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

Genetics in Medicine : Official Journal of the American College of Medical Genetics
Wei WeiPatrick F Chinnery

Abstract

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

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Citations

Nov 7, 2020·Brain : a Journal of Neurology·Jeroen van RooijJohn C van Swieten
Apr 20, 2021·Biological Psychiatry·Myeong-Heui KimJeong Ho Lee
Jul 18, 2021·Nature Reviews. Cardiology·Sarah U MortonChristine E Seidman
May 13, 2021·Annual Review of Genomics and Human Genetics·Michael B MillerChristopher A Walsh

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Datasets Mentioned

BETA
EGAS00001001599

Methods Mentioned

BETA
exome sequencing
genotyping
amplicon sequencing
deamination

Software Mentioned

BWA
GATK
Integrative Genomic Viewer ( IGV )
SIFT
Haplotype Caller from Genome Analysis Toolkit ( GATK
Haplotype Caller
ExAC
ANNOVAR
deepSNV
Integrative Genomic Viewer

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