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

Science 2026

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Authors: Jose de Los Rios Barreda, Maria E. Ferreiro, Natasha Jansz, Charles C. Bell, Juan Manuel Botto, Trung Viet Nguyen, Barun Pradhan, Minchun Chen, Ana Colomer-Boronat, Darwin J. Da Costa Guevara, Diane A. Flasch, Sabrina Gericke
+7 more Thomas E. Wilson, Adam D. Ewing, Sara R. Heras, Francisco Jose Sanchez-Luque, Ryan Lister, John V. Moran, Geoffrey J. Faulkner
DOI: 10.1126/science.adz8081
Cited by: 1
References: 160

Abstract

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.

Fields of Study & Subjects

Chromosomal and Genetic Variations Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities CRISPR and Genetic Engineering

Publication details

Journal / source
Science
Publisher
American Association for the Advancement of Science (AAAS)
Volume
393
Issue
6810
Pages
eadz8081–eadz8081
Publication date
30 July 2026
Language
EN