- [NATURE] Widespread somatic L1 retrotransposition in normal colorectal epithelium
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- 2024-07-03 15:56:41|
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- 2024-07-03 15:56:41|
[Title]
Widespread somatic L1 retrotransposition in normal colorectal epithelium
[Author]
Chang Hyun Nam1,10, Jeonghwan Youk1,2,3,10, Jeong Yeon Kim2 , Joonoh Lim1,2, Jung Woo Park4 , Soo A Oh1 , Hyun Jung Lee3 , Ji Won Park5 , Hyein Won1 , Yunah Lee1 , Seung-Yong Jeong5 , Dong-Sung Lee6 , Ji Won Oh7,8, Jinju Han1 , Junehawk Lee4 , Hyun Woo Kwon9 , Min Jung Kim5 & Young Seok Ju1,2
1 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
2 Genome Insight, Inc., Daejeon, Republic of Korea.
3 Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
4 Korea Institute of Science and Technology Information, Daejeon, Republic of Korea.
5 Department of Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea.
6 Department of Life Science, University of Seoul, Seoul, Republic of Korea.
7 Department of Anatomy, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
8 Department of Anatomy, Yonsei University College of Medicine, Seoul, Republic of Korea.
9 Department of Nuclear Medicine, Korea University College of Medicine, Seoul, Republic of Korea.
[Journal]
Nature volume 617, pages540–547 (2023)
[Abstract]
Throughout an individual’s lifetime, genomic alterations accumulate in somatic cells1,2,3,4,5,6,7,8,9,10,11. However, the mutational landscape induced by retrotransposition of long interspersed nuclear element-1 (L1), a widespread mobile element in the human genome12,13,14, 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.
Widespread somatic L1 retrotransposition in normal colorectal epithelium
[Author]
Chang Hyun Nam1,10, Jeonghwan Youk1,2,3,10, Jeong Yeon Kim2 , Joonoh Lim1,2, Jung Woo Park4 , Soo A Oh1 , Hyun Jung Lee3 , Ji Won Park5 , Hyein Won1 , Yunah Lee1 , Seung-Yong Jeong5 , Dong-Sung Lee6 , Ji Won Oh7,8, Jinju Han1 , Junehawk Lee4 , Hyun Woo Kwon9 , Min Jung Kim5 & Young Seok Ju1,2
1 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
2 Genome Insight, Inc., Daejeon, Republic of Korea.
3 Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
4 Korea Institute of Science and Technology Information, Daejeon, Republic of Korea.
5 Department of Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea.
6 Department of Life Science, University of Seoul, Seoul, Republic of Korea.
7 Department of Anatomy, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
8 Department of Anatomy, Yonsei University College of Medicine, Seoul, Republic of Korea.
9 Department of Nuclear Medicine, Korea University College of Medicine, Seoul, Republic of Korea.
[Journal]
Nature volume 617, pages540–547 (2023)
[Abstract]
Throughout an individual’s lifetime, genomic alterations accumulate in somatic cells1,2,3,4,5,6,7,8,9,10,11. However, the mutational landscape induced by retrotransposition of long interspersed nuclear element-1 (L1), a widespread mobile element in the human genome12,13,14, 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.