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PMID: 26430121 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Somatic mutation in single human neurons tracks developmental and transcriptional history.

Science (New York, N.Y.) ·Vol. 350 ·No. 6256 ·2015-10-02 ·Pages 94-98

Lodato MA, Woodworth MB, Lee S, Evrony GD, Mehta BK, Karger A, Lee S, Chittenden TW, D'Gama AM, Cai X, Luquette LJ, Lee E, Park PJ, Walsh CA

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.

MeSH Terms
Adolescent Cell Lineage Cerebral Cortex/cytology,growth & development DNA Mutational Analysis DNA Replication/genetics Female Genetic Loci Humans Male Mitosis/genetics Mutation Neurons/cytology,physiology Polymorphism, Single Nucleotide Single-Cell Analysis Transcription, Genetic
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Lodato Michael A
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.
Woodworth Mollie B
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.
Lee Semin
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
Evrony Gilad D
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.
Mehta Bhaven K
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.
Karger Amir
Research Computing, Harvard Medical School, Boston, MA, USA.
Lee Soohyun
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
Chittenden Thomas W
Research Computing, Harvard Medical School, Boston, MA, USA. | Complex Biological Systems Alliance, North Andover, MA, USA.
D'Gama Alissa M
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.
Cai Xuyu
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.
Luquette Lovelace J
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
Lee Eunjung
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. | Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA.
Park Peter J
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. | Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA.
Walsh Christopher A
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.
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Article Info
Journal
Science (New York, N.Y.)
Abbr.
Science
ISSN
1095-9203
DOI
10.1126/science.aab1785
Published
2015-10-02
Pages
94-98
Language
English
Region
United States
NLM ID
0404511
PMCID
PMC4664477
Subset
IM
Grants
NCRR NIH HHS · S10 RR028832 · United States
NINDS NIH HHS · R01 NS032457 · United States
NIMH NIH HHS · U01 MH106883 · United States
NIGMS NIH HHS · T32 GM007226 · United States
NIA NIH HHS · T32 AG000222 · United States
NCRR NIH HHS · 1S10RR028832-01 · United States
NIGMS NIH HHS · T32 GM007753 · United States
NINDS NIH HHS · R01 NS079277 · United States
Howard Hughes Medical Institute · United States
NIMH NIH HHS · P50 MH106933 · United States
Databases
SRA
SRP041470, SRP061939
Corrections
CommentIn
PMID: 26430106
External Links
PubMed source DOI: 10.1126/science.aab1785 PMC Full Text View journal details
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