L1 retrotransposition in human neural progenitor cells
Open accessAbstract
Long interspersed element 1 (LINE-1 or L1) retrotransposons have markedly affected the human genome. L1s must retrotranspose in the germ line or during early development to ensure their evolutionary success, yet the extent to which this process affects somatic cells is poorly understood. We previously demonstrated that engineered human L1s can retrotranspose in adult rat hippocampus progenitor cells in vitro and in the mouse brain in vivo. Here we demonstrate that neural progenitor cells isolated from human fetal brain and derived from human embryonic stem cells support the retrotransposition of engineered human L1s in vitro. Furthermore, we developed a quantitative multiplex polymerase chain reaction that detected an increase in the copy number of endogenous L1s in the hippocampus, and in several regions of adult human brains, when compared to the copy number of endogenous L1s in heart or liver genomic DNAs from the same donor. These data suggest that de novo L1 retrotransposition events may occur in the human brain and, in principle, have the potential to contribute to individual somatic mosaicism.
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Retrotransposition frequencies in tissues other than brain appear significantly lower, and the adult human brain might be a particularly permissive site for L1 activation.
“While retrotransposition frequencies in other tissues have not been investigated in detail, they appear to be significantly lower, and hence the adult human brain might be a particularly permissive site for L1 activation84, 85.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [85]
The tissue-comparison passage (indexed as Abstract; page unavailable) reports significantly higher L1 ORF2 copy number in adult brain samples than in matched heart and liver samples, consistent with the suggestion that brain might be more permissive. But the paper did not measure retrotransposition frequencies across tissues, and its discussion says new events must be identified to establish that endogenous L1s retrotranspose in the brain. The frequency claim therefore goes beyond the evidence. (LLM, conf=0.84)
Experimental — accuracy not yet measuredRetrotransposition occurs more frequently in the brain, and in particular in the hippocampus and striatum, relative to other somatic tissues such as blood, heart and liver.
“Several other reports have indicated that retrotransposition occurs more frequently in the brain, and in particular in the hippocampus and striatum, relative to other somatic tissues, such as blood, heart and liver45,46.”
From SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age (2014) · cites this paper as [46]
The adult-tissue comparison (section labelled Abstract; page unavailable) found higher L1 ORF2 copy number in the hippocampus than in matched heart and liver, and a smaller increase across grouped brain regions. It included the caudate among sampled regions, but did not establish a separate striatal increase or compare brain tissue with blood. The authors also describe increased copy number as suggestive of retrotransposition, not proof that it occurs more frequently in the adult brain. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe corrected RC-seq retrotransposition rate is consistent with rates measured in vitro in neuronal progenitors.
“This corrected rate is consistent with rates measured in vitro in neuronal progenitors (Coufal et al., 2009)”
From Resolving rates of mutation in the brain using single-neuron genomics (2016) · cites this paper as Coufal et al., 2009
Mutations driven by L1 mediated retrotransposition appear to occur in normal brain development.
“For example, mutations driven by L1 mediated retrotransposition, in which mobile elements relocate throughout the genome to inactivate genes and alter their expression profile, appear to occur in normal brain development.”
From The Cellular and Molecular Landscapes of the Developing Human Central Nervous System (2016) · cites this paper as Coufal et al., 2009
Somatic mutations and mobile DNA elements play a role in generation of diversity and complexity in developing human brain.
“Recent studies have also shown that somatic mutations and mobile DNA elements play a role in the generation of diversity and complexity in the developing human brain (Coufal et al., 2009).”
From The Cellular and Molecular Landscapes of the Developing Human Central Nervous System (2016) · cites this paper as Coufal et al., 2009
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Repetitive elements in aging and neurodegeneration
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euL1db: the European database of L1HS retrotransposon insertions in humans
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- Authors
- Coufal, N. G., Garcia-Perez, J. L., Peng, G. E., Yeo, G. W., Mu, Y., Lovci, M. T., Morell, M., O’Shea, K. S., Moran, J. V., & Gage, F. H.
- Affiliations
- Salk Institute for Biological Studies (US)
- University of Michigan (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Gage, Fred H.
- ORCID
- Venue
- Nature
- Published
- 2009-08
- Volume
- 460
- Issue
- 7259
- Pages
- 1127-1131
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2909034
- OpenAlex
- W2075224242
- Cited by
- 814
- References
- 28
- Citations by year
- 2026: 20 · 2025: 23 · 2024: 34 · 2023: 39 · 2022: 38 · 2021: 37 · 2020: 41 · 2019: 59 · 2018: 52 · 2017: 65 · 2016: 61 · 2015: 49 · 2014: 45 · 2013: 69 · 2012: 66
- FWCI
- 73.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Institutional Repository of the University of Granada (University of Granada) (submittedVersion, cc-by-nc-nd)
- Funders
- Howard Hughes Medical Institute
- National Institute of Mental Health (MH082070, R56MH082070)
- National Institute of General Medical Sciences (GM082970, R01GM082970, P20GM069985, R01GM060518, GM-069985)
- National Institute of Neurological Disorders and Stroke (NS 048187, R01NS048187)
- Topics
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- LINE-1 retrotransposons, retrotransposition, neural progenitor cells, human embryonic stem cells, somatic mosaicism, hippocampus, human brain, transposable elements
- MeSH terms
- Brain, Cell Line, Fetus, Humans, Neurons, Polymerase Chain Reaction, Retroelements, Gene Dosage, DNA Methylation, 5' Untranslated Regions, Chromatin Immunoprecipitation, Embryonic Stem Cells
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