研究组进行了长读DNA测序，对PA-1人胚胎癌细胞系的工程L1整合偏好进行了单倍型感知分析。关键是，PA-1细胞中的克隆XCI能够衍生出活性（Xa）和非活性（Xi） X染色体单倍型。L1整合强烈支持在S期后期进行DNA复制的Xi和其他基因组区域。这些结果表明，由于XCI， X染色体富含L1，这意味着XX个体对Xi的L1整合偏好可能会使其XY后代中X连锁致病性L1突变的频率增加一倍。
据悉，X染色体失活（XCI）使XX真兽的基因剂量补偿得以实现。长穿插元件-1 （LINE-1或L1）反转录转座子在人类X染色体上异常丰富，并被认为促进XCI。
附：英文原文
Title: X-chromosome inactivation draws L1 mutagenesis to the human X chromosome
Author: Jose de los Rios Barreda, Maria E. Ferreiro, Natasha Jansz, Charles C. Bell, Juan M. Botto, Trung V. Nguyen, Barun Pradhan, Minchun Chen, Ana Colomer-Boronat, Darwin J. Da Costa Guevara, Diane A. Flasch, Sabrina Gericke, Thomas E. Wilson, Adam D. Ewing, Sara R. Heras, Francisco J. Sanchez-Luque, Ryan Lister, John V. Moran, Geoffrey J. Faulkner
Issue&Volume: 2026-07-30
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.
DOI: adz8081
Source: https://www.science.org/doi/10.1126/science.adz8081