No abstract

A fatal transmissible tumor spread between individuals by biting has emerged in the Tasmanian devil (Sarcophilus harrisii), a carnivorous marsupial. Here we provide genetic evidence establishing that the tumor is clonal and therefore foreign to host devils. Thus, the disease is highly unusual because it is not just a tumor but also a tissue graft, passed between individuals without invoking an immune response. The MHC plays a key role in immune responses to both tumors and grafts. The most common mechanism of immune evasion by tumors is down-regulation of classical cell surface MHC molecules. Here we show that this mode of immune escape does not occur. However, because the tumor is a graft, it should still be recognized and rejected by the host's immune system due to foreign cell surface antigens. Mixed lymphocyte responses showed a lack of alloreactivity between lymphocytes of different individuals in the affected population, indicating a paucity of MHC diversity. This result was verified by genotyping, providing a conclusive link between a loss of MHC diversity and spread of a disease through a wild population. This novel disease arose as a direct result of loss of genetic diversity and the aggressive behavior of the host species. The neoplastic clone continues to spread although the population, and, without active disease control by removal of affected animals and the isolation of diseasefree animals, the Tasmanian devil faces extinction.conservation genetics ͉ Tasmanian devil ͉ wildlife disease ͉ immune evasion

The Tasmanian devil, a marsupial carnivore, is endangered because of the emergence of a transmissible cancer known as devil facial tumor disease (DFTD). This fatal cancer is clonally derived and is an allograft transmitted between devils by biting. We performed a large-scale genetic analysis of DFTD with microsatellite genotyping, a mitochondrial genome analysis, and deep sequencing of the DFTD transcriptome and microRNAs. These studies confirm that DFTD is a monophyletic clonally transmissible tumor and suggest that the disease is of Schwann cell origin. On the basis of these results, we have generated a diagnostic marker for DFTD and identify a suite of genes relevant to DFTD pathology and transmission. We provide a genomic data set for the Tasmanian devil that is applicable to cancer diagnosis, disease evolution, and conservation biology. † To whom correspondence should be addressed. DFTD appears to be a clonal cell line, transmitted (by biting) as an allograft between devils (5,6) and may be similar in transmission to canine transmissible venereal tumor (CTVT) and a transmissible sarcoma affecting Syrian hamsters (7-9). The prevalence and biology of such somatic cell parasites is generally unknown (10).Studies of captive Tasmanian devils have suggested that the species is prone to developing tumors, particularly carcinomas (11,12). However, DFTD does not resemble previously described devil cancers (3,13), and determining its etiology is critical for developing management strategies for the disease. Cytologically, DFTD appears as a soft tissue neoplasm consisting of undifferentiated round to spindle-shaped cells with few defining ultrastructural features (3,13). Immunohistochemistry suggests that the tumor is derived from neuroectoderm (13).Clonal transmission of DFTD was proposed on the basis of karyotypic evidence (5) and was supported by genetic analysis of DFTD tumors at microsatellite and major histocompatibility complex loci (6). We genotyped at 14 micro-satellite loci 25 paired tumor and host samples, as well as 10 samples from DFTD-unaffected devils from 16 locations in Tasmania (14) (figs. S1 and S2 and table S1). All DFTD tumors shared a similar genotype across all loci, regardless of location, sex, or age of the animal (P = 0.18, permutation test) (figs. S1 and S2). Furthermore, the tumor genotype was distinct from that of both the hosts and unaffected devils (P < 0.001, permutation test) (figs. S1 and S2). These data were consistent with previous studies (5,6) and support the supposition that DFTD is a single clonal cell line propagated as a tumor allograft.To further assess the clonal origin of DFTD, we sequenced a 1180-base pair fragment of the mitochondrial locus control region (LCR) from 14 tumors, 14 hosts, and 9 DFTD-unaffected devils (table S2). We found that all devils and tumors shared a single LCR haplotype in this region, except for one single-nucleotide polymorphism at position 15,711, which supported the idea that the tumors are clonal. Furthermore, this nucleotide variant was...

Abstract. A disfiguring and debilitating neoplastic condition known as devil facial tumor disease (DFTD) has been discovered in wild Tasmanian Devils (Sarcophilus harrisii) across 51% of its natural range, with population declines of up to 80% in some areas (C. Hawkins, personal communication). Between 2001 and 2004, 91 cases were examined. The tumors presented as large, solid, soft tissue masses usually with flattened, centrally ulcerated, and exudative surfaces. They were typically multicentric, appearing first in the oral, face, or neck regions. Histologically, the tumors were composed of circumscribed to infiltrative nodular aggregates of round to spindle-shaped cells, often within a pseudocapsule and divided into lobules by delicate fibrous septae. They were locally aggressive and metastasized in 65% of cases. There was minimal cytologic differentiation among the tumor cell population under light and electron microscopic examination. The results indicate DFTD to be an undifferentiated soft tissue neoplasm.

The Tasmanian devil ( Sarcophilus harrisii ) is threatened with extinction because of a contagious cancer known as Devil Facial Tumor Disease. The inability to mount an immune response and to reject these tumors might be caused by a lack of genetic diversity within a dwindling population. Here we report a whole-genome analysis of two animals originating from extreme northwest and southeast Tasmania, the maximal geographic spread, together with the genome from a tumor taken from one of them. A 3.3-Gb de novo assembly of the sequence data from two complementary next-generation sequencing platforms was used to identify 1 million polymorphic genomic positions, roughly one-quarter of the number observed between two genetically distant human genomes. Analysis of 14 complete mitochondrial genomes from current and museum specimens, as well as mitochondrial and nuclear SNP markers in 175 animals, suggests that the observed low genetic diversity in today's population preceded the Devil Facial Tumor Disease disease outbreak by at least 100 y. Using a genetically characterized breeding stock based on the genome sequence will enable preservation of the extant genetic diversity in future Tasmanian devil populations.