1. Cell Biology
  2. Evolutionary Biology
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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

  1. Michael Sulak
  2. Lindsey Fong
  3. Katelyn Mika
  4. Sravanthi Chigurupati
  5. Lisa Yon
  6. Nigel P Mongan
  7. Richard D Emes
  8. Vincent J Lynch  Is a corresponding author
  1. The University of Chicago, United States
  2. University of Nottingham, United Kingdom
Research Article
  • Cited 46
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Cite this article as: eLife 2016;5:e11994 doi: 10.7554/eLife.11994

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.

Article and author information

Author details

  1. Michael Sulak

    Department of Human Genetics, The University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Lindsey Fong

    Department of Human Genetics, The University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Katelyn Mika

    Department of Human Genetics, The University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Sravanthi Chigurupati

    Department of Human Genetics, The University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Lisa Yon

    Faculty of Medicine and Health Sciences, University of Nottingham, Leicestershire, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Nigel P Mongan

    Faculty of Medicine and Health Sciences, University of Nottingham, Leicestershire, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Richard D Emes

    Faculty of Medicine and Health Sciences, University of Nottingham, Leicestershire, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Vincent J Lynch

    Department of Human Genetics, The University of Chicago, Chicago, United States
    For correspondence
    vjlynch@uchicago.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5311-3824

Funding

We acknowledge the financial support of The University of Chicago (VJL) and the University of Nottingham (NPM, LY, RDE). RDE was additionally supported by funding through the Advanced Data Analysis CentreThe funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Joaquín M Espinosa, University of Colorado School of Medicine, United States

Publication history

  1. Received: October 1, 2015
  2. Accepted: September 17, 2016
  3. Accepted Manuscript published: September 19, 2016 (version 1)
  4. Version of Record published: October 12, 2016 (version 2)
  5. Version of Record updated: December 20, 2016 (version 3)

Copyright

© 2016, Sulak et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Further reading

Further reading

  1. Elephants have extra copies of a gene that protects against cancer.