L1-associated genomic regions are deleted in somatic cells of the healthy human brain.
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.
The Salk Institute for Biological Studies, La Jolla, California, USA.
Jennifer A
JA
Erwin
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.
Apuã C M
AC
Paquola
The Salk Institute for Biological Studies, La Jolla, California, USA.
Tatjana
T
Singer
The Salk Institute for Biological Studies, La Jolla, California, USA.
Iryna
I
Gallina
J. Craig Venter Institute, La Jolla, California, USA.
Mark
M
Novotny
The Salk Institute for Biological Studies, La Jolla, California, USA.
Carolina
C
Quayle
The Salk Institute for Biological Studies, La Jolla, California, USA.
Tracy A
TA
Bedrosian
University of São Paulo, Departamento de Microbiologia, Instituto de Ciências Biomédicas, São Paulo, Brazil.
Francisco I A
FI
Alves
The Salk Institute for Biological Studies, La Jolla, California, USA.
Cheyenne R
CR
Butcher
The Salk Institute for Biological Studies, La Jolla, California, USA.
Joseph R
JR
Herdy
The Salk Institute for Biological Studies, La Jolla, California, USA.
Anindita
A
Sarkar
J. Craig Venter Institute, La Jolla, California, USA.
Roger S
RS
Lasken
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.
Alysson R
AR
Muotri
The Salk Institute for Biological Studies, La Jolla, California, USA.
Fred H
FH
Gage
D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D018628:Gene Dosage; D055106:Genome-Wide Association Study / Q000379:methods; D023281:Genomics / Q000379:methods; D006801:Humans; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics*; D009474:Neurons / Q000378:metabolism*; D017384:Sequence Deletion