X-chromosome inactivation draws L1 mutagenesis to the human X chromosome
X-chromosome inactivation (XCI) enables gene dosage compensation in XX eutherians. Long interspersed element-1 (LINE-1 or L1) retrotransposons are unusually abundant on the human X chromosome and are hypothesized to facilitate XCI. Here, we used long-read DNA sequencing to conduct a haplotype-aware analysis of engineered L1 integration preferences in the PA-1 human embryonic carcinoma cell line. Crucially, clonal XCI in PA-1 cells enabled derivation of active (Xa) and inactive (Xi) X-chromosome haplotypes. L1 integration strongly favored the Xi and other genomic regions that undergo DNA replication late in S-phase. These results suggest that the X chromosome is L1 rich because of XCI and imply that L1 integration preference for the Xi in XX individuals could potentially double the frequency of X-linked pathogenic L1 mutations in their XY descendants.
Authors
- Trung Viet Nguyen (ORCID: https://orcid.org/0000-0002-1749-8509)
- Barun Pradhan (ORCID: https://orcid.org/0000-0001-6016-4443)
- John V. Moran (ORCID: https://orcid.org/0000-0002-5308-4864)
- Diane A. Flasch (ORCID: https://orcid.org/0000-0003-4825-2621)
- Adam D. Ewing (ORCID: https://orcid.org/0000-0002-4544-994X)
- Thomas E. Wilson (ORCID: https://orcid.org/0000-0002-8345-4985)
- Sara R. Heras (ORCID: https://orcid.org/0000-0003-1677-7685)
- Geoffrey J. Faulkner (ORCID: https://orcid.org/0000-0001-5769-4494)
- Natasha Jansz (ORCID: https://orcid.org/0000-0002-3319-8493)
- Ryan Lister (ORCID: https://orcid.org/0000-0001-6637-7239)
- Juan M. Botto (ORCID: https://orcid.org/0009-0007-8409-2203)
- Francisco J. Sánchez‐Luque (ORCID: https://orcid.org/0000-0003-1138-6124)
- Charles C. Bell (ORCID: https://orcid.org/0000-0003-2194-8311)
- Ana Colomer-Boronat (ORCID: https://orcid.org/0000-0003-2507-1748)
- Darwin J. Da Costa Guevara
- Jose de Los Rios Barreda (ORCID: https://orcid.org/0009-0003-6069-6847)
- Maria E. Ferreiro (ORCID: https://orcid.org/0000-0001-6077-986X)
- Sabrina Gericke
- Minchun Chen
Institutions
- Australian Research Council (AU)
- The University of Queensland (AU)
- Universidad de Granada (ES)
- University of Michigan (US)
- Harry Perkins Institute of Medical Research (AU)
- Mater Research (AU)
- Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research (ES)
- Instituto de Parasitología y Biomedicina "López - Neyra" (ES)
Publication Details
- Journal
- Science
- Published
- 2026-07-30
- DOI
- https://doi.org/10.1126/science.adz8081
- Citations
- 1
- Primary Topic
- Chromosomal and Genetic Variations
- Type
- article
- Field-Weighted Citation Impact
- 6.12
Funders
- Ministerio de Ciencia e Innovación
- National Institutes of Health
- Australian Research Council
- National Health and Medical Research Council