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

Abstract

As time passes, healthy cells are more likely to become cancerous because more and more damaging mutations accumulate in the cell’s DNA. Assuming that all cells have a similar risk of acquiring mutations, larger and longer-lived animals – like elephants – should have a higher risk of cancer than smaller, shorter-lived animals – like mice. However, there does not appear to be any link between the size of an animal and its risk of developing cancer. Consequently, a key question in cancer biology is how very large animals protect themselves against these diseases. One gene that is often damaged during an animal’s lifetime is called TP53. This gene normally produces a tumor suppressor protein that senses when DNA is damaged or a cell is under stress and either briefly slows the cell’s growth while the damage is repaired or triggers cell death if the stress is overwhelming. One way that large animals could reduce their risk of cancer is to have extra copies of TP53 or other genes that encode tumor suppressor proteins. Here Sulak et al. used an evolutionary genomics approach to study TP53 in 61 animals of various sizes, including several large animals such as African elephants and Minke whales. All of the animals studied had at least one copy of TP53, and several had a few extra copies, known as TP53 retrogenes. African elephants – the largest living land mammal – had more retrogenes than any of the others with 19 in total. To investigate why African elephants have so many TP53 retrogenes, Sulak et al. also analyzed DNA from Asian elephants and several other closely related, but now extinct species, including the woolly mammoth. As expected, as species evolved larger body sizes they also evolved more TP53 retrogenes. Further experiments indicate that several of the TP53 retrogenes in African elephants are likely to be able to produce the tumor suppressor protein and that they contribute to elephant cells being better equipped to deal with DNA damage. The next step following on from this work will be to find out exactly how TP53 retrogenes help to protect animals from cancer.