Fard Vahid Nikoonejad, Tollis Marc
School of Informatics, Computing, and Cyber Systems, Northern Arizona University, 1295 S Knoles Dr, Bldg. 90, Flagstaff, AZ 86011, USA.
Arizona Cancer Evolution Center, Arizona State University, 427 East Tyler Street, Tempe, AZ 85287, USA.
bioRxiv. 2025 Sep 4:2025.08.30.673284. doi: 10.1101/2025.08.30.673284.
Non-long terminal repeat retrotransposons (nLTRs), including long and short interspersed nuclear elements (L1 and SINEs), are the most abundant and active mobile elements in mammals. NLTRs play critical mutagenic and regulatory roles during oncogenesis in humans and model species. However, it is not known whether recent nLTR activity in the genome is related to the lifetime cancer risk of a species beyond humans and conventional model organisms. We examined whether recent nLTR activity predicts cancer prevalence across mammals using comparative analyses of whole-genome repeat annotations from 55 species, each with over 20 published zoo pathology records. We quantified nLTR activity as the number of potentially active elements, their proximity to protein-coding genes and cancer gene orthologs (CGOs), and insertions within these genes. Across all three metrics, neoplasia prevalence was associated with both L1 and combined L1-SINE activity, while malignancy was linked exclusively to the L1-SINE predictors. This pattern suggests a complementary and escalating trajectory, where L1s contribute to early tumorigenic events, while SINE activity, driven by L1s, amplifies their impact and fuels the transition to malignancy. Moreover, genomes harboring more CGOs tended to exhibit higher neoplasia prevalence, and the number of fusion cancer genes was strongly correlated with the number of potentially active L1s across species. Our results further revealed a pattern wherein species with minimal cancer prevalence exhibit restricted activity of at least one major nLTR superfamily, suggesting that preserving genome stability through limited retrotransposition may serve as a protective mechanism against cancer.
非长末端重复逆转座子（nLTRs），包括长散在核元件和短散在核元件（L1和SINEs），是哺乳动物中数量最多且最活跃的移动元件。在人类和模式生物的肿瘤发生过程中，NLTRs发挥着关键的诱变和调控作用。然而，基因组中近期的nLTR活性是否与人类及传统模式生物之外的物种的终生癌症风险相关尚不清楚。我们使用来自55个物种的全基因组重复注释的比较分析，研究了近期的nLTR活性是否能预测哺乳动物的癌症患病率，每个物种都有超过20条已发表的动物园病理学记录。我们将nLTR活性量化为潜在活跃元件的数量、它们与蛋白质编码基因和癌症基因直系同源物（CGOs）的接近程度以及这些基因内的插入情况。在所有这三个指标中，肿瘤形成患病率与L1以及L1-SINE的联合活性相关，而恶性肿瘤仅与L1-SINE预测因子相关。这种模式表明了一种互补且逐步升级的轨迹，其中L1促成早期致瘤事件，而由L1驱动的SINE活性放大了它们的影响并推动向恶性肿瘤的转变。此外，含有更多CGOs的基因组往往表现出更高的肿瘤形成患病率，并且融合癌基因的数量与跨物种潜在活跃L1的数量密切相关。我们的结果进一步揭示了一种模式，即癌症患病率最低的物种表现出至少一个主要nLTR超家族的活性受限，这表明通过有限的逆转座作用来维持基因组稳定性可能是一种抗癌保护机制。
