High prevalence of focal and multi-focal somatic genetic variants in the human brain.
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Authors
Keogh, Michael J
Aryaman, Juvid
Walker, Lauren
Van Den Ameele, Jelle
Coxhead, Jon
Wilson, Ian
Beck, Jon
West, John
Chen, Richard
Haudenschild, Christian
Bartha, Gabor
Luo, Shujun
Jones, Nick S
Publication Date
2018-10-15Journal Title
Nature communications
ISSN
2041-1723
Publisher
Springer Nature
Volume
9
Issue
1
Pages
4257
Language
eng
Type
Article
Physical Medium
Electronic
Metadata
Show full item recordCitation
Keogh, M. J., Wei, W., Aryaman, J., Walker, L., Van Den Ameele, J., Coxhead, J., Wilson, I., et al. (2018). High prevalence of focal and multi-focal somatic genetic variants in the human brain.. Nature communications, 9 (1), 4257. https://doi.org/10.1038/s41467-018-06331-w
Abstract
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.
Keywords
Brain, Clone Cells, Humans, Genetic Predisposition to Disease, Reproducibility of Results, Mutation, Genetic Variation, Genetic Association Studies, Genotyping Techniques
Sponsorship
WELLCOME TRUST (101876/Z/13/Z)
WELLCOME TRUST (103396/A/13/Z)
MRC (via University of Edinburgh) (162126)
Evelyn Trust (17/08)
Wellcome Trust (212219/Z/18/Z)
Identifiers
External DOI: https://doi.org/10.1038/s41467-018-06331-w
This record's URL: https://www.repository.cam.ac.uk/handle/1810/285076