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

Michael J. Keogh, Wei Wei, Juvid Aryaman, Lauren Walker, Jelle Ameele, Jon Coxhead, Ian Wilson, Matthew Bashton, Jon Beck, John West, Richard Chen, Christian Haudenschild, Gabor Bartha, Shujun Luo, Chris M. Morris, Nick S. Jones, Johannes Attems and Patrick F. Chinnery ()
Additional contact information
Michael J. Keogh: University of Cambridge, Cambridge Biomedical Campus
Wei Wei: University of Cambridge, Cambridge Biomedical Campus
Juvid Aryaman: Imperial College London
Lauren Walker: Newcastle University, Campus for Aging and Vitality
Jelle Ameele: University of Cambridge, Cambridge Biomedical Campus
Jon Coxhead: Newcastle University
Ian Wilson: Newcastle University
Matthew Bashton: Newcastle University
Jon Beck: Personalis Inc
John West: Personalis Inc
Richard Chen: Personalis Inc
Christian Haudenschild: Personalis Inc
Gabor Bartha: Personalis Inc
Shujun Luo: Personalis Inc
Chris M. Morris: Newcastle University, Campus for Aging and Vitality
Nick S. Jones: Imperial College London
Johannes Attems: Newcastle University, Campus for Aging and Vitality
Patrick F. Chinnery: University of Cambridge, Cambridge Biomedical Campus

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06331-w

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