The landscape of somatic mutation in cerebral cortex of autistic and neurotypical individuals revealed by ultra-deep whole-genome sequencing.

Autor:	Rodin RE; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA.; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA., Dou Y; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA., Kwon M; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA., Sherman MA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.; Department of Electrical Engineering and Computer Science, MIT, Cambridge, MA, USA.; Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA., D'Gama AM; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA.; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA., Doan RN; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA., Rento LM; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA.; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA., Girskis KM; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA.; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA., Bohrson CL; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA., Kim SN; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA.; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA., Nadig A; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA.; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA., Luquette LJ; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA., Gulhan DC; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA., Park PJ; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. peter_park@hms.harvard.edu.; Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA. peter_park@hms.harvard.edu., Walsh CA; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA. Christopher.walsh@childrens.harvard.edu.; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA. Christopher.walsh@childrens.harvard.edu.; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Christopher.walsh@childrens.harvard.edu.
Jazyk:	angličtina
Zdroj:	Nature neuroscience [Nat Neurosci] 2021 Feb; Vol. 24 (2), pp. 176-185. Date of Electronic Publication: 2021 Jan 11.
DOI:	10.1038/s41593-020-00765-6
Abstrakt:	We characterize the landscape of somatic mutations-mutations occurring after fertilization-in the human brain using ultra-deep (~250×) whole-genome sequencing of prefrontal cortex from 59 donors with autism spectrum disorder (ASD) and 15 control donors. We observe a mean of 26 somatic single-nucleotide variants per brain present in ≥4% of cells, with enrichment of mutations in coding and putative regulatory regions. Our analysis reveals that the first cell division after fertilization produces ~3.4 mutations, followed by 2-3 mutations in subsequent generations. This suggests that a typical individual possesses ~80 somatic single-nucleotide variants present in ≥2% of cells-comparable to the number of de novo germline mutations per generation-with about half of individuals having at least one potentially function-altering somatic mutation somewhere in the cortex. ASD brains show an excess of somatic mutations in neural enhancer sequences compared with controls, suggesting that mosaic enhancer mutations may contribute to ASD risk.
Databáze:	MEDLINE
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