No evidence for Peto's paradox in terrestrial vertebrates

Abstract

Larger, longer-lived species are expected to have a higher cancer prevalence compared to smaller, shorter-lived species owing to the greater number of cell divisions that occur during their lifespan. Yet, to date, no evidence has been found to support this expectation, and no association has been found between cancer prevalence and body size across species-a phenomenon known as Peto's paradox. Specifically, while anticancer mechanisms have been identified for individual species, wider phylogenetic evidence has remained elusive. Here, we show that there is no evidence for Peto's paradox across amphibians, birds, mammals, and squamate reptiles: Larger species do in fact have a higher cancer prevalence compared to smaller species. Moreover, we demonstrate that the accumulation of repeated instances of accelerated body size evolution in mammals and birds is associated with a reduction in the prevalence of neoplasia and malignancy, suggesting that increased rates of body size evolution are associated with the evolution of improved cellular growth control. These results represent empirical evidence showing that larger body size is related to higher cancer prevalence, thus rejecting Peto's paradox, and demonstrating the importance of heterogenous routes of body size evolution in shaping anticancer defenses.

Keywords: Peto’s paradox; cancer evolution; comparative phylogenetics.

Fig. 1.

A positive association between neoplasia or malignancy and body size in terrestrial vertebrates. In all cases, the posterior predicted slopes are plotted, and the mean average predicted slopes are highlighted. Insets show the posterior distribution of the estimated slopes, and the black vertical line indicates 0 on the x-axis. A slope is significant if less than 5% of the posterior distribution crosses 0. Neoplasia prevalence is positively associated with (A) snout–vent length (SVL) in amphibians (green) and reptiles (purple) (P_x = 0.002) and (B) body mass in birds (blue) and mammals (red) (P_x = 0.001). Malignancy prevalence is positively associated with (C) SVL in amphibians and reptiles (P_x = 0.003) and (D) body mass in birds and mammals (P_x = 0.001).

Fig. 2.

A negative association between neoplasia or malignancy and pathwise rate in birds and mammals. In all cases, the posterior predicted slopes are plotted, and the mean average predicted slopes are highlighted. Insets show the posterior distribution of the estimated slopes, and the black vertical line indicates 0 on the x-axis. A slope is significant if less than 5% of the posterior distribution crosses 0. (A) Neoplasia prevalence is negatively associated with pathwise rate (Materials and Methods) in birds (blue) and mammals (red) (P_x = 0.027) but (B) positively associated with body mass in the same model (P_x = 0). Likewise, (C) malignancy is negatively associated with pathwise rate in birds and mammals (P_x = 0.01) but (D) positively associated with body mass (P_x = 0.001).

Fig. 3.

A schematic depiction of how high rates of body mass evolution change the scaling of malignancy prevalence with body mass. The black dotted line shows the mean average predicted slope from a model with body mass as the only fixed effect. The black solid line shows the mean average predicted slope from a model with body mass and pathwise rate as fixed effects. The slope of the black solid line is plotted with the pathwise rate set equal to the pathwise rate of the non-rate-scaled tree. The slope of the solid line is steeper than the slope of the dotted line, meaning that after accounting for high rates of body mass evolution, there is a greater increase in malignancy prevalence with respect to an increase in species body mass. As a result, larger species experience a greater reduction in the predicted prevalence of malignancy compared to smaller species. For instance, high rates of body size evolution are associated with a 56% reduction in the predicted prevalence of malignancy in Elephas maximus but only a 12% reduction in Rousettus lanosus, as shown by the gray dotted and solid lines.

Fig. 4.

Predicted malignancy prevalence across birds and mammals. The branches of the phylogeny are colored with respect to the rate of body mass evolution, lighter shades correspond to faster rates. The bars at the tips of the phylogeny correspond to the difference between the predicted and observed prevalence of malignancy in birds and mammals with respect to body mass and pathwise rate. The solid black bars and white bars indicate species with a higher and lower-level prevalence of malignancy than would be expected. The gray bars indicate outlier species that were removed during the model fitting (Materials and Methods). The black arrows indicate species in which the prevalence difference is greater than 20.