@article{0be16f2885d74d5b9d18dbf39d3f1fc3,
title = "Somatic LINE-1 retrotransposition in cortical neurons and non-brain tissues of Rett patients and healthy individuals",
abstract = "Mounting evidence supports that LINE-1 (L1) retrotransposition can occur postzygotically in healthy and diseased human tissues, contributing to genomic mosaicism in the brain and other somatic tissues of an individual. However, the genomic distribution of somatic human-specific LINE-1 (L1Hs) insertions and their potential impact on carrier cells remain unclear. Here, using a PCR-based targeted bulk sequencing approach, we profiled 9,181 somatic insertions from 20 postmortem tissues from five Rett patients and their matched healthy controls. We identified and validated somatic L1Hs insertions in both cortical neurons and non-brain tissues. In Rett patients, somatic insertions were significantly depleted in exons—mainly contributed by long genes—than healthy controls, implying that cells carrying MECP2 mutations might be defenseless against a second exonic L1Hs insertion. We observed a significant increase of somatic L1Hs insertions in the brain compared with non-brain tissues from the same individual. Compared to germline insertions, somatic insertions were less sense-depleted to transcripts, indicating that they underwent weaker selective pressure on the orientation of insertion. Our observations demonstrate that somatic L1Hs insertions contribute to genomic diversity and MeCP2 dysfunction alters their genomic patterns in Rett patients.",
author = "Boxun Zhao and Qixi Wu and Ye, {Adam Yongxin} and Jing Guo and Xianing Zheng and Xiaoxu Yang and Linlin Yan and Liu, {Qing Rong} and Hyde, {Thomas M.} and Liping Wei and Huang, {August Yue}",
note = "Funding Information: This study was supported by the National Natural Science Foundation of China (31530092) and the Ministry of Science and Technology 863 Grant (2015AA020108). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We acknowledge the UMB Brain and Tissue Bank (University of Maryland, Baltimore, MD) and the Lieber Institute for Brain Development (Baltimore, MD) for providing postmortem human tissues. We are grateful to Drs Eunjung Alice Lee, Daniel R. Weinberger, Li-Lin Du, Meng-Qiu Dong, Yu Zhang, Ge Gao, Louis Tao, Cheng Li, Jian Lu, and Manyuan Long for their insightful comments and suggestions. We thank Drs Kazuya Iwamoto and Miki Bundo for providing detailed protocols of nuclei isolation. We thank Dr. Timothy W. Yu for providing experimental resources in the revision. We thank the reviewers for constructive feedback on the manuscript. Q-R.L. was supported in part by the Intramural Research Program at the National Institute on Aging, NIH. Publisher Copyright: Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.",
year = "2019",
doi = "10.1371/journal.pgen.1008043",
language = "English (US)",
volume = "15",
journal = "PLoS Genetics",
issn = "1553-7390",
publisher = "Public Library of Science",
number = "4",
}