High prevalence of focal and multi-focal somatic genetic variants in the human brain.

TitleHigh prevalence of focal and multi-focal somatic genetic variants in the human brain.
Publication TypeJournal Article
Year of Publication2018
AuthorsKeogh, MJ, 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, CM, Jones, NS, Attems, J, Chinnery, PF
JournalNat Commun
Volume9
Issue1
Pagination4257
Date Published2018 10 15
ISSN2041-1723
KeywordsBrain, Clone Cells, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Genotyping Techniques, Humans, Mutation, Reproducibility of Results
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.

DOI10.1038/s41467-018-06331-w
Alternate JournalNat Commun
Citation Key10.1038/s41467-018-06331-w
PubMed ID30323172
PubMed Central IDPMC6189186
Grant ListG1100540 / / Medical Research Council / United Kingdom
MC_UP_1501/2 / / Medical Research Council / United Kingdom
G0900652 / / Medical Research Council / United Kingdom
MC_UP_1501/2 / / Medical Research Council (MRC) / International
G0502157 / / Medical Research Council / United Kingdom
G0400074 / / Medical Research Council / United Kingdom
101876/Z/13/Z / / Wellcome Trust / United Kingdom
212219/Z/18/Z / / Wellcome Trust / United Kingdom
/ / Wellcome Trust / United Kingdom