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Harvard Medical School

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Cell, Mar 11 2024, S0092-8674(24)00227-7 | https://doi.org/10.1016/j.cell.2024.02.025 Contrasting somatic mutation patterns in aging human neurons and oligodendrocytes

Javier Ganz ^1,2,3,8,9, Lovelace J. Luquette^4,8, Sara Bizzotto ^1,2,3,5,8, Michael B. Miller ^1,3,6, Zinan Zhou^1,2,3, Craig L. Bohrson ⁴, Hu Jin ⁴, Antuan V. Tran ⁴, Vinayak V. Viswanadham ⁴, Gannon McDonough ⁶, Katherine Brown ⁶, Yasmine Chahine ¹, Brian Chhouk¹, Alon Galor⁴, Peter J. Park ^4,7, Christopher A. Walsh ^1,2,3,10

¹Division 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

²Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA

³Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA

⁴Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA

⁵Sorbonne Université, Institut du Cerveau (Paris Brain Institute) ICM, Inserm, CNRS, Hôpital de la Pitié Salpêtrière, 75013 Paris, France

⁶Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA

⁷Division of Genetics, Brigham and Women’s Hospital, Boston, MA 02115, USA

⁸These authors contributed equally

⁹Present address: Merck Research Laboratories, Cambridge, MA 02142, USA

¹⁰Lead contact

Corresponding authors: Peter J. Park, Christopher A. Walsh

Abstract

Characterizing somatic mutations in the brain is important for disentangling the complex mechanisms of aging, yet little is known about mutational patterns in different brain cell types. Here, we performed whole-genome sequencing (WGS) of 86 single oligodendrocytes, 20 mixed glia, and 56 single neurons from neurotypical individuals spanning 0.4-104 years of age and identified >92,000 somatic single-nucleotide variants (sSNVs) and small insertions/deletions (indels). Although both cell types accumulate somatic mutations linearly with age, oligodendrocytes accumulated sSNVs 81% faster than neurons and indels 28% slower than neurons. Correlation of mutations with single-nucleus RNA profiles and chromatin accessibility from the same brains revealed that oligodendrocyte mutations are enriched in inactive genomic regions and are distributed across the genome similarly to mutations in brain cancers. In contrast, neuronal mutations are enriched in open, transcriptionally active chromatin. These stark differences suggest an assortment of active mutagenic processes in oligodendrocytes and neurons.

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형식Research article
게재일2024년 03월 (BRIC 등록일 2024-04-02)
연구진국외 연구진
분야 의약학 > 유전 및 유전체의학

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