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Tasmanian Devil Study Retraces Evolution, Dynamics of Transmissible Cancer

NEW YORK – An international team led by investigators at the University of Cambridge has turned to genomics and phylogenetics to characterize two genetically distinct lineages of transmissible facial cancer in Tasmanian devils.

"Our analysis provides detailed insight into the evolution and diversification of two parallel cancer clones that have survived in a transmissible niche," senior author Elizabeth Murchison, a researcher in the University of Cambridge's Transmissible Cancer Group, and her colleagues wrote.

Tasmanian devils are afflicted by a form of usually fatal facial and oral cancer that is transmitted by bites. First observed in 1996, it has spread throughout the population in two lineages, devil facial tumor 1 (DFT1) and DFT2.

As they reported in Science on Thursday, the researchers performed deep whole-genome sequencing on 78 tumors from DFT1 and 41 tumors from DFT2, which is more recent, comparing the sequences to a non-transmissible carcinoma genome and a newly improved Tasmanian devil reference genome sequence.

"Our study provides many useful resources for the Tasmanian devil and broader genetics research communities," first author Maximilian Stammnitz, a researcher at the University of Cambridge who is currently affiliated with the Barcelona Institute of Science and Technology, said in an email.

By incorporating Oxford Nanopore long-read and ultra-long-read sequence data, 10x Genomics linked-read sequencing, Bionano Genomics optical mapping, and Hi-C chromatin interaction profiling, the team put together a chromosome-level assembly of the Tasmanian devil genome that closed more than 35,000 gaps. A re-annotation effort, helped along by a multi-tissue transcriptome atlas, highlighted more than 19,200 predicted protein-coding genes and thousands more noncoding genes.

When it came to the origins and evolution of the transmissible tumors, the team's time-resolved phylogenetic analyses — which relied on estimated substation mutation rates for each lineage — suggested the original lineage, DFT1, started nearly four decades ago, emerging from a female animal between 1982 to 1989. The more recent DFT2 lineage was traced to between 2009 and 2012, originating in a male devil.

With tumor subclone and phylogenetic clade features, the researchers flagged an early transmission from one donor devil to at least six other animals that occurred while the disease was still under the radar, prompting speculation that an "explosive" infection event may have helped the transmissible tumors take hold in the Tasmanian devil population — or at least shift the trajectory of the condition's inevitable spread.

The team's analyses also revealed genome similarities and differences between tumors in the more entrenched DFT1 lineage and the upstart DFT2 lineage. Although at least one DFT1 tumor branch was marked by DNA mismatch repair defects and elevated mutation rates, the DFT1 tumors tended to have lower mutation rates overall than their DFT2 counterparts.

In particular, the results revealed an uptick in the rate of substitution, small insertion or deletion, copy number, rearrangement, or other mutations in DFT2 tumors, consistent with a higher growth rate and more rapid cell division.

"Overall, our findings suggest that DFT2 has the potential to evolve rapidly and that this disease may turn into another population-level threat if it escapes beyond its current geographical confinements on a southeastern Tasmanian peninsula," Stammnitz said. "We believe that devil conservation leaders and policymakers should take DFT2 very seriously."

Intriguingly, genome sequences for the DFT2 lineage tumors contained somatic mutations linked to LINE-1 transposable element mobilization — a feature not found in DFT1 tumors. The team noted that the Y sex chromosome was missing from five DFT2 tumors characterized, whereas a subset of DFT1 tumors contained loss-of-function mutations affecting the transcription factor-coding gene MGA.

Together, findings from the new study suggest that "Tasmanian devils host a cell type that is poised for transmissible cancer transformation, with only minimal somatic genetic disruption required for these to be unleashed," the authors suggested. "Once established, DFT clones continue to acquire mutations at constant rates, and, although most of these are neutral, a small subset drive further adaptation to the niche."