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TP53 copy number expansion correlates with the evolution of increased body size and an enhanced DNA damage response in elephants

Michael Sulak, Lindsey Fong, Katelyn Mika, Sravanthi Chigurupati, Lisa Yon, Nigel P. Mongan, Richard D. Emes, View ORCID ProfileVincent J. Lynch
doi: https://doi.org/10.1101/028522
Michael Sulak
1Department of Human Genetics, The University of Chicago, Chicago, IL, 60637
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Lindsey Fong
1Department of Human Genetics, The University of Chicago, Chicago, IL, 60637
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Katelyn Mika
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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Lisa Yon
2School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences. University of Nottingham, Sutton Bonington Campus, Leicestershire, LE12 5RD. UK.
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Nigel P. Mongan
2School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences. University of Nottingham, Sutton Bonington Campus, Leicestershire, LE12 5RD. UK.
3Department of Pharmacology, Weill Cornell Medical College, New York, NY, 10065
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Richard D. Emes
2School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences. University of Nottingham, Sutton Bonington Campus, Leicestershire, LE12 5RD. UK.
4Advanced Data Analysis Centre, University of Nottingham UK.
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Vincent J. Lynch
1Department of Human Genetics, The University of Chicago, Chicago, IL, 60637
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  • ORCID record for Vincent J. Lynch
  • For correspondence: vjlynch@uchicago.edu
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SUMMARY

A major constraint on the evolution of large body sizes in animals is an increased risk of developing cancer. There is no correlation, however, between body size and cancer risk. This lack of correlation is often referred to as ‘Peto’s Paradox’. Here we show that the elephant genome encodes 20 copies of the tumor suppressor gene TP53 and that the increase in TP53 copy number occurred coincident with the evolution of large body sizes in the elephant (Proboscidean) lineage. Furthermore we show that several of the TP53 retrogenes are transcribed and translated and contribute to an enhanced sensitivity of elephant cells to DNA damage and the induction of apoptosis via a hyperactive TP53 signaling pathway. These results suggest that an increase in the copy number of TP53 may have played a direct role in the evolution of very large body sizes and the resolution of Peto’s paradox 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-NC 4.0 International license.
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Posted October 06, 2015.
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TP53 copy number expansion correlates with the evolution of increased body size and an enhanced DNA damage response in elephants
Michael Sulak, Lindsey Fong, Katelyn Mika, Sravanthi Chigurupati, Lisa Yon, Nigel P. Mongan, Richard D. Emes, Vincent J. Lynch
bioRxiv 028522; doi: https://doi.org/10.1101/028522
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TP53 copy number expansion correlates with the evolution of increased body size and an enhanced DNA damage response in elephants
Michael Sulak, Lindsey Fong, Katelyn Mika, Sravanthi Chigurupati, Lisa Yon, Nigel P. Mongan, Richard D. Emes, Vincent J. Lynch
bioRxiv 028522; doi: https://doi.org/10.1101/028522

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