Somatic evolution and global expansion of an ancient transmissible cancer lineage

Made available in DSpace on 2019-10-06T15:53:36Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-08-02GPD Charitable TrustLeverhulme TrustThe canine transmissible venereal tumor (CTVT) is a cancer lineage that arose several millennia ago and survives by “metastasizing” between hosts through cell transfer. The somatic mutations in this cancer record its phylogeography and evolutionary history. We constructed a time-resolved phylogeny from 546 CTVT exomes and describe the lineage's worldwide expansion. Examining variation in mutational exposure, we identify a highly context-specific mutational process that operated early in the cancer's evolution but subsequently vanished, correlate ultraviolet-light mutagenesis with tumor latitude, and describe tumors with heritable hyperactivity of an endogenous mutational process. CTVT displays little evidence of ongoing positive selection, and negative selection is detectable only in essential genes. We illustrate how long-lived clonal organisms capture changing mutagenic environments, and reveal that neutral genetic drift is the dominant feature of long-term cancer evolution.Transmissible Cancer Group Department of Veterinary Medicine University of CambridgeAnimal Management in Rural and Remote Indigenous Communities (AMRRIC)World VetsAnimal Shelter Stichting Dierenbescherming SurinameSikkim Anti-Rabies and Animal Health Programme Department of Animal Husbandry Livestock Fisheries and Veterinary Services Government of SikkimRoyal (Dick) School of Veterinary Studies Roslin Institute University of Edinburgh Easter Bush CampusConserLab Animal Preventive Medicine Department Faculty of Animal and Veterinary Sciences University of ChileCorozal Veterinary Hospital University of PanamáSt. George's UniversityNakuru District Veterinary Scheme LtdAnimal Medical CentreInternational Animal Welfare Training Institute UC Davis School of Veterinary MedicineCentro Universitário de Rio Preto (UNIRP)Department of Clinical and Veterinary Surgery São Paulo State University (UNESP)Ladybrand Animal ClinicVeterinary Clinic Sr. Dog'sWorld Vets Latin America Veterinary Training CenterNational Veterinary Research InstituteAnimal ClinicIntermunicipal Stray Animals Care Centre (DIKEPAZ)Animal Protection Society of SamoaFaculty of Veterinary Science University of ZuliaVeterinary Clinic BIOCONTROLFaculty of Veterinary Medicine School of Health Sciences University of ThessalyVeterinary Clinic El Roble Animal Healthcare Network Faculty of Animal and Veterinary Sciences University of ChileOnevetGroup Hospital Veterinário BernaUniversidade Vila VelhaVeterinary Clinic ZoovetservisÉcole Inter-états des Sciences et Médecine Vétérinaires de DakarDepartment of Small Animal Medicine Faculty of Veterinary Medicine Utrecht UniversityVetexpert Veterinary GroupVeterinary Clinic Lopez QuintanaClinique Veterinaire de Grand Fond Saint Gilles les BainsDepartment of Veterinary Sciences University of MessinaFacultad de Medicina Veterinaria y Zootecnia Universidad Autónoma del Estado de MéxicoSchool of Veterinary Medicine Universidad de las AméricasCancer Development and Innate Immune Evasion Lab Champalimaud Center for the UnknownTouray and Meyer Vet ClinicHillside Animal HospitalKampala Veterinary SurgeryAsavet Veterinary CharitiesVets Beyond BordersFaculty of Veterinary Medicine Autonomous University of YucatanLaboratorio de Patología Veterinaria Universidad de CaldasInterdisciplinary Centre of Research in Animal Health (CIISA) Faculty of Veterinary Medicine University of LisbonFour Paws InternationalHelp in SufferingVeterinary Clinic Dr José RojasDepartment of Biotechnology Balochistan University of Information Technology Engineering and Management SciencesCorozal Veterinary ClinicVeterinary Clinic VetmasterState Hospital of Veterinary MedicineJomo Kenyatta University of Agriculture and TechnologyLaboratory of Biomedicine and Regenerative Medicine Department of Clinical Sciences Faculty of Animal and Veterinary Sciences University of ChileFaculty of Veterinary and Agricultural Sciences University of MelbourneAnimal Anti Cruelty LeagueClinical Sciences Department Faculty of Veterinary Medicine BucharestDepartment of Pathology Faculty of Veterinary Medicine Ankara UniversityFaculty of Veterinary Sciences National University of AsuncionLilongwe Society for Protection and Care of Animals (LSPCA)Wellcome Sanger InstituteDepartment of Cellular and Molecular Medicine University of California San DiegoDepartment of Clinical and Veterinary Surgery São Paulo State University (UNESP)Leverhulme Trust: 102942/Z/13/

Recurrent horizontal transfer identifies mitochondrial positive selection in a transmissible cancer

Abstract: Autonomous replication and segregation of mitochondrial DNA (mtDNA) creates the potential for evolutionary conflict driven by emergence of haplotypes under positive selection for ‘selfish’ traits, such as replicative advantage. However, few cases of this phenomenon arising within natural populations have been described. Here, we survey the frequency of mtDNA horizontal transfer within the canine transmissible venereal tumour (CTVT), a contagious cancer clone that occasionally acquires mtDNA from its hosts. Remarkably, one canine mtDNA haplotype, A1d1a, has repeatedly and recently colonised CTVT cells, recurrently replacing incumbent CTVT haplotypes. An A1d1a control region polymorphism predicted to influence transcription is fixed in the products of an A1d1a recombination event and occurs somatically on other CTVT mtDNA backgrounds. We present a model whereby ‘selfish’ positive selection acting on a regulatory variant drives repeated fixation of A1d1a within CTVT cells