jakob Disease
Murley, A., Nie, Y.-Z., Golder, Z., Keogh, M., Smith, C., Ironside, J., & Chinnery, P. (2023) · Neurology: Genetics · doi:10.1212/nxg.0000000000200054 · Cited by 1 · see citing works
“DNA from control samples, with either a neuropathologic diagnosis of Alzheimer disease or cases without significant neuropathology, was collected from the Medical Research Council (MRC) UK Brain Banks.(11,12) A positive control with a heterozygous germline E211Q PRNP mutation was included in the sequencing pool.”
BackgroundMethodSelf-citationZhang, M., Bouland, G. A., Holstege, H., & Reinders, M. (2022) · medRxiv · doi:10.1101/2022.05.25.22275538 · Cited by 1 · see citing works
“This finding is in line with a previous report [11,21] 117”
ResultLi, T. L., & Bateup, H. S. (2026) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2026.102552
Somatic mosaicism in the brain: linking development, ageing and neurodegeneration
Zhou, Z., & Walsh, C. A. (2026) · Nature Reviews Neurology · doi:10.1038/s41582-026-01268-x
Morris, S. A. (2026) · Journal of Alzheimer s Disease Reports · doi:10.1177/25424823261472068
“Developmental neurogenesis is the most intense period of neuronal cell division and generation of somatic mutation 52 ; 200 – 400 somatic single nucleotide variant (SNV) mutations/neuron are present at 15 – 21 weeks gestation and the rate plateaus in late neurogenesis and peaks at about 1000…”
Probability and Neurodegeneration: Alzheimer’s Disease and Huntington’s Disease
Panegyres, P. K. (2025) · Brain Science · doi:10.3390/brainsci15080814
McDonough, G. A., Cheng, Y.-C., Morillo, K. S., Doan, R. N., Kenny, C. J., Foutz, A., Kim, C., Cohen, M. L., Appleby, B., Walsh, C. A., et al. (2024) · bioRxiv · doi:10.1101/2024.06.25.600668
“Studies in AD have also not identified significant pathogenic brain somatic mutations in genes linked to causative germline disease, namely APP, PSEN1, and PSEN2 [37, 67, 78] apart from a single reported case with a 14% VAF variant in PSEN1 [9].”
BackgroundPotential to use of viral reverse transcriptase inhibitors in oncology
Vlasova, O. A., Antonova, I., Magomedova, K., Usolkina, M. A., Игоревич, К. К., Belitsky, G. A., Valiev, T. T., & Геннадиевна, Я. М. (2024) · Advances in molecular oncology · doi:10.17650/2313-805x-2024-11-2-8-28 · Cited by 2 · see citing works
DNA typos spell trouble: Somatic mutations as a cause of idiopathic neurodegenerative diseases?
Sabir, M., & Scholz, S. W. (2019) · Movement Disorders · doi:10.1002/mds.27624
“To investigate if developmental, somatic mutagenesis is a potential mechanism underlying neurodegenerative diseases, Keogh and colleagues performed ultra-high-depth sequencing of 102 neurodegeneration and cancer genes in 173 brain regions from 54 postmortem tissues, including 20 Alzheimer’s disease cases, 20 Lewy body…”
BackgroundResultBox, P., & Capraro, A. (2019) · BJPsych International · doi:10.1192/bji.2018.32
- Authors
- Keogh, M. J., Wei, W., Aryaman, J., Walker, L., van den Ameele, J., Coxhead, J., Wilson, I., Bashton, M., Beck, J., West, J., Chen, R., Haudenschild, C., Bartha, G., Luo, S., Morris, C. M., Jones, N. S., Attems, J., & Chinnery, P. F.
- Affiliations
- University of Cambridge (GB)
- Imperial College London (GB)
- Newcastle University (GB)
- Personalis (United States) (US)
- Corresponding author
- Chinnery, Patrick F.
- ORCID
- Venue
- Nature Communications
- Published
- 2018-10-15
- Volume
- 9
- Issue
- 1
- Pages
- 4257-4257
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6189186
- OpenAlex
- W2897583224
- Cited by
- 74
- References
- 58
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 9 · 2023: 4 · 2022: 14 · 2021: 11 · 2020: 6 · 2019: 13 · 2018: 1
- FWCI
- 2.34
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Northumbria Research Link (Northumbria University) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, cc-by)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- Wellcome Trust (212219/Z/18/Z, 101876/Z/13/Z)
- Medical Research Council (MC_UP_1501/2)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- somatic mutations, human brain, brain development, DNMT3A, TET2, neurodegenerative diseases, approximate Bayesian inference, mutation spectrum
- MeSH terms
- Brain, Clone Cells, Humans, Mutation, Genetic Variation, Reproducibility of Results, Genetic Predisposition to Disease, Genetic Association Studies, Genotyping Techniques
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