Comparison against 186 canid whole genome sequences reveals survival strategies of an ancient clonally transmissible canine tumor
Ontology highlight
ABSTRACT: Whole genome sequencing of CTVT, breed dogs, and wild canids reveals pathways that are important in cancer cell survival. Comparison of these mutations with breed dogs shows that the original tumor came from a dog very similar to one of the modern Arctic breeds.
Project description:Whole genome sequencing of CTVT, breed dogs, and wild canids reveals pathways that are important in cancer cell survival. Comparison of these mutations with breed dogs shows that the original tumor came from a dog very similar to one of the modern Arctic breeds. DNA was collected from pedigreed dogs of the Alaskan Malamute (AMAL) and Siberian Husky (HUSK) breeds living in North America. SNPs were genotyed using the Illumina CanineHD SNP chip. These SNPs were compared to published data and seqeunced mutations from CTVT by principal component alnalysis to identify the breed of the CTVT originator.
Project description:Canine transmissible venereal tumor (CTVT) is a parasitic cancer clone that has propagated for thousands of years via sexual transfer of malignant cells. Little is understood about the mechanisms that converted an ancient tumor into the world's oldest known continuously propagating somatic cell lineage. We created the largest existing catalog of canine genome-wide variation and compared it against two CTVT genome sequences, thereby separating alleles derived from the founder's genome from somatic mutations that must drive clonal transmissibility. We show that CTVT has undergone continuous adaptation to its transmissible allograft niche, with overlapping mutations at every step of immunosurveillance, particularly self-antigen presentation and apoptosis. We also identified chronologically early somatic mutations in oncogenesis- and immune-related genes that may represent key initiators of clonal transmissibility. Thus, we provide the first insights into the specific genomic aberrations that underlie CTVT's dogged perseverance in canids around the world.
Project description:Dog breeding promotes within-group homogeneity through conformation to strict breed standards and also drives between-group heterogeneity in pursuit of distinct morphological forms and characteristic breed traits. In this study, the genotype-first approach was adapted to the dog genome to investigate coding variation from over 2000 dogs, leading to discoveries of new mutations related to craniofacial morphology and stature. Breed enriched variants were prioritized according to gene constraint, which was calculated using a mutation model derived from trinucleotide substitution probabilities in the dog. Most priority variants were not associated with genomic signatures for breed differentiation, as these regions were enriched for constrained genes intolerant to nonsynonymous variation, suggesting a model of breed phenotype diversification based on regulatory changes to essential genes. Identification of trait-associated variants in dogs informs new biological roles of genes. Improved collection of breed disease risk data, along with increased breed representation, will drive further discoveries.
Project description:Free-breeding dogs have occupied the Galápagos islands at least since the 1830s, however, it was not until the 1900s that dog populations grew substantially, endangering wildlife and spreading disease. In 1981, authorities sanctioned the culling of free-roaming dogs. Yet there are currently large free-roaming dog populations of unknown ancestry on the islands of Isabela and Santa Cruz, whose ancestry has never been assessed on a genome-wide scale. Thus, we performed a complete genomic analysis of the current Galápagos dog population as well as historical Galápagos dogs sampled between 1969 and 2003, testing for population structure, admixture, and shared ancestry. Our dataset included samples from 187 modern and six historical Galápagos dogs, together with whole genome sequence from over 2,000 modern purebred and village dogs. Our results indicate that modern Galápagos dogs are recently admixed with purebred dogs but show no evidence of a population bottleneck related to the culling. Additionally, IBD analyses reveal evidence of shared shepherd-dog ancestry in the historical Galápagos dogs. Overall, our results demonstrate that the 1980s culling of dogs was ineffective in controlling population size and did little to reduce genetic diversity, instead producing a stable and expanding population with genomic signatures of historical dogs remaining today. The insights from this study can be used to improve population control strategies for the Galápagos Islands and other endangered endemic communities worldwide.
Project description:DNA structural variation (SV) comprises a major portion of genetic diversity, but its biological impact is unclear. We propose that the genetic history and extraordinary phenotypic variation of dogs make them an ideal mammal in which to study the effects of SV on biology and disease. The hundreds of existing dog breeds were created by selection of extreme morphological and behavioral traits. And along with those traits, each breed carries increased risk for different diseases. We used array CGH to create the first map of DNA copy number variation (CNV) or SV in dogs. The extent of this variation, and some of the gene classes affected, are similar to those of mice and humans. Most canine CNVs affect genes, including disease and candidate disease genes, and are thus likely to be functional. We identified many CNVs that may be breed or breed class specific. Cluster analysis of CNV regions showed that dog breeds tend to group according to breed classes. Our combined findings suggest many CNVs are (1) in linkage disequilibrium with flanking sequence, and (2) associated with breed specific traits. We discuss how a catalog of structural variation in dogs will accelerate the identification of the genetic basis of canine traits and diseases, beginning with the use of whole genome association and candidate CNV/gene approaches. Chen WK, Swartz JD, Rush LJ, Alvarez, CE. Mapping DNA structural variation in dogs. Genome Res. 2009. 19: 500 509 PMID: 19015322 Array comparitive genomic hybridization analysis of structural variation in 9 dogs, and 1 lymphoma cell line.
Project description:DNA structural variation (SV) comprises a major portion of genetic diversity, but its biological impact is unclear. We propose that the genetic history and extraordinary phenotypic variation of dogs make them an ideal mammal in which to study the effects of SV on biology and disease. The hundreds of existing dog breeds were created by selection of extreme morphological and behavioral traits. And along with those traits, each breed carries increased risk for different diseases. We used array CGH to create the first map of DNA copy number variation (CNV) or SV in dogs. The extent of this variation, and some of the gene classes affected, are similar to those of mice and humans. Most canine CNVs affect genes, including disease and candidate disease genes, and are thus likely to be functional. We identified many CNVs that may be breed or breed class specific. Cluster analysis of CNV regions showed that dog breeds tend to group according to breed classes. Our combined findings suggest many CNVs are (1) in linkage disequilibrium with flanking sequence, and (2) associated with breed specific traits. We discuss how a catalog of structural variation in dogs will accelerate the identification of the genetic basis of canine traits and diseases, beginning with the use of whole genome association and candidate CNV/gene approaches. Chen WK, Swartz JD, Rush LJ, Alvarez, CE. Mapping DNA structural variation in dogs. Genome Res. 2009. 19: 500 509 PMID: 19015322
Project description:Diverse dataset of 1247 dogs from many breeds and wolves used to investigate the origins of dog domestication DNA for 1228 dogs from 35 breeds and 19 wolves was extracted from whole blood samples and genotyped on the Affymetrix Canine v2 Arrays. Genotypes were called using Affymetrix's snp5-probeset-genotype software and the BRLMM-P calling algorithm. The included breed designations are owner reported.
Project description:Through thousands of years of breeding and strong human selection, the dog (Canis lupus familiaris) exists today within hundreds of closed populations throughout the world, each with defined phenotypes. A singular geographic region with broad diversity in dog breeds presents an interesting opportunity to observe potential mechanisms of breed formation. Italy claims 14 internationally recognized dog breeds, with numerous additional local varieties. To determine the relationship among Italian dog populations, we integrated genetic data from 263 dogs representing 23 closed dog populations from Italy, seven Apennine gray wolves. Using 142,840 genome-wide SNPs, this dataset was used in the identification of breed development routes for the Italian breeds that included divergence from common populations for a specific purpose, admixture of regional stock with that from other regions, and isolated selection of local stock with specific attributes.
Project description:The intent of the experiment was to identify genes that were differentially expressed between dogs affected with anterior cruciate ligament (ACL) rupture and breed-matched controls. Anterior cruciate ligament and knee synovial tissue biopsies were collected from 4 ACL rupture affected cases and 4 unaffected control dogs. Cases and controls were matched as closely as possible based on breed, sex, neutered status, age, and weight. Medications that the dogs were taking at the time of sample collection were also considered. We prioritized sample size and quality above all other variables, therefore, two matched pairs of Golden Retrievers were chosen with two matched pairs of Labrador Retrievers for this analysis. Tissues from cases were collected during knee stabilization surgery. Tissues from unaffected control dogs were collected from dogs undergoing pelvic limb amputation or euthanasia for reasons unrelated to this study. Illumina TruSeq RNA libraries were constructed and 150bp paired-end sequencing was performed using the Illumina Hi-Seq 2500 platform. Table 1. Breed, sex, age, and weight of matched case and control pairs chosen for RNA sequencing analysis Cases Matched Controls Breed Sex Age (yr) Weight (kg) Breed Sex Age (yr) Weight (kg) GR1 CM 8.8 30.5 GR2 CM 14.9 N/A GR3 CM 5.6 44.0 GR4 CM 3.9 34.0 LR1 CM 9.7 36.0 LR2 CM 12.7 28.5 LR3 CM 13.3 36.0 LR4 CM 13.5 35.0 GR = Golden Retriever. LR = Labrador Retriever. CM= castrated male. Weight at the time of death was not available for one dog.
Project description:The inherent diversity of canines is closely intertwined with the unique color patterns of each dog population. These variations in color patterns are believed to have originated through mutations and selective breeding practices that occurred during and after the domestication of dogs from wolves. To address the significant gaps that persist in comprehending the evolutionary processes that underlie the development of these patterns, we generated and analyzed deep-sequenced genomes of 113 Korean indigenous Jindo dogs that represent five distinct color patterns to identify the associated mutations in CBD103, ASIP, and MC1R. The degree of linkage disequilibrium and estimated allelic ages consistently indicate that the black-and-tan dogs descend from the first major founding population on Jindo island, compatible with the documented literature. We additionally demonstrate that black-and-tan dogs, in contrast to other color variations within the breed, exhibit a closer genetic affinity to ancient wolves from western Eurasia than those from eastern Eurasia. Lastly, population-specific genetic variants with moderate effects were identified, particularly in loci associated with traits underlying body size and behavioral variations, potentially explaining the observed phenotypic diversity based on coat colors. Overall, comparisons of whole genome sequences of each coat color population diverged from the same breed provided an unprecedented glimpse into the properties of evolutionary processes maintaining variation in Korean Jindo dog populations that were previously inaccessible.