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

Abstract
Data availability
Article and author information
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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.

Data availability

The following data sets were generated

1. Sulak M
2. Fong L
3. Mika K
4. Chigurupati S
5. Yon L
6. Mongan NP
7. Emes RD
8. Lynch VJ
(2016) Data from: TP53 copy number expansion is associated with the evolution of increased body size and an enhanced DNA damage response in elephants
Available at Dryad Digital Repository under a CC0 Public Domain Dedication.

http://dx.doi.org/10.5061/dryad.968vr

The following previously published data sets were used

(2014) Whole genome sequencing of two Asian elephants (Elephas maximus) infected with Elephant Endotheliotropic Herpesvirus (EEHV)
Publicly available at the NCBI Short Read Archive (accession no: ERX334765, ERX334764).

http://www.ncbi.nlm.nih.gov/bioproject/PRJEB4905
(2013) Raw Illumina read files associated with Enk et al. publication on qPCR as a predictor of mapped reads after enrichment. Sequence data from non-enriched and enriched libraries deriving from Pleistocene-age bone and tooth remains of various Mammuthus sp.
Publicly available at the NCBI Short Read Archive (accession no: SRX329134, SRX329135, SRX327587, SRX327586, SRX327583, SRX327582).

http://www.ncbi.nlm.nih.gov/bioproject/PRJNA203139
1. Rohland N
2. Reich D
3. Mallick S
4. Meyer M
5. Green RE
6. Georgiadis NJ
7. Roca AL
8. Hofreiter M
(2010) Mastodon shotgun sequencing
Publicly available at the NCBI Short Read Archive (accession no: SRX015822, SRX015823).

http://www.ncbi.nlm.nih.gov/sra?term=SRP001730
(2013) Origins and functional evolution of Y chromosomes across mammals
Publicly available at the NCBI Short Read Archive (accession no: GSM1227965, GSM1227964).

http://www.ncbi.nlm.nih.gov/bioproject/PRJNA218629
1. Reddy PC
2. Sinha I
3. Kelkar A
4. Habib F
5. Pradhan SJ
6. Sukumar R
7. Galande S
(2015) Comparative sequence analyses of genome and transcriptome reveal novel transcripts and variants in the Asian elephant Elephas maximus
Publicly available at the NCBI Short Read Archive (accession no: SRX1423033).

http://www.ncbi.nlm.nih.gov/bioproject/PRJNA301482

Article and author information

Author details

Michael Sulak

Department of Human Genetics, The University of Chicago, Chicago, United States

Competing interests
The authors declare that no competing interests exist.
Lindsey Fong

Department of Human Genetics, The University of Chicago, Chicago, United States

Competing interests
The authors declare that no competing interests exist.
Katelyn Mika

Department of Human Genetics, The University of Chicago, Chicago, United States

Competing interests
The authors declare that no competing interests exist.
Sravanthi Chigurupati

Department of Human Genetics, The University of Chicago, Chicago, United States

Competing interests
The authors declare that no competing interests exist.
Lisa Yon

Faculty of Medicine and Health Sciences, University of Nottingham, Leicestershire, United Kingdom

Competing interests
The authors declare that no competing interests exist.
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.
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.
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.

"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.

Copyright

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.