Epistatic interactions in the evolution of Tasmanian devils and their transmissible cancer

Epistasis, the interaction among genetic loci whereby the effect of one variant depends on variation at other loci, shapes phenotypic variation and evolutionary trajectories across life. Cancer, a leading cause of death globally, provides a particularly compelling context for epistasis due to its clonal reproduction. Transmissible cancers, a rare subset of cancers capable of horizontal transmission between hosts, represent a unique evolutionary system in which tumor cells function as infectious agents. Considering the simultaneous maintenance of both within-host fitness and between-host transmissibility, many phenotypes in transmissible cancers and their hosts are likely governed by epistatic interactions. Yet the role of epistasis in the evolution of transmissible cancers remains largely unexplored. Here, we investigated epistatic interactions associated with host susceptibility to devil facial tumor disease 1 (DFT1), a species-specific transmissible cancer afflicting Tasmanian devils (Sarcophilus harrisii), using marginal epistasis tests applied to 312 matched devil–tumor paired genomes. We identified 50 candidate epistatic single nucleotide polymorphisms (SNPs) in devils, with gene ontology enrichment for glutathione transferase activity, adenosine triphosphate (ATP) synthesis, and sensory perception of chemical stimuli, implicating oxidative stress response, metabolic reprogramming, and potentially olfactory-mediated disease avoidance in shaping host susceptibility. In contrast, only two significant SNPs were detected in DFT1, potentially suggesting a reduced epistatic contribution to tumor transmissibility compared with host susceptibility. Here, we have documented evidence of epistasis contributing to a disease-related trait in both devils and DFT1, highlighting the need to account for epistatic interactions in future studies of transmissible cancer evolution and host-pathogen dynamics more broadly.