Contrasting patterns of somatic mutations in neurons and glia reveal differential predisposition to disease in the aging human brain.

Autor:	Ganz J; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Department of Pediatrics, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Luquette LJ; Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA., Bizzotto S; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Department of Pediatrics, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.; Sorbonne Université, Institut du Cerveau (Paris Brain Institute) ICM, Inserm, CNRS, Ho pital de la Pitié Salpe triére, Paris, France., Bohrson CL; Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA., Jin H; Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA., Miller MB; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Department of Pediatrics, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.; Departments of Pathology and Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA., Zhou Z; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Department of Pediatrics, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Galor A; Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA., Park PJ; Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.; Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA., Walsh CA; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Department of Pediatrics, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Jan 14. Date of Electronic Publication: 2023 Jan 14.
DOI:	10.1101/2023.01.14.523958
Abstrakt:	Characterizing the mechanisms of somatic mutations in the brain is important for understanding aging and disease, but little is known about the mutational patterns of different cell types. We performed whole-genome sequencing of 71 oligodendrocytes and 51 neurons from neurotypical individuals (0.4 to 104 years old) and identified >67,000 somatic single nucleotide variants (sSNVs) and small insertions and deletions (indels). While both cell types accumulate mutations with age, oligodendrocytes accumulate sSNVs 69% faster than neurons (27/year versus 16/year) whereas indels accumulate 42% slower (1.8/year versus 3.1/year). Correlation with single-cell RNA and chromatin accessibility from the same brains revealed that oligodendrocyte mutations are enriched in inactive genomic regions and are distributed similarly to mutations in brain cancers. In contrast, neuronal mutations are enriched in open, transcriptionally active chromatin. These patterns highlight differences in the mutagenic processes in glia and neurons and suggest cell type-specific, age-related contributions to neurodegeneration and oncogenesis.
Databáze:	MEDLINE
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