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

Sulak, Michael; Fong, Lindsey; Mika, Katelyn; Chigurupati, Sravanthi; Yon, Lisa; Mongan, Nigel P.; Emes, Richard D.; Lynch, Vincent J.

Authors

Michael Sulak

Lindsey Fong

Katelyn Mika

Sravanthi Chigurupati

LISA YON lisa.yon@nottingham.ac.uk
Associate Professor

RICHARD EMES richard.emes@nottingham.ac.uk
Professor of Bioinformatics

Vincent J. Lynch



Abstract

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, the evolution of extreme sensitivity to genotoxic stress, and a hyperactive TP53 signaling pathway in the elephant (Proboscidean) lineage. Furthermore, we show that several of the TP53 retrogenes (TP53RTGs) are transcribed and likely translated. While TP53RTGs do not appear to directly function as transcription factors, they do contribute to the enhanced sensitivity of elephant cells to DNA damage and the induction of apoptosis by regulating activity of the 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.

Citation

Sulak, M., Fong, L., Mika, K., Chigurupati, S., Yon, L., Mongan, N. P., …Lynch, V. J. (2016). TP53 copy number expansion is associated with the evolution of increased body size and an enhanced DNA damage response in elephants. eLife, 5(2016), https://doi.org/10.7554/eLife.11994.001

Journal Article Type Article
Acceptance Date Sep 17, 2016
Online Publication Date Sep 19, 2016
Publication Date Sep 19, 2016
Deposit Date Oct 20, 2016
Publicly Available Date Oct 20, 2016
Journal eLife
Electronic ISSN 2050-084X
Publisher eLife Sciences Publications
Peer Reviewed Peer Reviewed
Volume 5
Issue 2016
Article Number e11994
DOI https://doi.org/10.7554/eLife.11994.001
Public URL http://eprints.nottingham.ac.uk/id/eprint/37731
Publisher URL https://elifesciences.org/content/5/e11994
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

Files

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Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/

Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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