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Cancer control is a key functionality underlying evolution of extended lifespan in mammals

Amanda Kowalczyk, Raghavendran Partha, Nathan Clark, Maria Chikina
doi: https://doi.org/10.1101/615914
Amanda Kowalczyk
1Joint Carnegie Mellon University-University of Pittsburgh PhD Program in Computational Biology, Pittsburgh, PA
2University of Pittsburgh Department of Computational and Systems Biology, Pittsburgh, PA
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Raghavendran Partha
1Joint Carnegie Mellon University-University of Pittsburgh PhD Program in Computational Biology, Pittsburgh, PA
2University of Pittsburgh Department of Computational and Systems Biology, Pittsburgh, PA
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Nathan Clark
2University of Pittsburgh Department of Computational and Systems Biology, Pittsburgh, PA
3Pittsburgh Center for Evolutionary Biology and Medicine, University of Pittsburgh, Pittsburgh, PA
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Maria Chikina
2University of Pittsburgh Department of Computational and Systems Biology, Pittsburgh, PA
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  • For correspondence: mchikina@pitt.edu
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Abstract

The biological origin of life expectancy remains a fundamental and unanswered scientific question with important ramifications for human health, especially as the bulk of burden of human healthcare shifts from infectious to age-related diseases. The striking variability in life-span among animals occupying similar ecological niches1 and the numerous mutations that have been shown to increase lifespan in model organisms2–5 point to a considerable genetic contribution. Using mammalian comparative genomics, we correlate lifespan phenotypes with relative evolutionary rates, a measure of evolutionary selective pressure6. Our analysis demonstrates that many genes and pathways are under increased evolutionary constraint in both Long-Lived Large-bodied mammals (3L) and mammals Exceptionally Long-Lived given their size (ELL), suggesting that these genes and pathways contribute to the maintenance of both traits. For 3L species, we find strong evolutionary constraint on multiple pathways involved in controlling carcinogenesis, including cell cycle, apoptosis, and immune pathways. These findings provide additional perspective on the well-known Peto’s Paradox that large animals with large numbers of cells do not get cancer at higher rates than smaller animals with fewer cells7. For the ELL phenotype, our analysis strongly implicates pathways involved in DNA repair, further supporting the importance of DNA repair processes in aging8–12. Moreover, these correlations with lifespan phenotypes are consistent across the entire mammalian phylogeny, suggesting that additional constraint on these pathways is a universal requirement for long lifespan.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted April 23, 2019.
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Cancer control is a key functionality underlying evolution of extended lifespan in mammals
Amanda Kowalczyk, Raghavendran Partha, Nathan Clark, Maria Chikina
bioRxiv 615914; doi: https://doi.org/10.1101/615914
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Cancer control is a key functionality underlying evolution of extended lifespan in mammals
Amanda Kowalczyk, Raghavendran Partha, Nathan Clark, Maria Chikina
bioRxiv 615914; doi: https://doi.org/10.1101/615914

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