- Erwin, Jennifer A;
- Paquola, Apuã CM;
- Singer, Tatjana;
- Gallina, Iryna;
- Novotny, Mark;
- Quayle, Carolina;
- Bedrosian, Tracy A;
- Alves, Francisco IA;
- Butcher, Cheyenne R;
- Herdy, Joseph R;
- Sarkar, Anindita;
- Lasken, Roger S;
- Muotri, Alysson R;
- Gage, Fred H
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.