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 from: TP53 copy number expansion is associated with the evolution of increased body size and an enhanced DNA damage response in elephantsAvailable at Dryad Digital Repository under a CC0 Public Domain Dedication.
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).
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).
Mastodon shotgun sequencingPublicly available at the NCBI Short Read Archive (accession no: SRX015822, SRX015823).
Origins and functional evolution of Y chromosomes across mammalsPublicly available at the NCBI Short Read Archive (accession no: GSM1227965, GSM1227964).
Comparative sequence analyses of genome and transcriptome reveal novel transcripts and variants in the Asian elephant Elephas maximusPublicly available at the NCBI Short Read Archive (accession no: SRX1423033).
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.
- Joaquín M Espinosa, University of Colorado School of Medicine, United States
© 2016, Sulak et al.
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