Large-bodied organisms have more cells that can potentially turn cancerous than small-bodied organisms, imposing an increased risk of developing cancer. This expectation predicts a positive correlation between body size and cancer risk; however, there is no correlation between body size and cancer risk across species ("Peto's paradox"). Here, we show that elephants and their extinct relatives (proboscideans) may have resolved Peto's paradox in part through refunctionalizing a leukemia inhibitory factor pseudogene (LIF6) with pro-apoptotic functions. LIF6 is transcriptionally upregulated by TP53 in response to DNA damage and translocates to the mitochondria where it induces apoptosis. Phylogenetic analyses of living and extinct proboscidean LIF6 genes indicates that its TP53 response element evolved coincident with the evolution of large body sizes in the proboscidean stem lineage. These results suggest that refunctionalizing of a pro-apoptotic LIF pseudogene may have been permissive (although not sufficient) for the evolution of large body sizes in proboscideans.

A fishy tale of long and short life span Fish have wide variations in life span even within closely related species. One such example are the rockfish species found along North Pacific coasts, which have life spans ranging from 11 to more than 200 years. Kolora et al . sequenced and performed a genomic analysis of 88 rockfish species, including long-read sequencing of the genomes of six species (see the Perspective by Lu et al .). From this analysis, the authors unmasked the genetic drivers of longevity evolution, including immunity and DNA repair–related pathways. Copy number expansion in the butyrophilin gene family was shown to be positively associated with life span, and population historical dynamics and life histories correlated differently between long- and short-lived species. These results support the idea that inflammation may modulate the aging process in these fish. —LMZ

The risk of developing cancer is correlated with body size and lifespan within species. Between species, however, there is no correlation between cancer and either body size or lifespan, indicating that large, long-lived species have evolved enhanced cancer protection mechanisms. Elephants and their relatives (Proboscideans) are a particularly interesting lineage for the exploration of mechanisms underlying the evolution of augmented cancer resistance because they evolved large bodies recently within a clade of smaller bodied species (Afrotherians). Here, we explore the contribution of gene duplication to body size and cancer risk in Afrotherians. Unexpectedly, we found that tumor suppressor duplication was pervasive in Afrotherian genomes, rather than restricted to Proboscideans. Proboscideans, however, have duplicates in unique pathways that may underlie some aspects of their remarkable anti-cancer cell biology. These data suggest that duplication of tumor suppressor genes facilitated the evolution of increased body size by compensating for decreasing intrinsic cancer risk.

The risk of developing cancer is correlated with body size and lifespan within species. Between species, however, there is no correlation between cancer and either body size or lifespan, indicating that large, long-lived species have evolved enhanced cancer protection mechanisms. Elephants and their relatives (Proboscideans) are a particularly interesting lineage for the exploration of mechanisms underlying the evolution of augmented cancer resistance because they evolved large bodies recently within a clade of smaller bodied species (Afrotherians). Here, we explore the contribution of gene duplication to body size and cancer risk in Afrotherians. Unexpectedly, we found that tumor suppresxssor duplication was pervasive in Afrotherian genomes, rather than restricted to Proboscideans. Proboscideans, however, have duplicates in unique pathways that may underlie some aspects of their remarkable anti-cancer cell biology. These data suggest that duplication of tumor suppressor genes facilitated the evolution of increased body size by compensating for decreasing intrinsic cancer risk.