Data from: TP53 copy number expansion is associated with the evolution of increased body size and an enhanced DNA damage response in elephants

A major constraint on the evolution of large body sizes in animals is an increased risk of developing cancer. There is no correlation, however, between body size and cancer risk. This lack of correlation is often referred to as 'Peto's Paradox'. Here we show that the elephant genome encodes 20 copies of the tumor suppressor gene TP53 and that the increase in TP53 copy number occurred coincident with the evolution of large body sizes, the evolution of extreme sensitivity to genotoxic stress, and a hyperactive TP53 signaling pathway in the elephant (Proboscidean) lineage. Furthermore we show that several of the TP53 retrogenes (TP53RTGs) are transcribed and likely translated. While TP53RTGs do not appear to directly function as transcription factors, they do contribute to the enhanced sensitivity of elephant cells to DNA damage and the induction of apoptosis by regulating activity of the TP53 signaling pathway. These results suggest that an increase in the copy number of TP53 may have played a direct role in the evolution of very large body sizes and the resolution of Peto's paradox in Proboscideans.

动物体型大型化演化的主要限制因素之一，是罹患癌症的风险显著升高。然而，体型大小与癌症风险之间并无相关性，这种相关性缺失现象常被称为“佩托悖论（Peto's Paradox）”。本研究表明，大象基因组共编码20份肿瘤抑制基因TP53的拷贝；而TP53拷贝数的增加，恰好与长鼻类（Proboscidean）支系中大型体型的演化、对遗传毒性应激的极端敏感性演化，以及TP53信号通路的过度激活同步发生。此外，本研究还发现，部分TP53逆转录基因（TP53RTGs）可发生转录，且大概率能够被翻译为蛋白。尽管TP53RTGs似乎无法直接作为转录因子发挥功能，但它们可通过调控TP53信号通路的活性，增强大象细胞对DNA损伤的敏感性，并诱导细胞凋亡。上述研究结果表明，TP53拷贝数的增加，可能在长鼻类动物的超大型体型演化以及佩托悖论的解决过程中发挥了直接作用。