000002553 001__ 2553 000002553 005__ 20240523045518.0 000002553 0247_ $$2doi$$a10.6082/uchicago.2553 000002553 041__ $$aen 000002553 245__ $$aThe Role of Gene Duplication in Mediating Peto's Paradox in Afrotheria and Chiroptera 000002553 260__ $$bThe University of Chicago 000002553 269__ $$a2020-08 000002553 300__ $$a145 000002553 336__ $$aDissertation 000002553 502__ $$bPh.D. 000002553 520__ $$aCancer is a disease intrinsic to multicellularity. Within a species, body size and lifespan are strongly correlated with cancer risk; between species, however, this correlation no longer holds. This phenomena, known as Peto’s Paradox, requires that species evolve cancer suppression mechanisms alongside increases in size and lifespan. Previous studies have identified instances of tumor suppressor duplications in large, long-lived species, suggesting a greater role for gene duplication in resolving Peto’s Paradox. Thus, in this thesis, I identified all protein-coding gene duplications in available genomes to determine if tumor suppressor pathways were enriched among duplicated genes in large, long-lived species. Then, I selected two hits in large, long-lived species to characterize in primary fibroblasts, and determine their effects on cell cycle and cell death in response to stress: LIF in the African Elephant (Loxodonta africana) and TP53 in the Little Brown Bat (Myotis lucifugus). To determine if tumor suppressors gene duplications are more common in large-bodied Atlantogenatans, I used a Reciprocal Best-Hit BLAT strategy to obtain copy numbers of all protein-coding genes in Atlantogenatan genomes. From an initial set of 18,011 protein-coding genes, I identified a median of 13,880 genes in Atlantogenatan genomes, of which a median of 940 genes are duplicated. Just as body size fluctuates throughout Atlantogenata, tumor suppressor genes also duplicated throughout the phylogenetic tree; furthermore, many of them remain transcriptionally active in extant elephants. Together, the data suggest that the duplication of tumor suppressor genes facilitated the evolution of increased body size in Atlantogenata. The resurrection and re-functionalization of a LIF pseudogene (LIF6) with pro-apoptotic functions in elephants and their extinct relatives (Proboscideans) may have played a role in resolving Peto’s Paradox. LIF6 is transcriptionally up-regulated by TP53 in response to DNA damage, and translocates to the mitochondria where it induces apoptosis. Phylogenetic analyses of living and extinct Proboscidean LIF6 genes indicates its TP53 response element evolved coincident with the evolution of large body sizes in the Proboscidean stem-lineage. These results suggest that re-functionalizing of a pro-apoptotic LIF pseudogene may have been permissive (though not sufficient) for the evolution of large body sizes in Proboscideans. In the long-lived bat, Myotis lucifugus, I describe a duplication of the TP53-WRAP53 locus which may play a role in shaping its unique stress response. While pseudogene copies of TP53 are common in Myotis bats, M. lucifugus has a unique, syntenic duplication of TP53-WRAP53 that has conserved both regulatory and transcriptional functionality. Relative to 4 other closely related bat species (M. evotis, M. thysanodes, M. yumanensis, and E. fuscus), the M. lucifugus demonstrates a unique resistance to DNA damage and generalized oxidative stress, resembling the phenotype of a TP53-WRAP53 locus duplication in a previously-described transgenic mouse model. Overall, these results suggest that gene duplication plays an important role in Peto’s Paradox. While tumor suppressor duplications may facilitate the evolution of increased lifespans and body sizes in the short term, my work suggests the need for a polygenic or omnigenic model for Peto's Paradox in order to comprehensively lay this question to rest. 000002553 542__ $$fCC BY-NC-SA 000002553 650__ $$aBiology 000002553 650__ $$aBioinformatics 000002553 650__ $$aEvolution & development 000002553 653__ $$aBats 000002553 653__ $$aComparative Biology 000002553 653__ $$aElephants 000002553 653__ $$aFunctional Genomics 000002553 653__ $$aPeto's Paradox 000002553 653__ $$aTumor Suppressor Genes 000002553 690__ $$aBiological Sciences Division 000002553 690__ $$aPritzker School of Medicine 000002553 691__ $$aHuman Genetics 000002553 7001_ $$aVázquez Díaz, Juan Manuel$$uUniversity of Chicago 000002553 72012 $$aVincent J. Lynch 000002553 72014 $$aMarcelo Nobrega 000002553 72014 $$aJoseph Thorton 000002553 72014 $$aYang Li 000002553 72014 $$aYoav Gilad 000002553 8564_ $$94eace51f-a780-415a-8d26-f1e9ff6a6262$$ePublic$$s3689150$$uhttps://knowledge.uchicago.edu/record/2553/files/VxE1zquezDxEDaz_uchicago_0330D_15280.pdf 000002553 909CO $$ooai:uchicago.tind.io:2553$$pDissertations$$pGLOBAL_SET 000002553 983__ $$aDissertation