Today’s story begins with Peto’s paradox – the observation that larger animals should have higher cancer incidence than smaller animals, but don’t (1). Fundamentally, cancer is caused by DNA damage. Large animals have many cells and usually also have long lifespans. As a result, their numerous cells duplicate many times and are exposed to a myriad of carcinogens that should increase the likelihood of accruing DNA damage and, therefore, acquiring cancer. However, rates of cancer are constant across species of various sizes, which suggests that large, long-lived species must have robust anti-cancer mechanisms. Furthermore, large species must have evolved increased cancer resistance to make it possible for them to grow to such large sizes.
Cue p53 – the guardian of the genome. The TP53 gene that encodes the p53 protein is a tumor-suppressor gene that is essential for cancer prevention in humans; nearly all human cancers involve p53 inactivation. Cancer cannot progress in the presence of active p53 because the protein is an incredibly effective DNA-damage-checker. If DNA is damaged, p53 stops the cell from dividing until the DNA is repaired. If the DNA cannot be repaired, p53 triggers cell death (2). In either case, cancerous cells cannot proliferate, so tumors cannot form.
As important as p53 is in humans, it may be even more important to other large and long-lived species. The Lynch lab at the University of Chicago undertook a project to investigate the role of p53 in elephants, one of only a few groups of species – namely elephants, whales, and the now-extinct giant hornless rhinoceros nicknamed “Walter”– to dramatically exemplify Peto’s paradox (3). These gigantic species must have rigorous cancer-fighting adaptations to achieve such massive sizes, and Sulak and colleagues hypothesized that more copies of the TP53 gene is part of those adaptations for elephants.
Most animal species have a single TP53 gene, and select species have a few TP53 retrogenes, or copies. Elephants are a marked exception to this trend. Using the African elephant genome sequence, the scientists found an astounding 20 copies of the TP53 gene in African elephants – one original gene and 19 retrogenes. They also found between 12 and 17 retrogenes in the closely-related Asian elephant. To see if these increases in TP53 copy number may have helped the elephant lineage resolve Peto’s paradox, Sulak and colleagues investigated ancestral elephant genomes. These species also had extra copies of TP53 – the Columbian and wooly mammoths had 14 TP53 retrogenes and the American mastodon had between three and eight. Using phylogenetic models, or sophisticated mathematical models that predict how genome sequences evolved given the evolutionary relationships between species, the scientists found that the rapid increase in TP53 copy number in elephants started about 40 million years ago – around the same time that ancestral elephants started getting bigger. In fact, the ancient increase in TP53 copy number and increase in ancestral elephant body size show starkly similar trends through time, which suggests that having more copies of TP53 may have facilitated the evolution of elephant gigantism.
However, just having more copies of the TP53 gene isn’t enough to fight cancer and defeat Peto’s Paradox – the genes must also be turned into functional proteins. Sulak and colleagues’ next step was to see if TP53 retrogenes in elephants caused increased p53 protein activity, and therefore enhanced cancer-prevention mechanisms. They exposed elephant cells to DNA-damaging agents, and found increased p53 protein activity compared to other closely-related mammals, suggesting that those extra copies of TP53 are suppressing tumors more effectively than single copies.
The elephant TP53 gene is a noteworthy example of how increased gene copy number can play an adaptive role in species evolution. Although the correlation between increased ancestral elephant body size and TP53 copy number is striking, it is impossible to say for certain whether increased copy number facilitated body size increase or vice versa. However, we now know that modern elephants have a greater response to DNA damage, resulting in increased cancer resistance, thanks to their huge number of TP53 retrogenes. Understanding natural cancer-fighting mechanisms such as TP53 copy number increase in elephants can contribute greatly to our understanding of human cancer prevention, and further inquiry into exceptionally large and long-lived species in the animal kingdom will surely contribute additional information to help scientists tackle human cancers.
- R. Peto, Epidemiology, multistage models, and short-term mutagenicity tests. Int. J. Epidemiol. 45, 621–637 (2016).
- D. P. Lane, p53, Guardian of the Genome. Nature. 358, 15–16 (1992).
- M. Sulak et al., TP53 copy number expansion is associated with the evolution of increased body size and an enhanced DNA damage response in elephants. Elife. 5 (2016), doi:10.7554/eLife.11994.
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