The Role of Gene Duplication in Mediating Peto's Paradox in Afrotheria and Chiroptera

Based on emperical studies of humans, mice, and various other species, an individual's cancer risk is directly proportional to their cell count (body size) and lifespan. This leads to a theoretical prediction that large and/or long-lived species would possess a higher predisposition to cancer compared to smaller, shorter-lived species; compounding this risk is the fact that body size and lifespan are strongly correlated. However, in a phenomenon known as Peto's Paradox, cancer risk between species does not correlate with either their body sizes or lifespans. This implies that enhanced cancer resistance mechanisms must co-evolve with increases in body size and lifespan; however, there are many ways this can come about. Rather than reinventing the wheel, species can carry an increased load of cancer risk by increasing the number of wheels they have. My thesis focuses on the role tumor suppressor gene duplications play in Peto's Paradox: Chapter 1 explores whether or not tumor suppressor genes are especially enriched among duplicated genes in large, long lived species, while Chapters 2 and 3 functionally characterize two such duplications. Overall, my work here highlights the vital role that tumor suppressor gene duplicates play in lowering the cancer risk of large, long-lived species, while also highlighting new questions for future work, especially regarding antagonistic pleitropy and growth-suppression paradoxes with these duplicates.

A Zombie LIF Gene in Elephants Is Upregulated by TP53 to Induce Apoptosis in Response to DNA Damage

Larger organisms with increased cell counts have a theoretically increased risk of cancer; the observation that larger species do not seem to have an increased cancer risk in contradiction to the patterns observed between members within species is known as Peto's Paradox. ere, we show that elephants and their extinct relatives (proboscideans) may have resolved Peto’s paradox in part through refunctionalizing a leukemia inhibitory factor pseudogene (LIF6) with pro-apoptotic functions. LIF6 is transcriptionally upregulated by TP53 in response to DNA damage and translocates to the mitochondria where it induces apoptosis.

The Role of Tumor-Supressor Duplications in Mediating Peto's Paradox

A poster presented at the 2017 Gordon Research Conference on the Biology of Aging, it describes the early data for the LIF publication in addition to unpublished data on a CDKN2C duplication in the Bowhead Whale.