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Nat Commun. 2018 Oct 15;9(1):4257. doi: 10.1038/s41467-018-06331-w.

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

Author information

1
Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
2
Department of Mathematics, Imperial College London, London, SW7 2AZ, UK.
3
Institute of Neuroscience, Newcastle University, Campus for Aging and Vitality, Newcastle upon Tyne, NE4 5PL, UK.
4
Institute of Genetic Medicine, Central Parkway, Newcastle University, Newcastle Upon Tyne, NE1 3BZ, UK.
5
Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, NE1 7RU, UK.
6
Personalis Inc, 1330O'Brien Dr, Menlo Park, CA, 94025, USA.
7
EPSRC Centre for Mathematics of Precision Healthcare, Imperial College London, London, SW7 2AZ, UK.
8
Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK. pfc25@cam.ac.uk.
9
MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, CB2 0XY, UK. pfc25@cam.ac.uk.

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.

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