Heritable L1 retrotransposition in the mouse primordial germline and early embryo (original) (raw)

1. Patricia Gerdes1,
2. Daniel J. Gerhardt1,2,
3. Francisco J. Sanchez-Luque1,3,
4. Gabriela-Oana Bodea1,
5. Martin Muñoz-Lopez3,
6. J. Samuel Jesuadian1,
7. Marie-Jeanne H.C. Kempen1,
8. Patricia E. Carreira1,
9. Jeffrey A. Jeddeloh4,
10. Jose L. Garcia-Perez3,5,
11. Haig H. Kazazian Jr.6,
12. Adam D. Ewing1 and
13. Geoffrey J. Faulkner1,7,8
14. 1Mater Research Institute–University of Queensland, Woolloongabba QLD 4102, Australia;
15. 2Invenra, Incorporated, Madison, Wisconsin 53719, USA;
16. 3Department of Genomic Medicine, GENYO, Centre for Genomics and Oncological Research, Pfizer–University of Granada–Andalusian Regional Government, PTS Granada, 18016 Granada, Spain;
17. 4Roche Sequencing Solutions, Incorporated, Madison, Wisconsin 53719, USA;
18. 5Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom;
19. 6Institute of Genetic Medicine and Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
20. 7School of Biomedical Sciences,
21. 8Queensland Brain Institute, University of Queensland, Brisbane QLD 4072, Australia

• Corresponding authors: sandra.richardson{at}mater.uq.edu.au, faulknergj{at}gmail.com

Abstract

LINE-1 (L1) retrotransposons are a noted source of genetic diversity and disease in mammals. To expand its genomic footprint, L1 must mobilize in cells that will contribute their genetic material to subsequent generations. Heritable L1 insertions may therefore arise in germ cells and in pluripotent embryonic cells, prior to germline specification, yet the frequency and predominant developmental timing of such events remain unclear. Here, we applied mouse retrotransposon capture sequencing (mRC-seq) and whole-genome sequencing (WGS) to pedigrees of C57BL/6J animals, and uncovered an L1 insertion rate of ≥1 event per eight births. We traced heritable L1 insertions to pluripotent embryonic cells and, strikingly, to early primordial germ cells (PGCs). New L1 insertions bore structural hallmarks of target-site primed reverse transcription (TPRT) and mobilized efficiently in a cultured cell retrotransposition assay. Together, our results highlight the rate and evolutionary impact of heritable L1 retrotransposition and reveal retrotransposition-mediated genomic diversification as a fundamental property of pluripotent embryonic cells in vivo.

Footnotes

• [Supplemental material is available for this article.]

• Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.219022.116.

• Freely available online through the Genome Research Open Access option.

• Received December 4, 2016.

• Accepted May 2, 2017.

• © 2017 Richardson et al.; Published by Cold Spring Harbor Laboratory Press

This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.