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Nat Neurosci. 2016 Dec;19(12):1583-1591. doi: 10.1038/nn.4388. Epub 2016 Sep 12.

L1-associated genomic regions are deleted in somatic cells of the healthy human brain.

Author information

1
The Salk Institute for Biological Studies, La Jolla, California, USA.
2
Department of Cellular &Molecular Medicine, University of California San Diego, School of Medicine, La Jolla, California, USA.
3
J. Craig Venter Institute, La Jolla, California, USA.
4
University of São Paulo, Departamento de Microbiologia, Instituto de Ciências Biomédicas, São Paulo, Brazil.
5
Department of Pediatrics, Rady Children's Hospital, San Diego, California, USA.

Abstract

The healthy human brain is a mosaic of varied genomes. Long interspersed element-1 (LINE-1 or L1) retrotransposition is known to create mosaicism by inserting L1 sequences into new locations of somatic cell genomes. Using a machine learning-based, single-cell sequencing approach, we discovered that somatic L1-associated variants (SLAVs) are composed of two classes: L1 retrotransposition insertions and retrotransposition-independent L1-associated variants. We demonstrate that a subset of SLAVs comprises somatic deletions generated by L1 endonuclease cutting activity. Retrotransposition-independent rearrangements in inherited L1s resulted in the deletion of proximal genomic regions. These rearrangements were resolved by microhomology-mediated repair, which suggests that L1-associated genomic regions are hotspots for somatic copy number variants in the brain and therefore a heritable genetic contributor to somatic mosaicism. We demonstrate that SLAVs are present in crucial neural genes, such as DLG2 (also called PSD93), and affect 44-63% of cells of the cells in the healthy brain.

PMID:
27618310
PMCID:
PMC5127747
DOI:
10.1038/nn.4388
[Indexed for MEDLINE]
Free PMC Article

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