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Cell. 2019 May 2;177(4):837-851.e28. doi: 10.1016/j.cell.2019.02.050. Epub 2019 Apr 4.

Genome-wide de novo L1 Retrotransposition Connects Endonuclease Activity with Replication.

Author information

1
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, 48109, USA. Electronic address: daflasch@umich.edu.
2
Department of Genomic Medicine, GENYO: Centre for Genomics and Oncology (Pfizer-University of Granada and Andalusian Regional Government), PTS Granada, 18016, Spain.
3
Department of Radiation Oncology, University of Michigan Comprehensive Cancer Center, Translational Oncology Program and Center for RNA Biomedicine, University of Michigan, Ann Arbor, Michigan, 48109, USA; Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, Michigan, 48109, USA.
4
Department of Genomic Medicine, GENYO: Centre for Genomics and Oncology (Pfizer-University of Granada and Andalusian Regional Government), PTS Granada, 18016, Spain; Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
5
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, 48109, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, 48109, USA. Electronic address: wilsonte@umich.edu.
6
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, 48109, USA; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, 48109, USA. Electronic address: moranj@umich.edu.

Abstract

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.

KEYWORDS:

DNA replication; Fanconi anemia; LINE-1; chromatin; evolution; human genome; integration; retrotransposon; transcription; transposable element

PMID:
30955886
PMCID:
PMC6558663
[Available on 2020-05-02]
DOI:
10.1016/j.cell.2019.02.050

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