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Tasmanian devils ( Sarcophilus harrisii ) are evolving in response to a unique transmissible cancer, devil facial tumour disease (DFTD), first described in 1996. Persistence of wild populations and the recent emergence of a second independently evolved transmissible cancer suggest that transmissible cancers may be a recurrent feature in devils. Here, we compared signatures of selection across temporal scales to determine whether genes or gene pathways under contemporary selection (six to eight generations) have also been subject to historical selection (65-85 Myr). First, we used targeted sequencing, RAD-capture, in approximately 2500 devils in six populations to identify genomic regions subject to rapid evolution. We documented genome-wide contemporary evolution, including 186 candidate genes related to cell cycling and immune response. Then we used a molecular evolution approach to identify historical positive selection in devils compared to other marsupials and found evidence of selection in 1773 genes. However, we found limited overlap across time scales, with only 16 shared candidate genes, and no overlap in enriched functional gene sets. Our results are consistent with a novel, multi-locus evolutionary response of devils to DFTD. Our results can inform conservation by identifying high priority targets for genetic monitoring and guiding maintenance of adaptive potential in managed populations.

Genetic structure in host species is often used to predict disease spread. However, host and pathogen genetic variation may be incongruent. Understanding landscape factors that have either concordant or divergent influence on host and pathogen genetic structure is crucial for wildlife disease management. Devil facial tumour disease (DFTD) was first observed in 1996 and has spread throughout almost the entire Tasmanian devil geographic range, causing dramatic population declines. Whereas DFTD is predominantly spread via biting among adults, devils typically disperse as juveniles, which experience low DFTD prevalence. Thus, we predicted little association between devil and tumour population structure and that environmental factors influencing gene flow differ between devils and tumours. We employed a comparative landscape genetics framework to test the influence of environmental factors on patterns of isolation by resistance (IBR) and isolation by environment (IBE) in devils and DFTD. Although we found evidence for broad-scale costructuring between devils and tumours, we found no relationship between host and tumour individual genetic distances. Further, the factors driving the spatial distribution of genetic variation differed for each. Devils exhibited a strong IBR pattern driven by major roads, with no evidence of IBE. By contrast, tumours showed little evidence for IBR and a weak IBE pattern with respect to elevation in one of two tumour clusters we identify herein. Our results warrant caution when inferring pathogen spread using host population genetic structure and suggest that reliance on environmental barriers to host connectivity may be ineffective for managing the spread of wildlife diseases. Our findings demonstrate the utility of comparative landscape genetics for identifying differential factors driving host dispersal and pathogen transmission., (© 2020 John Wiley & Sons Ltd.)

Understanding the genetic basis of disease-related phenotypes, such as cancer susceptibility, is crucial for the advancement of personalized medicine. Although most cancers are somatic in origin, a small number of transmissible cancers have been documented. Two such cancers have emerged in the Tasmanian devil (Sarcophilus harrisii) and now threaten the species with extinction. Recently, cases of natural tumor regression in Tasmanian devils infected with the clonally contagious cancer have been detected. We used whole-genome sequencing and FST-based approaches to identify the genetic basis of tumor regression by comparing the genomes of seven individuals that underwent tumor regression with those of three infected individuals that did not. We found three highly differentiated candidate genomic regions containing several genes related to immune response and/or cancer risk, indicating that the genomic basis of tumor regression was polygenic. Within these genomic regions, we identified putative regulatory variation in candidate genes but no nonsynonymous variation, suggesting that natural tumor regression may be driven, at least in part, by differential host expression of key loci. Comparative oncology can provide insight into the genetic basis of cancer risk, tumor development, and the pathogenicity of cancer, particularly due to our limited ability to monitor natural, untreated tumor progression in human patients. Our results support the hypothesis that host immune response is necessary for triggering tumor regression, providing candidate genes that may translate to novel treatments in human and nonhuman cancers.

Identifying the genetic architecture of complex phenotypes is a central goal of modern biology, particularly for disease-related traits. Genome-wide association methods are a classical approach for identifying the genomic basis of variation in disease phenotypes, but such analyses are particularly challenging in natural populations due to sample size difficulties. Extensive mark-recapture data, strong linkage disequilibrium and a lethal transmissible cancer make the Tasmanian devil (Sarcophilus harrisii) an ideal model for such an association study. We used a RAD-capture approach to genotype 624 devils at ~16,000 loci and then used association analyses to assess the heritability of three cancer-related phenotypes: infection case-control (where cases were infected devils and controls were devils that were never infected), age of first infection and survival following infection. The SNP array explained much of the phenotypic variance for female survival (>80%) and female case-control (>61%). We found that a few large-effect SNPs explained much of the variance for female survival (~5 SNPs explained >61% of the total variance), whereas more SNPs (~56) of smaller effect explained less of the variance for female case-control (~23% of the total variance). By contrast, these same SNPs did not account for a significant proportion of phenotypic variance in males, suggesting that the genetic bases of these traits and/or selection differ across sexes. Loci involved with cell adhesion and cell-cycle regulation underlay trait variation, suggesting that the devil immune system is rapidly evolving to recognize and potentially suppress cancer growth through these pathways. Overall, our study provided necessary data for genomics-based conservation and management in Tasmanian devils., (© 2018 John Wiley & Sons Ltd.)