Genome-wide de novo L1 Retrotransposition Connects Endonuclease Activity with Replication
Open accessAbstract
L1 retrotransposon-derived sequences comprise approximately 17% of the human genome. Darwinian selective pressures alter L1 genomic distributions during evolution, confounding the ability to determine initial L1 integration preferences. Here, we generated high-confidence datasets of greater than 88,000 engineered L1 insertions in human cell lines that act as proxies for cells that accommodate retrotransposition in vivo. Comparing these insertions to a null model, in which L1 endonuclease activity is the sole determinant dictating L1 integration preferences, demonstrated that L1 insertions are not significantly enriched in genes, transcribed regions, or open chromatin. By comparison, we provide compelling evidence that the L1 endonuclease disproportionately cleaves predominant lagging strand DNA replication templates, while lagging strand 3'-hydroxyl groups may prime endonuclease-independent L1 retrotransposition in a Fanconi anemia cell line. Thus, acquisition of an endonuclease domain, in conjunction with the ability to integrate into replicating DNA, allowed L1 to become an autonomous, interspersed retrotransposon.
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LINE-1 comprises 17% of the human genome, about 500,000 copies, but only some 100-150 evolutionarily recent copies are full-length and lack mutations expected to affect function.
“LINE-1 (L1) comprises 17% of the human genome (~500,000 copies); however, only some 100–150 evolutionarily recent element copies are full-length and lack mutations that would be expected to affect function10–12.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [11]
The Introduction (page unavailable) states that L1 sequences comprise about 17% of human DNA and that a small number of retrotransposition-competent L1s account for most new insertions. It does not give the claimed ~500,000 total copies or 100–150 evolutionarily recent, full-length copies lacking function-affecting mutations. (LLM, conf=0.86)
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References 91 · Cited by 127
- Authors
- Flasch, D. A., Macia, Á., Sánchez, L., Ljungman, M., Heras, S. R., García-Pérez, J. L., Wilson, T. E., & Moran, J. V.
- Affiliations
- University of Michigan (US)
- Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research (ES)
- Corresponding author
- Flasch, Diane A.
- Wilson, Thomas E.
- Moran, John V.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2019-05
- Volume
- 177
- Issue
- 4
- Pages
- 837-851.e28
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6558663
- OpenAlex
- W2929611872
- Cited by
- 127
- References
- 91
- Citations by year
- 2026: 15 · 2025: 17 · 2024: 13 · 2023: 18 · 2022: 13 · 2021: 21 · 2020: 20 · 2019: 10
- FWCI
- 11.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RISalud Institutional Health Repository of Andalucía (submittedVersion, other-oa)
- Institutional Repository of the University of Granada (University of Granada) (submittedVersion, cc-by-nc-nd)
- Funders
- NIH (HG000040, HG009382, CA200731, GM120767, GM060518, U01MH106892)
- MINECO-FEDER (SAF2017-89745-R)
- European Research Council (ERC-STG-2012-309433)
- Howard Hughes Medical Institut (IECS-55007420)
- 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 › Biochemistry, Genetics and Molecular Biology › Genetics › Genome Rearrangement Algorithms
- Keywords
- LINE-1 retrotransposons, retrotransposition, 3'-hydroxyl group, Fanconi anemia, retrotransposon evolution, human genome
- MeSH terms
- Cell Line, Endonucleases, HeLa Cells, Humans, Genome, Human, Mutagenesis, Insertional, Retroelements, Long Interspersed Nucleotide Elements, Genomics, Genome-Wide Association Study
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