title: TP53copy number expansion is associated with the evolution of increased body size and an enhanced DNA damage response in elephants.
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 geneTP53and that the increase inTP53copy 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 theTP53retrogenes (TP53RTGs) are transcribed and likely translated. WhileTP53RTGsdo 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 ofTP53may have played a direct role in the evolution of very large body sizes and the resolution of Peto's paradox in Proboscideans.
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Sulak
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, United States.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Fong
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, United States.
authors.forename: Katelyn
authors.initials: K
authors.lastname: Mika
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, United States.
authors.forename: Sravanthi
authors.initials: S
authors.lastname: Chigurupati
authors.affiliation: School of Veterinary Medicine and Science, University of Nottingham, Leicestershire, United Kingdom.|Faculty of Medicine and Health Sciences, University of Nottingham, Leicestershire, United Kingdom.
authors.forename: Lisa
authors.initials: L
authors.lastname: Yon
authors.affiliation: School of Veterinary Medicine and Science, University of Nottingham, Leicestershire, United Kingdom.|Faculty of Medicine and Health Sciences, University of Nottingham, Leicestershire, United Kingdom.|Department of Pharmacology, Weill Cornell Medical College, New York, United States.
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Mongan
authors.affiliation: School of Veterinary Medicine and Science, University of Nottingham, Leicestershire, United Kingdom.|Faculty of Medicine and Health Sciences, University of Nottingham, Leicestershire, United Kingdom.|Advanced Data Analysis Centre, University of Nottingham UK, Nottingham, United Kingdom.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Emes
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, United States.
authors.forename: Vincent J
authors.identifier: 0000-0001-5311-3824
authors.initials: VJ
authors.lastname: Lynch
mesh_terms: D000818:Animals; D017209:Apoptosis; D049628:Body Size; D004260:DNA Repair; D004606:Elephants; D019143:Evolution, Molecular; D018628:Gene Dosage; D020869:Gene Expression Profiling; D016158:Genes, p53; D014176:Protein Biosynthesis; D015398:Signal Transduction; D014158:Transcription, Genetic
keywords: African elephant; Asian elephant; aardvark; armadillo; cell biology; evolutionary biology; genomics; hyrax