Author:
Motyer Allan,Jackson Stacey,Yang Bicheng,Harliwong Ivon,Tian Wei,Shiu Wingin,Shao Yunchang,Wang Bo,McLean Catriona,Barnett Michael,Kilpatrick Trevor J.,Leslie Stephen,Rubio Justin P.
Abstract
AbstractNeuroinflammation has been linked to DNA damage in multiple sclerosis (MS), but its impact on neural cell genomes at nucleotide resolution is unknown. To address this question, we performed single nucleus whole genome sequencing to determine the landscape of somatic mutation in 172 neurons and oligodendrocytes (OLs) extracted from post-mortem brain tissue from 5 MS cases and three controls. We identified two cases with a significant excess of somatic single nucleotide variants (sSNV) in neurons and OLs from MS inflammatory demyelinated lesions. For a case with primary progressive MS, this translated to a 68% increase in sSNV frequency and 32-year equivalent increase in biological age of lesion-resident cells. Mutational signature analysis conducted on all cells revealed that defective DNA repair and transcription-associated DNA damage are important mutagenic mechanism in both neurons and OLs in MS. Our findings provide the first evidence that inflammation in the brains of people with MS is associated with DNA damage, which may have implications for other neurodegenerative diseases and future drug development.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
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