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Cancers in pet dogs are prevalent, progress rapidly, and closely resemble human cancers, positioning them as powerful models for precision oncology. While genetic drivers of human cancer often transcend histologic boundaries, most comparative studies have focused on matched cancer types, leaving the broader scope of genomic similarity unresolved. We performed the first exome-wide, histology-agnostic comparison of canine and human cancers, analyzing 429 dog and 14,966 human tumors across 39 types. Mutational signatures and genes under selection are widely shared between species, and cancer types are as genomically similar between species as within species, with no greater similarity within dog breeds than between breeds. Machine-learning models identify genetic features shared by dog and human tumors of different histologies, mirroring cross-histology patterns in human cancer. These findings establish dog cancer as a powerful system for genomics-informed precision oncology and support pan cancer approaches to discover translationally relevant models beyond histologic classification. 

Abstract Timber rattlesnakes (Crotalus horridus) face escalating threats in the Northeastern Appalachians, including habitat fragmentation, human encroachment, and the fungal pathogenOphidiomyces ophiodiicola. Using untargeted sequencing of DNA extracted from scale clips, we generated both host whole-genome and metagenomic data for 97 snakes from eight populations. Analysis of the snake genomes shows the populations surveyed exhibit relatively low levels of inbreeding and are genetically distinct, but that the degree of separation correlates only weakly with geographic distance. A genome-wide association analysis identified a locus associated with black-to-yellow color variation that contains an aldehyde dehydrogenase gene (ALDH4A1) related to genes involved in hair color differences in humans. Metagenomic analysis showed thatO. ophiodiicolaread counts were generally higher in snakes exhibiting clinical signs of Snake Fungal Disease, but some visually asymptomatic snakes had high pathogen loads. Together, these findings highlight the dual utility of untargeted sequencing for population genetics and pathogen surveillance, providing a foundation for future studies of adaptation, disease dynamics, and conservation in this declining species.