Peto's Paradox and the Evolution of Cancer Suppression
In order to successfully build and maintain a multicellular body, somatic cells must be constrained from proliferating uncontrollably and destroying the organism. If all mammalian cells were equally susceptible to oncogenic mutations and had identical tumor suppressor mechanisms, one would expect th...
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ftunivpenn:oai:repository.upenn.edu:20.500.14332/28019 2024-02-04T10:01:04+01:00 Peto's Paradox and the Evolution of Cancer Suppression Caulin, Aleah Fox Shane T. Jensen Carlo C. Maley 2015-11-16T20:14:00-08:00 202 p. application/pdf https://repository.upenn.edu/handle/20.500.14332/28019 https://hdl.handle.net/20.500.14332/28019 en eng https://repository.upenn.edu/handle/20.500.14332/28019 Aleah Fox Caulin 1228 Publicly Accessible Penn Dissertations published African elephant cancer prevention cancer suppression evolution humpback whale peto's paradox Bioinformatics Biology Dissertation/Thesis 2015 ftunivpenn https://doi.org/20.500.14332/28019 2024-01-06T23:29:02Z In order to successfully build and maintain a multicellular body, somatic cells must be constrained from proliferating uncontrollably and destroying the organism. If all mammalian cells were equally susceptible to oncogenic mutations and had identical tumor suppressor mechanisms, one would expect that the risk of cancer would be proportional to the body size and lifespan of a species. This is because a greater number of cells and cell divisions over a lifetime would increase the chance of accumulating mutations that result in malignant transformation. Peto’s paradox is the clash between the theory that cancer incidence should increase with body size and lifespan, and the observation that it does not. In this thesis, I present the first comprehensive survey of empirical evidence across mammals in support of Peto’s paradox in addition to computational models that explore the numerous hypotheses that may help resolve the paradox. I provide a detailed examination of tumor suppression in African elephants (Loxodonta africana) and show that the genome contains redundant copies of the tumor suppressor gene TP53. I give evidence that these redundant copies are actively transcribed and also observe an increased apoptotic response after exposure to ionizing radiation, which may be linked to the expression of these genes. Few genomes of large, long-lived organisms are currently available, which motivated my work to provide the sequence and de novo assembly of the humpback whale (Megaptera novaeangliae) genome. In this genome, I discovered a set of tumor suppressor genes that have evolved at an accelerated rate along the whale lineage, which is suggestive of adaptation. Additionally, I find one gene that has undergone convergent evolution between the African elephant and the humpback whale. The overarching goal of my research is to gain a better understanding of how evolution has suppressed cancer in large, long-lived organisms in the hopes of ultimately developing improved cancer prevention in humans. Doctor of ... Thesis Humpback Whale Megaptera novaeangliae University of Pennsylvania: ScholaryCommons@Penn |
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University of Pennsylvania: ScholaryCommons@Penn |
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ftunivpenn |
language |
English |
topic |
African elephant cancer prevention cancer suppression evolution humpback whale peto's paradox Bioinformatics Biology |
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African elephant cancer prevention cancer suppression evolution humpback whale peto's paradox Bioinformatics Biology Caulin, Aleah Fox Peto's Paradox and the Evolution of Cancer Suppression |
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African elephant cancer prevention cancer suppression evolution humpback whale peto's paradox Bioinformatics Biology |
description |
In order to successfully build and maintain a multicellular body, somatic cells must be constrained from proliferating uncontrollably and destroying the organism. If all mammalian cells were equally susceptible to oncogenic mutations and had identical tumor suppressor mechanisms, one would expect that the risk of cancer would be proportional to the body size and lifespan of a species. This is because a greater number of cells and cell divisions over a lifetime would increase the chance of accumulating mutations that result in malignant transformation. Peto’s paradox is the clash between the theory that cancer incidence should increase with body size and lifespan, and the observation that it does not. In this thesis, I present the first comprehensive survey of empirical evidence across mammals in support of Peto’s paradox in addition to computational models that explore the numerous hypotheses that may help resolve the paradox. I provide a detailed examination of tumor suppression in African elephants (Loxodonta africana) and show that the genome contains redundant copies of the tumor suppressor gene TP53. I give evidence that these redundant copies are actively transcribed and also observe an increased apoptotic response after exposure to ionizing radiation, which may be linked to the expression of these genes. Few genomes of large, long-lived organisms are currently available, which motivated my work to provide the sequence and de novo assembly of the humpback whale (Megaptera novaeangliae) genome. In this genome, I discovered a set of tumor suppressor genes that have evolved at an accelerated rate along the whale lineage, which is suggestive of adaptation. Additionally, I find one gene that has undergone convergent evolution between the African elephant and the humpback whale. The overarching goal of my research is to gain a better understanding of how evolution has suppressed cancer in large, long-lived organisms in the hopes of ultimately developing improved cancer prevention in humans. Doctor of ... |
author2 |
Shane T. Jensen Carlo C. Maley |
format |
Thesis |
author |
Caulin, Aleah Fox |
author_facet |
Caulin, Aleah Fox |
author_sort |
Caulin, Aleah Fox |
title |
Peto's Paradox and the Evolution of Cancer Suppression |
title_short |
Peto's Paradox and the Evolution of Cancer Suppression |
title_full |
Peto's Paradox and the Evolution of Cancer Suppression |
title_fullStr |
Peto's Paradox and the Evolution of Cancer Suppression |
title_full_unstemmed |
Peto's Paradox and the Evolution of Cancer Suppression |
title_sort |
peto's paradox and the evolution of cancer suppression |
publishDate |
2015 |
url |
https://repository.upenn.edu/handle/20.500.14332/28019 https://hdl.handle.net/20.500.14332/28019 |
genre |
Humpback Whale Megaptera novaeangliae |
genre_facet |
Humpback Whale Megaptera novaeangliae |
op_source |
1228 Publicly Accessible Penn Dissertations published |
op_relation |
https://repository.upenn.edu/handle/20.500.14332/28019 |
op_rights |
Aleah Fox Caulin |
op_doi |
https://doi.org/20.500.14332/28019 |
_version_ |
1789966705050517504 |