Peto’s Paradox and why Elephants don’t get cancer

Overview:

Cells within multi-celled organisms accumulate mutations over time. These mutations occur either through exposure to mutagens (e.g. radiation damage) or are introduced through errors that occur during cell replication. On occasion, these mutations will be oncogenic – that is, they take place in genes that are implicated in cancers. If a cell accumulates enough deleterious mutations in oncogenes, it can become cancerous. This is why your doctor recommends avoiding carcinogens by doing things like wearing sunscreen and not smoking cigarettes.

Certain traits that vary between different species are expected to put organisms at a higher lifetime risk of cancer – these include size and lifespan. Assuming each a cell replicates some number of new mutations are introduced, species that have more cells and live for a longer time should have a higher chance of cancer developing in one of their cell lines. Consider it this way - if a cell becoming cancerous is like winning the lottery, an elephant will purchase many more lottery tickets over its lifetime than a mouse. Thus, long lifespans and large body sizes come with an evolutionary trade-off – any benefit from living longer or growing larger comes with an increased risk of cancer.

However, when cancer rates are examined across taxa, there is no evidence that larger or longer-lived species get cancer more frequently than smaller, shorter-lived species. This counterintuitive finding is referred to as Peto’s paradox. Resolving this paradox requires some more sophisticated evolutionary thinking and empirical investigation.

The main evolutionary hypothesis for why large and long-lived species do not have increased risks of cancer is that as species evolved larger bodies and longer lifespans, they must have simultaneously evolved more stringent defense mechanisms that help prevent cancer. These defenses can come in many forms. For example, slowing down metabolic rates or increasing rates of programmed cell death (apoptosis). With this idea in mind, evolutionary-minded cancer researchers have looked for evidence of these kinds of mechanisms in large-bodied and long-lived species, including elephants.

One of the best-known genes that is critical for preventing cancer is the tumor suppressor gene TP53. The p53 protein product is an important signaling molecule, with involvement in both DNA repair and the initiation of apoptosis. Humans carry one copy of the TP53 gene (two alleles) and are at a greater risk of developing cancer if one of these copies is dysfunctional (and much greater risk if both copies are dysfunctional).

Elephants also have TP53, but they have 19 more copies of this gene than humans. With 20 total copies (40 alleles total), the p53 concentration in elephant cells is much higher than seen in humans. Consequently, when exposed to radiation, elephant cells are much quicker to initiating apoptosis.

Elephants also carry extra copies of another gene involved in tumor suppression that most mammals only have one copy of – leukemia inhibitory factor (LIF), which also plays a role in apoptosis. Phylogenetic analyses revealed that the duplication of the LIF gene likely occurred starting in the common ancestor of elephants and their closest living taxa - manatees, hyraxes. That is, manatees and hyraxes also have duplicated copies of the LIF gene. Interestingly, most of these duplicated gene copies of LIF are not expressed – they are lacking the region of DNA that helps activate gene expression (the promoter). These unexpressed gene copies are often called “pseudogenes.” In elephants, however, one of their LIF pseudogenes does have a working promoter. The phylogenetic analysis revealed that accumulated mutations in the elephant resulted in a functional promoter region of the DNA. Thus, these LIF pseudogenes sat around dormant for millions of years until random mutations led to a working promoter, and ancestral elephants with this now functional LIF gene likely had some selective advantage. Now, when DNA is damaged in elephants, p53 works with LIF to amplify apoptotic responses, which helps explain why elephants rarely get cancer.

Of course, elephants are not the only large species, nor are they the only species with a long lifespan. It is likely that evolution has found many different ways to decrease cancer risk – information that may prove valuable in the hunt for ways to prevent and treat cancer.

Principles this example illustrates:

Life History Theory and Coevolution

A complete understanding of life history evolution requires considering cancer-risk as an introduced trade-off in the evolution of larger body sizes and increased lifespans. This increased risk of cancer is likely not quite as powerful as other extrinsic risks that drive life history evolution (e.g. predation risk). However, that cancer rates are similar across species regardless of size or lifespan, and evidence of derived mechanisms in elephants, indicates that defense mechanisms against cancer may be important pre-requisite adaptations for certain life history traits to evolve.

Phylogeny

The evolution of cancer defense mechanisms provides an opportunity to practice tree-thinking. Large body size and long lifespans have independently evolved in many taxa, presenting repeated instances where increased risks of cancers must be counteracted. Knowing the phylogenetic relationship between taxa that both exhibit large body size, long life spans, or both, allows one to make predictions about whether the any cancer defense mechanisms seen in these taxa are homologous, derived, or convergent.

In the case of LIF6, phylogenetic analysis helps uncover evolutionary history. In this case, it allows us to understand the steps through which a “zombie gene” came back to life to serve an important role in cancer defense. The phylogenetic analysis suggests the duplication events that increased the number of pseudogenes occurred in a common ancestor of elephants, manatees, and hyraxes, and the ‘rebirth’ of one of these duplications (through a derived functional promoter region) was unique to elephants.

Additional resources:

Readings

https://www.nationalgeographic.com/science/2018/08/news-cancer-elephants-genes-dna-new-research/

https://www.theatlantic.com/science/archive/2018/08/did-a-zombie-gene-help-elephants-to-beat-cancer/567583/

https://www.nytimes.com/2018/08/14/science/the-zombie-gene-that-may-protect-elephants-from-cancer.html

https://www.nih.gov/news-events/nih-research-matters/how-elephants-defend-against-cancer

Videos


Journal articles

Abegglen LM, Caulin AF, Chan A, et al. Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans. JAMA. 2015;314(17):1850–1860. doi:10.1001/jama.2015.13134

Peto, R., Roe, F. J., Lee, P. N., Levy, L., & Clack, J. (1975). Cancer and ageing in mice and men. British journal of cancer, 32(4), 411.

Sulak, M., Fong, L., Mika, K., Chigurupati, S., Yon, L., Mongan, N. P., ... & Lynch, V. J. (2016). TP53 copy number expansion is associated with the evolution of increased body size and an enhanced DNA damage response in elephants. Elife, 5, e11994.

Callaway, E. (2015). How elephants avoid cancer. Nature, 1038, 18534.

Tollis, M., Boddy, A. M., & Maley, C. C. (2017). Peto’s Paradox: how has evolution solved the problem of cancer prevention?. BMC biology, 15(1), 60.

Vazquez, J. M., Sulak, M., Chigurupati, S., & Lynch, V. J. (2018). A zombie LIF gene in elephants is upregulated by TP53 to induce apoptosis in response to DNA damage. Cell reports, 24(7), 1765-1776.

Teaching materials:

Links to materials here

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