Massively parallel jumping assay decodes Alu retrotransposition activity
The human genome contains millions of copies of retrotransposons that are silenced but many of these copies have potential to become active if mutated, having phenotypic consequences, including disease. However, it is not thoroughly understood how nucleotide changes in retrotransposons affect their jumping activity. Here, we develop a massively parallel jumping assay (MPJA) that tests the jumping potential of thousands of transposons en masse. We generate a nucleotide variant library of four Alu retrotransposons containing 165,087 different haplotypes and test them for their jumping ability using MPJA. We found 66,821 unique jumping haplotypes, allowing us to pinpoint domains and variants vital for transposition. Mapping these variants to the Alu-RNA secondary structure revealed stem-loop features that contribute to jumping potential. Combined, our work provides a high-throughput assay that assesses the ability of retrotransposons to jump and identifies nucleotide changes that have the potential to reactivate them in the human genome.
Authors
- Jasmine Sims
- Ajuni Sohota (ORCID: https://orcid.org/0000-0003-2874-8099)
- Sawitree Rattanasopha (ORCID: https://orcid.org/0000-0002-3901-101X)
- Kelly An
- Lucia Carbone (ORCID: https://orcid.org/0000-0002-2118-107X)
- Zizheng Li (ORCID: https://orcid.org/0000-0002-6953-7733)
- Thomas J. Meyer (ORCID: https://orcid.org/0000-0002-7185-5597)
- Martin Kircher (ORCID: https://orcid.org/0000-0001-9278-5471)
- Nadav Ahituv (ORCID: https://orcid.org/0000-0002-7434-8144)
- Navneet Matharu (ORCID: https://orcid.org/0000-0002-9426-1484)
- Linbei Deng
- Yan Hung
- Jingjing Zhao (ORCID: https://orcid.org/0000-0002-4298-8817)
Institutions
- Oregon National Primate Research Center (US)
- Leidos (United States) (US)
- Oregon Health & Science University (US)
- University of California, San Francisco (US)
- Frederick National Laboratory for Cancer Research (US)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- University of Lübeck (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-08
- DOI
- https://doi.org/10.1038/s41467-025-59347-4
- Citations
- 2
- Primary Topic
- Chromosomal and Genetic Variations
- Type
- article
- Field-Weighted Citation Impact
- 3.50
Funders
- Innovative Genomics Institute
- National Human Genome Research Institute
- National Institute of General Medical Sciences