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Cell Rep. 2019 Jan 22;26(4):825-835.e7. doi: 10.1016/j.celrep.2018.12.107.

Neurons with Complex Karyotypes Are Rare in Aged Human Neocortex.

Author information

1
Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
2
Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; Universidad San Sebastian, Escuela de Medicina, Sede de la Patagonia, Puerto Montt, Chile.
3
Lieber Institute for Brain Development, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
4
Lieber Institute for Brain Development, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
5
Lieber Institute for Brain Development, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
6
Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
7
Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; Center for Brain Immunology and Glia, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; Child Health Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. Electronic address: mikemc@virginia.edu.

Abstract

A subset of human neocortical neurons harbors complex karyotypes wherein megabase-scale copy-number variants (CNVs) alter allelic diversity. Divergent levels of neurons with complex karyotypes (CNV neurons) are reported in different individuals, yet genome-wide and familial studies implicitly assume a single brain genome when assessing the genetic risk architecture of neurological disease. We assembled a brain CNV atlas using a robust computational approach applied to a new dataset (>800 neurons from 5 neurotypical individuals) and to published data from 10 additional neurotypical individuals. The atlas reveals that the frequency of neocortical neurons with complex karyotypes varies widely among individuals, but this variability is not readily accounted for by tissue quality or CNV detection approach. Rather, the age of the individual is anti-correlated with CNV neuron frequency. Fewer CNV neurons are observed in aged individuals than in young individuals.

PMID:
30673605
DOI:
10.1016/j.celrep.2018.12.107
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