Mapping recurrent mosaic copy number variation in human neurons

Chen Sun, Kunal Kathuria, Sarah B. Emery, ByungJun Kim, Ian E. Burbulis, Joo Heon Shin, Daniel R. Weinberger, John V. Moran, Jeffrey M. Kidd, Ryan E. Mills () and Michael J. McConnell ()
Additional contact information
Chen Sun: University of Michigan Medical School
Kunal Kathuria: Lieber Institute for Brain Development
Sarah B. Emery: University of Michigan Medical School
ByungJun Kim: University of Michigan Medical School
Ian E. Burbulis: School of Medicine
Joo Heon Shin: Lieber Institute for Brain Development
Daniel R. Weinberger: Lieber Institute for Brain Development
John V. Moran: University of Michigan Medical School
Jeffrey M. Kidd: University of Michigan Medical School
Ryan E. Mills: University of Michigan Medical School
Michael J. McConnell: Lieber Institute for Brain Development

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract When somatic cells acquire complex karyotypes, they often are removed by the immune system. Mutant somatic cells that evade immune surveillance can lead to cancer. Neurons with complex karyotypes arise during neurotypical brain development, but neurons are almost never the origin of brain cancers. Instead, somatic mutations in neurons can bring about neurodevelopmental disorders, and contribute to the polygenic landscape of neuropsychiatric and neurodegenerative disease. A subset of human neurons harbors idiosyncratic copy number variants (CNVs, “CNV neurons”), but previous analyses of CNV neurons are limited by relatively small sample sizes. Here, we develop an allele-based validation approach, SCOVAL, to corroborate or reject read-depth based CNV calls in single human neurons. We apply this approach to 2,125 frontal cortical neurons from a neurotypical human brain. SCOVAL identifies 226 CNV neurons, which include a subclass of 65 CNV neurons with highly aberrant karyotypes containing whole or substantial losses on multiple chromosomes. Moreover, we find that CNV location appears to be nonrandom. Recurrent regions of neuronal genome rearrangement contain fewer, but longer, genes.

Date: 2024
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DOI: 10.1038/s41467-024-48392-0

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