Engineered LINE-1 retrotransposition in nondividing human neurons

¹Department of Genomic Medicine and Centre for Genomics and Oncology (Pfizer—University of Granada and Andalusian Regional Government), PTS Granada, 18016 Granada, Spain;
²Department of Oncology, GENYO, Centre for Genomics and Oncology (Pfizer—University of Granada and Andalusian Regional Government), PTS Granada, 18016 Granada, Spain;
³Unidad de Biotecnología Celular, ISCIII, Madrid, E-28021, Spain;
⁴Josep Carreras Leukemia Research Institute, Department of Biomedicine, School of Medicine, University of Barcelona, Instituciò Catalana Recerca Estudis Avançats (ICREA), 08036 Barcelona, Spain;
⁵Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA;
⁶Department of Pediatrics/Rady Children's Hospital San Diego, University of California San Diego, La Jolla, California 92093, USA;
⁷McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
⁸Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom

Corresponding authors:amaciaortega{at}ucsd.edu,jose.garcia-perez{at}igmm.ed.ac.uk

↵9 These authors contributed equally to this work.

↵10 Present address: Department of Pediatrics/Rady Children's Hospital San Diego, University of California San Diego, La Jolla, CA 92093, USA

Abstract

Half the human genome is made of transposable elements (TEs), whose ongoing activity continues to impact our genome. LINE-1 (or L1) is an autonomous non-LTR retrotransposon in the human genome, comprising 17% of its genomic mass and containing an average of 80–100 active L1s per average genome that provide a source of inter-individual variation. New LINE-1 insertions are thought to accumulate mostly during human embryogenesis. Surprisingly, the activity of L1s can further impact the somatic human brain genome. However, it is currently unknown whether L1 can retrotranspose in other somatic healthy tissues or if L1 mobilization is restricted to neuronal precursor cells (NPCs) in the human brain. Here, we took advantage of an engineered L1 retrotransposition assay to analyze L1 mobilization rates in human mesenchymal (MSCs) and hematopoietic (HSCs) somatic stem cells. Notably, we have observed that L1 expression and engineered retrotransposition is much lower in both MSCs and HSCs when compared to NPCs. Remarkably, we have further demonstrated for the first time that engineered L1s can retrotranspose efficiently in mature nondividing neuronal cells. Thus, these findings suggest that the degree of somatic mosaicism and the impact of L1 retrotransposition in the human brain is likely much higher than previously thought.

Footnotes

[Supplemental material is available for this article.]
Article published online before print. Article, supplemental material, and publication date are athttp://www.genome.org/cgi/doi/10.1101/gr.206805.116.

ReceivedMarch 9, 2016.
AcceptedDecember 1, 2016.

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