Throughout an individual’s lifetime, genomic alterations accumulate in somatic cells. However, the mutational landscape induced by retrotransposition of long interspersed nuclear element-1 (L1), a widespread mobile element in the human genome, is poorly understood in normal cells. With an intensive exploration of genome sequences of single-cells, this study illustrates L1 retrotransposition-induced somatic mosaicism in normal cells and provides insight into the genomic and epigenomic regulation of transposable elements over the human lifetime.

The lab of COSMOS (Comprehensive Observation of Somatic Mosaicism, its Origins and Significance) at the Graduate School of Medical Science and Engineering conducted a groundbreaking study targeting ‘jumping genes’ in the entire genomes of the human large intestine. Published in Nature on May 18 2023, the research unveils the surprising activity of ‘Long interspersed nuclear element-1 (L1)’, a type of jumping gene previously thought to be mostly dormant in human genomes. The study shows that L1 genes can become activated and disrupt genomic functions throughout an individual’s lifetime, particularly in the colorectal epithelium.

The approximately 500,000 L1 jumping genes, accounting for 17% of the human genome, have long been recognized for their contribution to the evolution of the human species by introducing ‘disruptive innovation’ to genome sequences. Until now, it was believed that most L1 elements had lost their ability to jump in normal tissues of modern humans. However, this study reveals that some L1 jumping genes can be widely activated in normal cells, leading to the accumulation of genomic mutations over an individual’s lifetime. The rates of L1 jumping and resulting genomic changes vary among different cell types, with a notable concentration observed in aged colon epithelial cells and an almost absence in the fibroblasts and blood cells. This study illustrates that every colonic epithelial cell experiences an L1 jumping event by age 30 on average.

The research, led by co-first authors Chang Hyun Nam (a graduate student) and Dr. Jeonghwan Youk (currently an assistant clinical professor at Seoul National University Hospital), involved an analysis of whole-genome sequences from 899 single cells obtained from skin (fibroblasts), blood, and colon epithelial tissues collected from 28 individuals. The study uncovered the mobilization of L1 jumping genes in normal cells, resulting in the gradual accumulation of genomic mutations over time. Additionally, the team explored epigenomic (DNA methylation) sequences to understand the mechanism behind L1 jumping gene activation. They found that cells with activated L1 jumping genes exhibited epigenetic instabilities that arose during the early stages of embryogenesis. The study provides valuable insight into the aging process and the development of diseases in human colorectal tissues.

“This study illustrates that genomic damage in normal cells is acquired not only through exposure to carcinogens but also through the activity of endogenous components whose impact was previously unclear. Genomes of apparently healthy aged cells, particularly in the colorectal epithelium, become mosaic due to the activity of L1 jumping genes,” said Prof. Young Seok Ju, the principal investigator of the COSMOS lab.

“We emphasize the essential and ongoing collaboration among researchers in clinical medicine and basic medical sciences,” said Prof. Min Jung Kim of the Department of Surgery at Seoul National University Hospital. “This case highlights the critical role of systematically collected human tissues from clinical settings in unraveling the complex process of disease development in humans.”

“I am delighted that the research team’s advancements in single-cell genome technology have come to fruition. We will persistently strive to lead in single-cell genome technology,” said Prof. Hyun Woo Kwon of the Department of Nuclear Medicine at Korea University School of Medicine.

The research team received support from the Research Leader Program and the Young Researcher Program of the National Research Foundation of Korea, a grant from the MD-PhD/Medical Scientist Training Program through the Korea Health Industry Development Institute, and the Suh Kyungbae Foundation.

#LINE-1 retrotransposon #somatic mosaicism #genome #sequencing #mutation

Web address for full article : https://www.nature.com/articles/s41586-023-06046-z

the Name of Journal : Nature

Laboratory web-address of the author : https://www.julab.kaist.ac.kr