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

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

Research output: Contribution to journalArticlepeer-review

86 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1583-1591
Number of pages9
JournalNature neuroscience
Issue number12
StatePublished - Dec 1 2016
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)


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