Structural features of somatic and germline retrotransposition events in humans

Päivi Nummi; Tatiana Cajuso; Tuukka Norri; Aurora Taira; Heli Kuisma; Niko Välimäki; Anna Lepistö; Laura Renkonen-Sinisalo; Selja Koskensalo; Toni T Seppälä; Ari Ristimäki; Kyösti Tahkola; Anne Mattila; Jan Böhm; Jukka-Pekka Mecklin; Emma Siili; Annukka Pasanen; Oskari Heikinheimo; Ralf Bützow; Auli Karhu; Kathleen H Burns; Kimmo Palin; Lauri A Aaltonen

doi:10.1186/s13100-025-00357-w

Structural features of somatic and germline retrotransposition events in humans

Mob DNA. 2025 Apr 22;16(1):20. doi: 10.1186/s13100-025-00357-w.

Authors

Päivi Nummi^{1

2}, Tatiana Cajuso^{3

4}, Tuukka Norri^{1

2

5}, Aurora Taira^{1

2}, Heli Kuisma^{1

2}, Niko Välimäki^{1

2}, Anna Lepistö⁶, Laura Renkonen-Sinisalo⁶, Selja Koskensalo⁶, Toni T Seppälä^{1

7

8

9

10}, Ari Ristimäki^{1

11}, Kyösti Tahkola¹², Anne Mattila¹², Jan Böhm¹², Jukka-Pekka Mecklin^{13

14}, Emma Siili¹¹, Annukka Pasanen¹¹, Oskari Heikinheimo¹⁵, Ralf Bützow^{11

15}, Auli Karhu^{1

2}, Kathleen H Burns^{4

16}, Kimmo Palin^{17

18

19}, Lauri A Aaltonen^{1

2

10}

Affiliations

¹ Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, 00014, Finland.
² Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, 00014, Finland.
³ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00014, Helsinki, Finland.
⁴ Department of Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA.
⁵ Department of Computer Science, University of Helsinki, Helsinki, 00014, Finland.
⁶ Department of Gastrointestinal Surgery, Helsinki University Central Hospital, University of Helsinki, Helsinki, 00290, Finland.
⁷ Faculty of Medicine and Health Technology, University of Tampere and TAYS Cancer Centre, Tampere, 33100, Finland.
⁸ Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, 33520, Finland.
⁹ Abdominal Center, Helsinki University Hospital, Helsinki University, Helsinki, 00290, Finland.
¹⁰ iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Helsinki, 00290, Finland.
¹¹ Department of Pathology, HUS Diagnostic Center, Helsinki University Hospital and University of Helsinki, Helsinki, 00290, Finland.
¹² Department of Surgery, Wellbeing Services County of Central Finland / Hospital Nova of Central Finland, Jyväskylä, 40620, Finland.
¹³ Department of Science, Well Being Services County of Central Finland, Jyväskylä, 40620, Finland.
¹⁴ Department of Health Sciences, Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, 40014, Finland.
¹⁵ Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, 00290, Finland.
¹⁶ Department of Pathology, Mass General Brigham and Harvard Medical School, Boston, MA, 02115, USA.
¹⁷ Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, 00014, Finland. kimmo.palin@helsinki.fi.
¹⁸ Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, 00014, Finland. kimmo.palin@helsinki.fi.
¹⁹ iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Helsinki, 00290, Finland. kimmo.palin@helsinki.fi.

Abstract

Background: Transposons are DNA sequences able to move or copy themselves to other genomic locations leading to insertional mutagenesis. Although transposon-derived sequences account for half of the human genome, most elements are no longer transposition competent. Moreover, transposons are normally repressed through epigenetic silencing in healthy adult tissues but become derepressed in several human cancers, with high activity detected in colorectal cancer. Their impact on non-malignant and malignant tissue as well as the differences between somatic and germline retrotransposition remain poorly understood. With new sequencing technologies, including long read sequencing, we can access intricacies of retrotransposition, such as insertion sequence details and nested repeats, that have been previously challenging to characterize.

Results: In this study, we investigate somatic and germline retrotransposition by analyzing long read sequencing from 56 colorectal cancers and 112 uterine leiomyomas. We identified 1495 somatic insertions in colorectal samples, while striking lack of insertions was detected in uterine leiomyomas. Our findings highlight differences between somatic and germline events, such as transposon type distribution, insertion length, and target site preference. Leveraging long-read sequencing, we provide an in-depth analysis of the twin-priming phenomenon, detecting it across transposable element types that remain active in humans, including Alus. Additionally, we detect an abundance of germline transposons in repetitive DNA, along with a relationship between replication timing and insertion target site.

Conclusions: Our study reveals a stark contrast in somatic transposon activity between colorectal cancers and uterine leiomyomas, and highlights differences between somatic and germline transposition. This suggests potentially different conditions in malignant and non-malignant tissues, as well as in germline and somatic tissues, which could be involved in the transposition process. Long-read sequencing provided important insights into transposon behavior, allowing detailed examination of structural features such as twin priming and nested elements.

Keywords: Colorectal cancer; L1; Long read sequencing; Retrotransposition; Transposable element; Uterine leiomyoma.