Matthews Sophie, Nikoonejad Fard Vahid, Tollis Marc, Seoighe Cathal
School of Mathematical and Statistical Science, University of Galway, Galway, Ireland.
The SFI Centre for Research Training in Genomics Data Science, University of Galway, Galway, Ireland.
Mol Biol Evol. 2025 Mar 5;42(3). doi: 10.1093/molbev/msaf056.
Cancer is a disease of multicellularity, observed across the tree of life. In principle, animals with larger body sizes and longer lifespans should be at increased risk of developing cancer. However, there is no strong relationship between these traits and cancer across mammals. Previous studies have proposed that increased copy number of cancer-related genes may enhance the robustness of cancer suppression pathways in long-lived mammals, but these studies have not extended beyond known cancer-related genes. In this study, we conducted a phylogenetic generalized least squares analysis to test for associations between copy number of all protein-coding genes and longevity, body size, and cancer prevalence across 94 species of mammals. In addition to investigating the copy number of individual genes, we tested sets of related genes for a relationship between the aggregated gene copy number of the set and these traits. We did not find strong evidence to support the hypothesis that adaptive changes in gene copy number contribute to the lack of correlation between cancer prevalence and body size or lifespan. However, we found several biological processes where aggregate copy number was associated with malignancy rate. The strongest association was for the gene set relating to transforming growth factor beta, a cytokine that plays a role in cancer progression. Overall, this study provides a comprehensive evaluation of the role of gene copy number in adaptation to body size and lifespan and sheds light on the contribution of gene copy number to variation in cancer prevalence across mammals.
癌症是一种多细胞生物的疾病，在整个生命之树中都有发现。原则上，体型较大、寿命较长的动物患癌症的风险应该更高。然而，在哺乳动物中，这些特征与癌症之间并没有很强的关联。先前的研究提出，癌症相关基因拷贝数的增加可能会增强长寿哺乳动物癌症抑制途径的稳健性，但这些研究并未超出已知的癌症相关基因。在本研究中，我们进行了系统发育广义最小二乘法分析，以测试94种哺乳动物中所有蛋白质编码基因的拷贝数与寿命、体型和癌症患病率之间的关联。除了研究单个基因的拷贝数外，我们还测试了相关基因集内基因拷贝数总和与这些特征之间的关系。我们没有找到有力证据支持基因拷贝数的适应性变化导致癌症患病率与体型或寿命之间缺乏相关性这一假设。然而，我们发现了几个生物学过程，其中基因拷贝数总和与恶性肿瘤发生率相关。最强的关联是与转化生长因子β相关的基因集，转化生长因子β是一种在癌症进展中起作用的细胞因子。总的来说，这项研究全面评估了基因拷贝数在适应体型和寿命方面的作用，并揭示了基因拷贝数对哺乳动物癌症患病率差异的贡献。
