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

Lookup NU author(s): Dr Lauren Walker, Dr Jonathan Coxhead, Dr Ian Wilson, Dr Matthew Bashton, Dr Christopher Morris, Professor Johannes Attems, Professor Patrick Chinnery

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2018, The Author(s). 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.


Publication metadata

Author(s): Keogh 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

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2018

Volume: 9

Issue: 1

Online publication date: 15/10/2018

Acceptance date: 30/08/2018

Date deposited: 29/10/2018

ISSN (electronic): 2041-1723

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/s41467-018-06331-w

DOI: 10.1038/s41467-018-06331-w

PubMed id: 30323172


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