Shrinking to bird size with dinosaur-level cancer defences

 

. 2025 Sep 9;21(9):e1013432. doi: 10.1371/journal.pcbi.1013432

Shrinking to bird size with dinosaur-level cancer defences: Evolution of cancer suppression over macroevolutionary time

E Yagmur Erten 1,2,3,4,*, Marc Tollis 2,5, Hanna Kokko 1,6,7

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Abstract

Ubiquity of cancer across the tree of life yields opportunities to understand variation in cancer defences across species. Peto’s paradox, the finding that large-bodied species do not suffer from more cancer despite having more cells at risk of oncogenic mutations compared to small species, can be explained if large size selects for better cancer defences. Since birds live longer than non-flying mammals of equivalent size, and are descendants of moderate-sized dinosaurs, we ask whether ancestral cancer defences are retained if body size shrinks in a lineage. Our model derives selection coefficients and fixation events for changes in cancer defences over macroevolutionary time, based on known relationships between body size, cancer risk, extrinsic mortality, metabolic rate, and effective population size. We show that, if mutation rate is sufficiently high and cancer defences are costly, we expect birds to have lower cancer defences than their dinosaurian ancestors. However, if the evolution of cancer suppression is mutation limited, due to e.g. pleiotropy, birds may have kept excessive dinosaurian cancer defences, possibly explaining their low cancer risk. Counterintuitively, birds can then be ‘too robust’ for their own good, if excessive cancer suppression requires compromising reproductive rates. Yet, evolutionary innovations such as flight can increase longevity and keep selection for cancer suppression intact in birds, even if flight requires small body size. Retaining dinosaur-level cancer defences can then be adaptive, particularly if the evolution of flight is accompanied by an increase in cancer risk due to metabolic scaling. Overall, our study suggests that studying cancer suppression in birds can reveal alternative mechanisms to those found in mammals, possibly inherited from birds’ dinosaurian ancestors.

Author summary

Humans are not the only species suffering from cancer, yet cancer does not impact all life equally. Body size is relevant because maintaining a large number of cells in a tumour-free state necessitates improved cancer defences. Present-day birds appear adept at avoiding cancer, and live longer than similarly sized mammals. Since birds arose from a large-bodied dinosaur lineage rather than having always been small, we ask if evolutionary lags might explain their superior cancer defences. We model the circumstances under which dinosaurian anti-cancer innovations can still persist, making birds more cancer-resistant and longer-lived than mammals. We show that unless the process is mutation-limited, dinosaur-level cancer defences will decay over macroevolutionary time. However, evolutionary lags, when they do occur, can render birds cancer-robust and explain their relatively long lifespans. Eroding defences is made less likely by evolution of flight, which by reducing extrinsic mortality risk can make long lifespans feasible, and by metabolic scaling during shrinkage, if increasing mass-specific metabolic rate translates into an increase in the rate of cancer-causing mutations.