Cancer susceptibility across the Mammalian tree

While most multicellular organisms face the challenge of cancer, it is apparent that some species, such as the bowhead whale (Balaena mysticetus), have developed mechanisms that confer a resistance to cancer. However, there are species, like the Tasmanian devil (Sarcophilus harrisii), that appear to have an increased susceptibility to the development of cancer. The mechanism behind cancer resistance has received substantial attention in the field of comparative genomics. However, due to limited available genomes, studies were often only able to cover a small fraction of Mammalian species and underrepresented Marsupials. The aim of this study was to expand on previous work with the analysis of 386 Mammalian species across 6 cancer associated genes (GRB2, FGL2, LITAF, Casp8, IL2 andCD274). To investigate the evolutionary history of the selected genes the study first reconstructed their phylogenetic relationship, and then conducted gene wise and sitespecific selection analysis to determine the level of positive and negative selection on the genes.The analysis showed the genes mostly follow expected phylogenetic relationship and that while there is variation in amino acids amongst genes the important functional sites are typically highly conserved across Mammals. The lack of clear cancer associated pattern in the evolutionary history of the studied genes can be explained by their role in fundamental cellular, organismal and physiological functions, that also constrain their evolution. An important, previously unidentified finding was that the two apoptosis associated domains of the Casp8 gene of bats (Chiroptera) showed different positive and negative signatures of selection. These results highlight the importance of site-specific analyses of selection in order to understand the evolution of highly complex gene families. This study provided an extensive assessment of the cancer associated genes in Mammals with the most representative sample size for a comparative genomic analysis in the field and identified various avenues for future research into the mechanism of cancer resistance and susceptibility in Mammals.