A Zombie LIF Gene in Elephants Is Upregulated by TP53 to Induce Apoptosis in Response to DNA Damage

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.

The Evolution of Human Cancer Gene Duplications across Mammals

“…The evolutionary relatedness of other mammals to humans has led to the realization that patterns of tumor suppressor gene duplication in mammalian genomes may shed light on cancer resistance mechanisms and lead to novel therapies (Caulin and Maley 2011;Abegglen et al 2015;Caulin et al 2015;Keane et al 2015;Tollis et al 2017;Vazquez et al 2018).…”

“…The genetic controls of cancer suppression in nature's giants has been the focus of much research (Abegglen et al 2015;Caulin et al 2015;Sulak et al 2016;Vazquez et al 2018;Tollis et al 2019), as well as in mammals with pronounced longevity such as naked mole rats (Heterocephalus glaber) (Seluanov et al 2009;Tian et al 2013). Low cancer mortality rates in elephants may be related to the redundancy provided by as many as 20 genomic copies of the tumor suppressor gene TP53 (Abegglen et al 2015;Caulin et al 2015;Sulak et al 2016), which is responsible for apoptosis, senescence, and cell-cycle arrest in the presence of damaged DNA (Kumari et al 2014).…”

“…If the evolution of large bodies and long lifespans was accompanied by compensatory and independent anti-cancer adaptations such as tumor suppressor gene duplications, then we should be able to predict lineage-specific tumor suppressor gene expansions in certain lineages. However, to date, the genomic investigations into any link between tumor suppressor gene duplications and the evolution of large bodies or long lifespans have been limited to either a single taxon (Seluanov et al 2007;Abegglen et al 2015;Vazquez et al 2018) or a small number of genomes . The recent availability of a large number of diverse mammalian genome assemblies (Koepfli et al 2015;Lewin et al 2018) provides an unsourced opportunity to learn about potential genetic mechanisms underlying cancer suppression.…”

Genetic signatures of evolution of the pluripotency gene regulating network across mammals

“…We observed multiple PSSs on the functional motif basic helix-loop-helix (bHLH) of TCF3 in the large flying fox (Pteropus vampyrus), among the largest species of bat with a wingspan of up to 1.5m (Kunz & Jones 2000). Potential mechanisms of reducing cancer risk through response to DNA damage has been reported in elephants (Abegglen et al 2015;Vazquez et al 2018). Interestingly, we also observed PSSs on the bHLH of TCF3 in elephants, implying the resolution to Peto's paradox and the underlying convergent evolution between species that have developed a larger body size compered to their phylogenetic relatives.…”

The second biennial meeting of the Pan‐American Society for Evolutionary Developmental Biology

“…Lynch's work shows that elephants not only have multiple copies of tumor suppressor p53; they also have duplicates of a gene called LIF. Most copies of LIF in the elephant genome are pseudogenes, but one of them (LIF6) has been refunctionalized to increase cell sensitivity to DNA damage, thus allowing elephants to cull potentially cancerous cells early, Lynch found (Vazquez, Sulak, Chigurupati, & Lynch, ). Understanding how large, long‐lived species solved Peto's Paradox may suggest new approaches to cancer prevention and treatment in humans.…”