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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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