Single-cell, genome-wide sequencing identifies clonal somatic copy-number variation in the human brain

Xuyu Cai; Gilad D Evrony; Hillel S Lehmann; Princess C Elhosary; Bhaven K Mehta; Annapurna Poduri; Christopher A Walsh

doi:10.1016/j.celrep.2014.07.043

Single-cell, genome-wide sequencing identifies clonal somatic copy-number variation in the human brain

Cell Rep. 2014 Sep 11;8(5):1280-9. doi: 10.1016/j.celrep.2014.07.043. Epub 2014 Aug 21.

Authors

Xuyu Cai¹, Gilad D Evrony¹, Hillel S Lehmann², Princess C Elhosary², Bhaven K Mehta², Annapurna Poduri³, Christopher A Walsh⁴

Affiliations

¹ 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.
² 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.
³ 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.
⁴ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Brain / cytology
Brain / metabolism*
Chromosomes, Human, Pair 1 / genetics
Chromosomes, Human, Pair 18 / genetics
DNA Copy Number Variations*
Genome, Human*
Hemimegalencephaly / genetics
Humans
Lymphocytes / metabolism
Neurons / metabolism
Sequence Analysis, DNA
Single-Cell Analysis
Tetrasomy*
Trisomy*

Abstract

Publication types

MeSH terms

Grants and funding