title: Single-cell, genome-wide sequencing identifies clonal somatic copy-number variation in the human brain.
abstract: De novo copy-number variants (CNVs) can cause neuropsychiatric disease, but the degree to which they occur somatically, and during development, is unknown. Single-cell whole-genome sequencing (WGS) in >200 single cells, including >160 neurons from three normal and two pathological human brains, sensitively identified germline trisomy of chromosome 18 but found most (≥ 95%) neurons in normal brain tissue to be euploid. Analysis of a patient with hemimegalencephaly (HMG) due to a somatic CNV of chromosome 1q found unexpected tetrasomy 1q in ∼ 20% of neurons, suggesting that CNVs in a minority of cells can cause widespread brain dysfunction. Single-cell analysis identified large (>1 Mb) clonal CNVs in lymphoblasts and in single neurons from normal human brain tissue, suggesting that some CNVs occur during neurogenesis. Many neurons contained one or more large candidate private CNVs, including one at chromosome 15q13.2-13.3, a site of duplication in neuropsychiatric conditions. Large private and clonal somatic CNVs occur in normal and diseased human brains.
authors.affiliation: Division of Genetics and Genomics, Manton Center for Orphan Disease Research and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02138, USA; Program of Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Xuyu
authors.initials: X
authors.lastname: Cai
authors.affiliation: Division of Genetics and Genomics, Manton Center for Orphan Disease Research and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02138, USA; Program of Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Gilad D
authors.initials: GD
authors.lastname: Evrony
authors.affiliation: Division of Genetics and Genomics, Manton Center for Orphan Disease Research and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02138, USA.
authors.forename: Hillel S
authors.initials: HS
authors.lastname: Lehmann
authors.affiliation: Division of Genetics and Genomics, Manton Center for Orphan Disease Research and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02138, USA.
authors.forename: Princess C
authors.initials: PC
authors.lastname: Elhosary
authors.affiliation: Division of Genetics and Genomics, Manton Center for Orphan Disease Research and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02138, USA.
authors.forename: Bhaven K
authors.initials: BK
authors.lastname: Mehta
authors.affiliation: Division of Genetics and Genomics, Manton Center for Orphan Disease Research and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02138, USA; Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Annapurna
authors.initials: A
authors.lastname: Poduri
authors.affiliation: Division of Genetics and Genomics, Manton Center for Orphan Disease Research and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02138, USA; Program of Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA. Electronic address: christopher.walsh@childrens.harvard.edu.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Walsh
mesh_terms: D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D056915:DNA Copy Number Variations; D015894:Genome, Human; D065705:Hemimegalencephaly / Q000235:genetics; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D017422:Sequence Analysis, DNA; D059010:Single-Cell Analysis; D058670:Tetrasomy; D014314:Trisomy