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A zombie LIF gene in elephants is up-regulated by TP53 to induce apoptosis in response to DNA damage

View ORCID ProfileJuan Manuel Vazquez, Michael Sulak, Sravanthi Chigurupati, View ORCID ProfileVincent J. Lynch
doi: https://doi.org/10.1101/187922
Juan Manuel Vazquez
1Department of Human Genetics, The University of Chicago, Chicago, IL, 60637
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Michael Sulak
1Department of Human Genetics, The University of Chicago, Chicago, IL, 60637
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Sravanthi Chigurupati
1Department of Human Genetics, The University of Chicago, Chicago, IL, 60637
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Vincent J. Lynch
1Department of Human Genetics, The University of Chicago, Chicago, IL, 60637
2Department of Organismal Biology and Anatomy, The University of Chicago, Chicago, IL, 60637
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  • For correspondence: vjlynch@uchicago.edu
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Abstract

Large bodied organisms have more cells that can potentially turn cancerous than smallbodied organisms with fewer cells, 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 re-functionalizing a leukemia inhibitory factor pseudogene (LIF6) with pro-apoptotic functions. The LIF6 gene is transcriptionally up-regulated 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 its TP53 response element evolved coincident with the evolution of large body sizes in the Proboscidean stem-lineage. These results suggest that re-functionalizing of a pro-apoptotic LIF pseudogene may have been permissive (though not sufficient) for the evolution of large body sizes in Proboscideans.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted June 22, 2018.
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A zombie LIF gene in elephants is up-regulated by TP53 to induce apoptosis in response to DNA damage
Juan Manuel Vazquez, Michael Sulak, Sravanthi Chigurupati, Vincent J. Lynch
bioRxiv 187922; doi: https://doi.org/10.1101/187922
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A zombie LIF gene in elephants is up-regulated by TP53 to induce apoptosis in response to DNA damage
Juan Manuel Vazquez, Michael Sulak, Sravanthi Chigurupati, Vincent J. Lynch
bioRxiv 187922; doi: https://doi.org/10.1101/187922

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