L1-associated genomic regions are deleted in somatic cells of the healthy human brain
Open accessAbstract
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.
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Retrotransposition during development or adulthood leads to somatic mosaicism and has been estimated in adult neurons at varying but generally low frequencies.
“Retrotransposition during development or adulthood would lead to somatic mosaicism, and has been estimated to occur in adult neurons by qPCR or single-cell genomic studies at varying (but generally low) frequencies (events/cell): < 0.04–0.680, 13.781, 0.58–182, 0.283 and 0.63–1.6684.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [82]
The Introduction reports that L1 retrotransposition creates somatic mosaicism and gives conflicting estimates of L1 insertions in neurons. The section on L1-associated variants estimates 0.58–1 events per cell, but says approximately half of those variants may occur independently of retrotransposition. That estimate therefore cannot be attributed wholly to retrotransposition. (LLM, conf=0.88)
Experimental — accuracy not yet measuredLINE/Alu retro-mobility is a normal part of specific synaptic neuronal brain development.
“So as discussed already LINE/Alu retro-mobility now appears as a normal part of speci fi c synaptic neuronal Brain development (Erwin et al., 2016).”
From Cause of Cambrian Explosion - Terrestrial or Cosmic? (2018) · cites this paper as Erwin et al., 2016
LINE retro-element transposition, and Alu repeat element co-mobility, is a normal part of genomic rearrangement during specific neuron commitment.
“Indeed LINE retro-element transposition (and Alu repeat element co-mobility, Appendix B) is a normal part of genomic rearrangement during speci fi c neuron commitment, much like the V-> DJ rearrangement in speci fi c B and T lymphocyte commitment in the Immune System (Erwin et al., 2016).”
From Cause of Cambrian Explosion - Terrestrial or Cosmic? (2018) · cites this paper as Erwin et al., 2016
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“We do not have evidence from our studies that TDP-43 pathology is associated with retrotransposition per se, although retrotransposition has been observed in neuronal cells (Baillie et al., 2011; Erwin et al., 2016; Evrony et al., 2012, 2015, 2016; Faulkner and Garcia-Perez, 2017; Macia et al., 2017; Up-ton et al., 20…”
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- Authors
- Erwin, J. A., Paquola, A. C. M., Singer, T., Gallina, I., Novotny, M., Quayle, C., Bedrosian, T. A., Alves, F. I. A., Butcher, C. R., Herdy, J. R., Sarkar, A., Lasken, R. S., Muotri, A. R., & Gage, F. H.
- Affiliations
- Salk Institute for Biological Studies (US)
- J. Craig Venter Institute (US)
- Universidade de São Paulo (BR)
- University of California San Diego (US)
- Corresponding author
- Gage, Fred H
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2016-09-12
- Volume
- 19
- Issue
- 12
- Pages
- 1583-1591
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC5127747
- OpenAlex
- W2519643400
- Cited by
- 195
- References
- 41
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 15 · 2023: 10 · 2022: 17 · 2021: 24 · 2020: 27 · 2019: 22 · 2018: 28 · 2017: 26 · 2016: 5
- FWCI
- 21.79
- Type
- journal article
- Language
- en
- Update notices
- Open access
- green
- europepmc.org
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute for Materials Science
- National Institute of Mental Health (R01MH088485, U01MH106882, R01MH095741)
- National Cancer Institute (T32CA009370, P30CA014195)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- somatic mosaicism, LINE-1 retrotransposition, somatic deletions, single-cell sequencing, DLG2, human brain
- MeSH terms
- Brain, Cells, Cultured, Humans, Neurons, Sequence Deletion, Gene Dosage, Long Interspersed Nucleotide Elements, Genomics, Genome-Wide Association Study
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