Presenter Freddie McNay
Authors Freddie McNay, Kevin Gori, Elizabeth Murchison
Affiliations Department of Veterinary Medicine, University of Cambridge
Presentation Type Poster
Abstract
Transmissible cancers spread between individuals via direct transfer of cancer cells, enabling persistence beyond the lifetime of their original host. The Canine Transmissible Venereal Tumour (CTVT), which arose approximately 6000 years ago, is the oldest known somatic cell lineage and provides a powerful model for studying somatic evolution over extended timescales. Since diverging from their last common ancestor, CTVT has diversified into multiple clades, each with distinct genetic features.
Tandem repeat arrays are ubiquitous but unstable genomic regions that represent one of the largest sources of variation in eukaryotic genomes. Repeat instability increases in both cancer and aging, making CTVT an ideal model to investigate long-term tandem repeat dynamics during somatic evolution, offering insight into how repeats accumulate, stabilize, or diversify over extended time periods.
One striking repeat expansion in CTVT is the Homogeneously Staining Region (HSR), a large negatively heteropyknotic region visible cytogenetically as a paler, lightly staining area along the long arm of the second largest submetacentric chromosome. Oshimura et al. (1973) identified the HSR as a massive 45S ribosomal DNA (rDNA) expansion, but its precise structure and function remained unclear.
Using modern long-read sequencing, we have elucidated the HSR’s repeat unit structure, revealing that the expansion primarily involves the intergenic spacer region, with modest amplification of rDNA genes themselves. Fluorescent in-situ hybridization validates this structure. The HSR is highly methylated, suggesting epigenetic silencing of expanded rDNA copies, and spans approximately 10Mb, though this size varies considerably across CTVT cases and clades.
This comprehensive characterization of an ancient, massive rDNA expansion in a naturally occurring transmissible cancer provides further evidence of the high rDNA instability documented in cancer and aging.