title: Somatic mutation in single human neurons tracks developmental and transcriptional history.
abstract: Neurons live for decades in a postmitotic state, their genomes susceptible to DNA damage. Here we survey the landscape of somatic single-nucleotide variants (SNVs) in the human brain. We identified thousands of somatic SNVs by single-cell sequencing of 36 neurons from the cerebral cortex of three normal individuals. Unlike germline and cancer SNVs, which are often caused by errors in DNA replication, neuronal mutations appear to reflect damage during active transcription. Somatic mutations create nested lineage trees, allowing them to be dated relative to developmental landmarks and revealing a polyclonal architecture of the human cerebral cortex. Thus, somatic mutations in the brain represent a durable and ongoing record of neuronal life history, from development through postmitotic function.
authors.affiliation: Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA; Departments of Neurology and Pediatrics, Harvard Medical School, Boston, MA, USA; and Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Lodato
authors.affiliation: Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA; Departments of Neurology and Pediatrics, Harvard Medical School, Boston, MA, USA; and Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: Mollie B
authors.initials: MB
authors.lastname: Woodworth
authors.affiliation: Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
authors.forename: Semin
authors.initials: S
authors.lastname: Lee
authors.affiliation: Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA; Departments of Neurology and Pediatrics, Harvard Medical School, Boston, MA, USA; and Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: Gilad D
authors.initials: GD
authors.lastname: Evrony
authors.affiliation: Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA; Departments of Neurology and Pediatrics, Harvard Medical School, Boston, MA, USA; and Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: Bhaven K
authors.initials: BK
authors.lastname: Mehta
authors.affiliation: Research Computing, Harvard Medical School, Boston, MA, USA.
authors.forename: Amir
authors.initials: A
authors.lastname: Karger
authors.affiliation: Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
authors.forename: Soohyun
authors.initials: S
authors.lastname: Lee
authors.affiliation: Research Computing, Harvard Medical School, Boston, MA, USA.|Complex Biological Systems Alliance, North Andover, MA, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Chittenden
authors.affiliation: Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA; Departments of Neurology and Pediatrics, Harvard Medical School, Boston, MA, USA; and Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: Alissa M
authors.initials: AM
authors.lastname: D'Gama
authors.affiliation: Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA; Departments of Neurology and Pediatrics, Harvard Medical School, Boston, MA, USA; and Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: Xuyu
authors.initials: X
authors.lastname: Cai
authors.affiliation: Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
authors.forename: Lovelace J
authors.initials: LJ
authors.lastname: Luquette
authors.affiliation: Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.|Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Eunjung
authors.initials: E
authors.lastname: Lee
authors.affiliation: Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.|Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Park
authors.affiliation: Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA; Departments of Neurology and Pediatrics, Harvard Medical School, Boston, MA, USA; and Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Walsh
mesh_terms: D000293:Adolescent; D019070:Cell Lineage; D002540:Cerebral Cortex / Q000166:cytology* / Q000254:growth & development*; D004252:DNA Mutational Analysis; D004261:DNA Replication / Q000235:genetics; D005260:Female; D056426:Genetic Loci; D006801:Humans; D008297:Male; D008938:Mitosis / Q000235:genetics; D009154:Mutation; D009474:Neurons / Q000166:cytology* / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D059010:Single-Cell Analysis; D014158:Transcription, Genetic