Nummi Päivi, Cajuso Tatiana, Norri Tuukka, Taira Aurora, Kuisma Heli, Välimäki Niko, Lepistö Anna, Renkonen-Sinisalo Laura, Koskensalo Selja, Seppälä Toni T, Ristimäki Ari, Tahkola Kyösti, Mattila Anne, Böhm Jan, Mecklin Jukka-Pekka, Siili Emma, Pasanen Annukka, Heikinheimo Oskari, Bützow Ralf, Karhu Auli, Burns Kathleen H, Palin Kimmo, Aaltonen Lauri A
Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, 00014, Finland.
Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, 00014, Finland.
Mob DNA. 2025 Apr 22;16(1):20. doi: 10.1186/s13100-025-00357-w.
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.
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.
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.
转座子是能够将自身移动或复制到其他基因组位置从而导致插入诱变的DNA序列。尽管转座子衍生序列占人类基因组的一半，但大多数元件已不再具有转座能力。此外，转座子在健康成人组织中通常通过表观遗传沉默受到抑制，但在几种人类癌症中会去抑制，在结直肠癌中检测到其高活性。它们对非恶性和恶性组织的影响以及体细胞和生殖系逆转录转座之间的差异仍知之甚少。借助包括长读长测序在内的新测序技术，我们能够了解逆转录转座的复杂性，例如插入序列细节和嵌套重复序列，而这些在以前很难进行表征。
在本研究中，我们通过分析56例结直肠癌和112例子宫平滑肌瘤的长读长测序来研究体细胞和生殖系逆转录转座。我们在结直肠样本中鉴定出1495个体细胞插入，而在子宫平滑肌瘤中则明显缺乏插入。我们的发现突出了体细胞和生殖系事件之间的差异，如转座子类型分布、插入长度和靶位点偏好。利用长读长测序，我们对双引物现象进行了深入分析，在包括Alu在内的人类中仍具有活性的转座元件类型中均检测到了该现象。此外，我们在重复DNA中检测到大量生殖系转座子，以及复制时间与插入靶位点之间的关系。
我们的研究揭示了结直肠癌和子宫平滑肌瘤在体细胞转座子活性方面的鲜明对比，并突出了体细胞和生殖系转座之间的差异。这表明恶性和非恶性组织以及生殖系和体细胞组织中可能存在不同的条件，这些条件可能参与转座过程。长读长测序为转座子行为提供了重要见解，使得能够详细检查双引物和嵌套元件等结构特征。
