期刊
GENETICS IN MEDICINE
卷 21, 期 4, 页码 904-912出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41436-018-0274-3
关键词
somatic variant; brain; neurodegenerative disorders; exome sequencing; embryogenesis
资金
- UK Medical Research Council [13044]
- Medical Research Council Mitochondrial Biology Unit [MC_UP_1501/2, 101876/Z/13/Z]
- Medical Research Council (UK) Centre for Translational Muscle Disease [G0601943]
- EU FP7 TIRCON
- NIHR Biomedical Research Centre based at Cambridge University Hospitals National Health Service (NHS) Foundation Trust and the University of Cambridge
- EPSRC [EP/N014529/1] Funding Source: UKRI
- MRC [G0601943, G1100540, G0400074, G0502157, G0900652, MR/K01014X/1, G0600953, MR/L016397/1, MR/R014140/1, MC_PC_13044] Funding Source: UKRI
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 (R) 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 x 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.
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