Frequency and signature of somatic variants in 1461 human brain exomes

Wei Wei,Ian Wilson,Zoe Golder,Colin Smith,Johannes Attems,Peter J Kullar,James W Ironside,Nick S Jones,Patrick F Chinnery,Claire Troakes,Chris-Anne Mckenzie,Chris M Morris,Martin R Turner,Safa Al Sarraj,Juvid Aryaman,Kevin Talbot,Olaf Ansorge,Michael J Keogh

doi:10.1038/s41436-018-0274-3

Abstract

PurposeTo systematically study somatic variants arising during development in the human brain across a spectrum of neurodegenerative disorders.MethodsIn 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.ResultsWe 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.ConclusionThese 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.

Highlights

Pathogenic genetic variants affecting over 50 nuclear genes contribute to the pathogenesis of late onset neurological disorders.[1]
None of the identified somatic variants were seen in the heterozygote state in the 1461 brains, and all were extremely rare in the background population.[13]
There was no difference in the frequency of somatic variants between the different disease and control groups (Fisher exact test p > 0.05) (Fig. 2b) indicating that, whilst mutational rates may not be increased in patients with neurodegenerative diseases compared with healthy aged individuals, somatic variants at high variant allele frequencies are relatively common in the human brain

Summary

Introduction

Pathogenic genetic variants affecting over 50 nuclear genes contribute to the pathogenesis of late onset neurological disorders.[1] Present in every cell in the body, these genetic variants are either inherited or arise through a de novo variant in the gamete. Some age-related disorders such as cancer arise through the accumulation of somatic variants within a cell lineage during life, creating genetic heterogeneity within a tissue or organ (somatic mosaicism). Almost half of these variants arise decades before tumor initiation,[2,3,4] raising the possibility that somatic variants acquired by a similar process during development are present within nonmalignant human tissues. The frequency of somatic variants in the human brain, and in those late onset neurological disorders, has not been studied systematically

Methods

Results

Conclusion