Contrasting somatic mutation patterns in aging human neurons and oligodendrocytes.
Javier Ganz, Lovelace J Luquette, Sara Bizzotto, Michael B Miller, Zinan Zhou, Craig L Bohrson, Hu Jin, Antuan V Tran, Vinayak V Viswanadham, Gannon McDonough, Katherine Brown, Yasmine Chahine, Brian Chhouk, Alon Galor, Peter J Park, Christopher A Walsh
Author Information
Javier Ganz: 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.
Lovelace J Luquette: Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
Sara Bizzotto: 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, Hôpital de la Pitié Salpêtrière, 75013 Paris, France.
Michael B Miller: 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; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Zinan Zhou: 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.
Craig L Bohrson: Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
Hu Jin: Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
Antuan V Tran: Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
Vinayak V Viswanadham: Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
Gannon McDonough: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Katherine Brown: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Yasmine Chahine: 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.
Brian Chhouk: 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.
Alon Galor: Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
Peter J Park: Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA. Electronic address: peter_park@hms.harvard.edu.
Christopher A Walsh: 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. Electronic address: christopher.walsh@childrens.harvard.edu.
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.
