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Genet Med. 2019 Apr;21(4):904-912. doi: 10.1038/s41436-018-0274-3. Epub 2018 Sep 14.

Frequency and signature of somatic variants in 1461 human brain exomes.

Author information

1
Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
2
Department of Mathematics, Imperial College London, London, UK.
3
Institute of Genetic Medicine, Central Parkway, Newcastle University, Newcastle Upon Tyne, UK.
4
Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, UK.
5
National CJD Research & Surveillance Unit, University of Edinburgh, Western General Hospital, Edinburgh, UK.
6
Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, London, UK.
7
Institute of Neuroscience, Newcastle University, Campus for Aging and Vitality, Newcastle upon Tyne, UK.
8
Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK. pfc25@cam.ac.uk.
9
MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK. pfc25@cam.ac.uk.

Abstract

PURPOSE:

To systematically study somatic variants arising during development in the human brain across a spectrum of neurodegenerative disorders.

METHODS:

In this study we developed a pipeline to identify somatic variants from exome sequencing data in 1461 diseased and control human brains. Eighty-eight percent of the DNA samples were extracted from the cerebellum. Identified somatic variants were validated by targeted amplicon sequencing and/or PyroMark® Q24.

RESULTS:

We observed somatic coding variants present in >10% of sampled cells in at least 1% of brains. The mutational signature of the detected variants showed a predominance of C>T variants most consistent with arising from DNA mismatch repair, occurred frequently in genes that are highly expressed within the central nervous system, and with a minimum somatic mutation rate of 4.25 × 10-10 per base pair per individual.

CONCLUSION:

These findings provide proof-of-principle that deleterious somatic variants can affect sizeable brain regions in at least 1% of the population, and thus have the potential to contribute to the pathogenesis of common neurodegenerative diseases.

KEYWORDS:

brain; embryogenesis; exome sequencing; neurodegenerative disorders; somatic variant

PMID:
30214067
PMCID:
PMC6544539
DOI:
10.1038/s41436-018-0274-3
[Indexed for MEDLINE]
Free PMC Article

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