X-chromosome inactivation draws L1 mutagenesis to the human X chromosome

• 成果类型: Article
• 署名作者: de los Rios Barreda, Jose; Ferreiro, Maria E.; Jansz, Natasha; Bell, Charles C.; Botto, Juan M.; Nguyen, Trung V.; Pradhan, Barun; Chen, Minchun; Colomer-Boronat, Ana; Da Costa Guevara, Darwin J.; Flasch, Diane A.; Gericke, Sabrina; Wilson, Thomas E.; Ewing, Adam D.; Heras, Sara R.; Sanchez-Luque, Francisco J.; Lister, Ryan; Moran, John V.; Faulkner, Geoffrey J.
• 署名单位: University of Queensland; Mater Research; University of Queensland; Harry Perkins Institute of Medical Research; University of Granada; Pfizer; Pfizer Spain; University of Granada; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Instituto de Parasitologia y Biomedicina Lopez-Neyra (IPBLN); University of Michigan System; University of Michigan
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adz8081
• 发表日期: 2026-07-30
• 页码: eadz8081
• 关键词: embryonic stem-cells; LINE-1 RETROTRANSPOSITION; gene-expression; transposable elements; sequence; replication; dna; methylation; chromatin; mouse

摘要

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.