Disease Associated Loss of an MHC Locus in the Tasmanian Devil: Evolutionary Consequences for Devil Facial Tumour Disease Resistance

Abstract Transmissible cancers in the Tasmanian devil ( Sarcophilus harrisii ) provide a rare natural experiment for understanding how strong, contemporary disease pressure shapes vertebrate immune gene evolution. The emergence and spread of devil facial tumour disease (DFTD) have long been hypothesised to favour host–tumour MHC dissimilarity and to drive selection at MHC class I (MHC-I) loci, yet direct empirical evidence has been lacking. Here we demonstrate, for the first time, disease mediated loss (“death”) of an MHC-I locus in the wild. These findings extend the classical birth-and-death model by showing that “death” of an MHC locus can be an adaptive, disease-driven process, rather than only a passive outcome of duplication and relaxed constraint. Using long read MHC genotyping combined with temporal population sampling and a functional immune phenotype, we show that devils whose MHC-I alleles differ from those expressed by devil facial tumour 1 (DFT1) cells are more likely to mount alloreactive antibody responses. A non functional deletion of the classical MHC-I gene Saha UA is strongly associated with antibody production, and this deletion has increased in frequency across multiple DFTD affected sites within just a few generations. In parallel, MHC-I supertypes shared with the tumour (notably supertype 2) have declined in frequency, demonstrating directional selection against tumour matching alleles and reshaping of MHC-I gene architecture at the population level. In contrast, MHC-I allele frequencies remained stable at the only long term DFTD free site, confirming that these shifts are disease driven rather than neutral drift. These findings provide the first clear evidence of pathogen driven contraction of MHC-I diversity in a wildlife species. While this evolutionary response may enhance resistance to DFT1, the loss of MHC-I diversity may reduce future resilience to emerging pathogens, underscoring the importance of maintaining immunogenetic variation in ongoing conservation management.