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Title: Genome diversity and evolution in canine transmissible venereal tumour
Author: Strakova, Andrea
ISNI:       0000 0004 7227 9469
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2018
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The canine transmissible venereal tumour (CTVT) is a contagious cancer that is naturally transmitted between dogs by the allogeneic transfer of living cancer cells during coitus. CTVT first arose several thousand years ago and has been reported in dog populations worldwide. The goals of this Thesis were (1) to gain further understanding of CTVT distribution patterns and prevalence around the world, (2) to use genetics to trace the historical spread of CTVT and (3) to map the genetic as well as phenotypic diversity of CTVT tumours around the world. To understand the distribution patterns of CTVT, I obtained information from 645 veterinarians and animal health workers in 109 countries, and generated a snapshot of the locations in which this disease is found. Additionally, as preparation for further genetic analysis, I collected samples from over one thousand CTVT cases from more than 50 countries, optimised methods for high-throughput DNA extraction and quantification and optimised a qPCR-based assay for CTVT diagnosis and host contamination detection. With the goal of tracing the historical spread of CTVT and learning about the genetic diversity of this disease, I sequenced complete mitochondrial genomes of 449 CTVT tumours and their matched hosts. The analysis of the CTVT mitochondrial diversity revealed that CTVT has captured mitochondrial DNA (mtDNA) through horizontal transfer events at least five times during the history of the lineage, delineating five tumour clades. CTVT appears to have spread rapidly around the world within the last 2,000 years, perhaps transported by dogs travelling along historic maritime trade routes. This work indicated that negative selection has operated to prevent accumulation of deleterious mutations in captured mtDNA, and that recombination has caused occasional mtDNA re-assortment. A histology-based screen of CTVT clades did not show any significant phenotypic differences between groups. In order to determine how the five mtDNA clades relate to each other, I analysed data from 539 CTVT exomes. This revealed that a single canine mtDNA haplogroup has recurrently and recently undergone multiple horizontal transfer events. Analysis of this haplotype highlighted a number of candidate genetic variants which may be conferring a selective advantage to this haplotype in CTVT, possibly by influencing mtDNA transcription or replication. Overall, genetic and phenotypic analysis of CTVT tumours from across the globe has broadened our understanding of CTVT diversity, and provided important insights into the biology of a unique transmissible cancer.
Supervisor: Murchison, Elizabeth P. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: canine transmissible venereal tumour ; cancer ; veterinary ; transmissible cancer ; canine ; dog ; genetics ; DNA sequencing ; evolution ; CTVT ; worldwide distribution ; histology ; mitochondrial genome ; contagious cancer ; CTVT distribution and prevalence ; historical spread ; genetic diversity ; phenotypic diversity