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PMID: 27618310 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Nature neuroscience ·Vol. 19 ·No. 12 ·2016-00-00 ·Pages 1583-1591

Erwin JA, Paquola AC, Singer T, Gallina I, Novotny M, Quayle C, Bedrosian TA, Alves FI, Butcher CR, Herdy JR, Sarkar A, Lasken RS, Muotri AR, Gage FH

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.

MeSH Terms
Brain/metabolism Cells, Cultured Gene Dosage Genome-Wide Association Study/methods Genomics/methods Humans Long Interspersed Nucleotide Elements/genetics Neurons/metabolism Sequence Deletion
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Erwin Jennifer A
The Salk Institute for Biological Studies, La Jolla, California, USA.
Paquola Apuã C M
The Salk Institute for Biological Studies, La Jolla, California, USA. | Department of Cellular &Molecular Medicine, University of California San Diego, School of Medicine, La Jolla, California, USA.
Singer Tatjana
The Salk Institute for Biological Studies, La Jolla, California, USA.
Gallina Iryna
The Salk Institute for Biological Studies, La Jolla, California, USA.
Novotny Mark
J. Craig Venter Institute, La Jolla, California, USA.
Quayle Carolina
The Salk Institute for Biological Studies, La Jolla, California, USA.
Bedrosian Tracy A
The Salk Institute for Biological Studies, La Jolla, California, USA.
Alves Francisco I A
University of São Paulo, Departamento de Microbiologia, Instituto de Ciências Biomédicas, São Paulo, Brazil.
Butcher Cheyenne R
The Salk Institute for Biological Studies, La Jolla, California, USA.
Herdy Joseph R
The Salk Institute for Biological Studies, La Jolla, California, USA.
Sarkar Anindita
The Salk Institute for Biological Studies, La Jolla, California, USA.
Lasken Roger S
J. Craig Venter Institute, La Jolla, California, USA.
Muotri Alysson R
Department of Cellular &Molecular Medicine, University of California San Diego, School of Medicine, La Jolla, California, USA. | Department of Pediatrics, Rady Children's Hospital, San Diego, California, USA.
Gage Fred H
The Salk Institute for Biological Studies, La Jolla, California, USA.
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Article Info
Journal
Nature neuroscience
Abbr.
Nat Neurosci
ISSN
1546-1726
DOI
10.1038/nn.4388
Published
2016-00-00
Epub
2016-00-12
Pages
1583-1591
Language
English
Region
United States
NLM ID
9809671
PMCID
PMC5127747
Subset
IM
Grants
NIMH NIH HHS · R01 MH095741 · United States
NCI NIH HHS · T32 CA009370 · United States
NIMH NIH HHS · U01 MH106882 · United States
NIMH NIH HHS · R01 MH088485 · United States
NCI NIH HHS · P30 CA014195 · United States
Corrections
ErratumIn
PMID: 28949329
ErratumIn
PMID: 29703932
External Links
PubMed source DOI: 10.1038/nn.4388 PMC Full Text View journal details
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