Widespread somatic L1 retrotransposition in normal colorectal epithelium

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.

Locus-specific LINE-1 expression in clinical ovarian cancer specimens at the single-cell level

“…Fibroblasts in healthy fallopian tube samples showed negligible L1 activity, in agreement with previous studies of fibroblasts in the normal epithelium 8 , 9 . Our finding that fibroblasts in tumor samples showed signal in certain L1 loci – validated by RT-PCR for L1-4344 – was thus surprising.…”

“…This was also true for many cases detected both in bulk and scRNA-seq. Even though this finding may be caused by the presence of false-positive loci, emerging evidence indicates that unlike previously thought, L1 activity in certain tissues is not restricted to malignant cells 8 , 9 , and our findings suggest that this is true for normal fallopian tube epithelium as well.…”

“…CAF-specific L1 activity likely reflects the epigenetic dysregulation of fibroblasts residing in the tumor microenvironment. It is also important to note that L1 retrotransposition events has been shown to positively correlate with age 8 , 9 , and the average age of the HGSOC cohort analysed was 67 years.…”

“…L1s are repressed in most normal adult tissues 6 , 7 . However, recent studies have shown L1 activity to also occur in normal epithelia 8 , 9 . Nevertheless, L1 activity is significantly higher in many cancers, especially in those of epithelial origin 6 , 8 , 9 .…”

“…However, recent studies have shown L1 activity to also occur in normal epithelia 8 , 9 . Nevertheless, L1 activity is significantly higher in many cancers, especially in those of epithelial origin 6 , 8 , 9 . One of these cancer types is ovarian cancer 10 – 12 .…”