Abstract
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.
Highlights
The risk of developing cancer places severe constraints on the evolution of large body sizes and long life spans in animals
LIF6 encodes a separation of function isoform structurally similar to LIF-T that induces apoptosis when overexpressed in multiple cell types and is required for the elephant-specific enhanced cell death in response to DNA damage. These results suggest that the origin of a zombie LIF gene may have contributed to the evolution of enhanced cancer resistance in the elephant lineage and the evolution large body sizes and long life spans
We found that most mammalian genomes encoded a single LIF gene; the manatee (Trichechus manatus), rock hyrax (Procavia capensis), and African elephant genomes contained 7–11 additional copies of LIF (Figure 1)
Summary
The risk of developing cancer places severe constraints on the evolution of large body sizes and long life spans in animals. Organisms with long life spans have more time to accumulate cancer-causing mutations than organisms with shorter life spans and should be at an increased risk of developing cancer, a risk that is compounded in large-bodied, long-lived organisms (Cairns, 1975; Caulin and Maley, 2011; Doll, 1971; Peto, 2015; Peto et al, 1975). Consistent with these expectations, there is a strong positive correlation between body size and cancer incidence within species. There are no correlations between body size or life span and cancer risk between species (Abegglen et al, 2015); this lack of correlation is often referred to as ‘‘Peto’s paradox’’ (Caulin and Maley, 2011; Leroi et al, 2003; Peto et al, 1975)
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