Mapping the Complex Genetic Landscape of Human Neurons.

Autor:	Sun C; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, 100 Washtenaw Avenue, Ann Arbor, MI 48109, USA., Kathuria K; Lieber Institute for Brain Development, 855 North Wolfe Street, Baltimore, MD 21205, USA., Emery SB; Department of Human Genetics, University of Michigan Medical School, 1241 East Catherine Street, Ann Arbor, MI 48109, USA., Kim B; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, 100 Washtenaw Avenue, Ann Arbor, MI 48109, USA., Burbulis IE; Department of Biochemistry and Molecular Genetics, University of Virginia, School of Medicine, Charlottesville, VA 22902, USA.; Facultad de Medicina y Ciencia, Universidad San Sebastián, Sede de la Patagonia, Puerto Montt, Chile., Shin JH; Lieber Institute for Brain Development, 855 North Wolfe Street, Baltimore, MD 21205, USA., Weinberger DR; Lieber Institute for Brain Development, 855 North Wolfe Street, Baltimore, MD 21205, USA.; Department of Psychiatry and Behavioral Sciences and Neuroscience, Johns Hopkins School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, USA.; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, 733 North Broadway, Baltimore, MD 21230, USA., Moran JV; Department of Human Genetics, University of Michigan Medical School, 1241 East Catherine Street, Ann Arbor, MI 48109, USA.; Department of Internal Medicine, University of Michigan Medical School, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA., Kidd JM; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, 100 Washtenaw Avenue, Ann Arbor, MI 48109, USA.; Department of Human Genetics, University of Michigan Medical School, 1241 East Catherine Street, Ann Arbor, MI 48109, USA., Mills RE; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, 100 Washtenaw Avenue, Ann Arbor, MI 48109, USA.; Department of Human Genetics, University of Michigan Medical School, 1241 East Catherine Street, Ann Arbor, MI 48109, USA., McConnell MJ; Lieber Institute for Brain Development, 855 North Wolfe Street, Baltimore, MD 21205, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Mar 07. Date of Electronic Publication: 2023 Mar 07.
DOI:	10.1101/2023.03.07.531594
Abstrakt:	When somatic cells acquire complex karyotypes, they 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 have been limited by relatively small sample sizes. Here, we developed an allele-based validation approach, SCOVAL, to corroborate or reject read-depth based CNV calls in single human neurons. We applied this approach to 2,125 frontal cortical neurons from a neurotypical human brain. This approach identified 226 CNV neurons, as well as a class of CNV neurons with complex karyotypes containing whole or substantial losses on multiple chromosomes. Moreover, we found that CNV location appears to be nonrandom. Recurrent regions of neuronal genome rearrangement contained fewer, but longer, genes. Competing Interests: Competing interests J.V.M. is an inventor on patent US6150160, is a paid consultant for Gilead Sciences, serves on the scientific advisory board of Tessera Therapeutics Inc. (where he is paid as a consultant and has equity options), has licensed reagents to Merck Pharmaceutical, and recently served on the American Society of Human Genetics Board of Directors. The other authors do not declare competing interests.
Databáze:	MEDLINE
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