Widespread somatic L1 retrotransposition in normal colorectal epithelium

Chang Hyun Nam, Jeonghwan Youk, Jeong Yeon Kim, Joonoh Lim, Jung Woo Park, Soo A Oh, Hyun Jung Lee, Ji Won Park, Hyein Won, Yunah Lee, Seung-Yong Jeong, Dong-Sung Lee, Ji Won Oh, Jinju Han, Junehawk Lee, Hyun Woo Kwon (), Min Jung Kim () and Young Seok Ju ()
Additional contact information
Chang Hyun Nam: Korea Advanced Institute of Science and Technology
Jeonghwan Youk: Korea Advanced Institute of Science and Technology
Jeong Yeon Kim: Genome Insight, Inc.
Joonoh Lim: Korea Advanced Institute of Science and Technology
Jung Woo Park: Korea Institute of Science and Technology Information
Soo A Oh: Korea Advanced Institute of Science and Technology
Hyun Jung Lee: Seoul National University Hospital
Ji Won Park: Seoul National University College of Medicine
Hyein Won: Korea Advanced Institute of Science and Technology
Yunah Lee: Korea Advanced Institute of Science and Technology
Seung-Yong Jeong: Seoul National University College of Medicine
Dong-Sung Lee: University of Seoul
Ji Won Oh: Kyungpook National University
Jinju Han: Korea Advanced Institute of Science and Technology
Junehawk Lee: Korea Institute of Science and Technology Information
Hyun Woo Kwon: Korea University College of Medicine
Min Jung Kim: Seoul National University College of Medicine
Young Seok Ju: Korea Advanced Institute of Science and Technology

Nature, 2023, vol. 617, issue 7961, 540-547

Abstract: Abstract Throughout an individual’s lifetime, genomic alterations accumulate in somatic cells1–11. However, the mutational landscape induced by retrotransposition of long interspersed nuclear element-1 (L1), a widespread mobile element in the human genome12–14, is poorly understood in normal cells. Here we explored the whole-genome sequences of 899 single-cell clones established from three different cell types collected from 28 individuals. We identified 1,708 somatic L1 retrotransposition events that were enriched in colorectal epithelium and showed a positive relationship with age. Fingerprinting of source elements showed 34 retrotransposition-competent L1s. Multidimensional analysis demonstrated that (1) somatic L1 retrotranspositions occur from early embryogenesis at a substantial rate, (2) epigenetic on/off of a source element is preferentially determined in the early organogenesis stage, (3) retrotransposition-competent L1s with a lower population allele frequency have higher retrotransposition activity and (4) only a small fraction of L1 transcripts in the cytoplasm are finally retrotransposed in somatic cells. Analysis of matched cancers further suggested that somatic L1 retrotransposition rate is substantially increased during colorectal tumourigenesis. In summary, this study illustrates L1 retrotransposition-induced somatic mosaicism in normal cells and provides insights into the genomic and epigenomic regulation of transposable elements over the human lifetime.

Date: 2023
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DOI: 10.1038/s41586-023-06046-z

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