Publications (10)102.92 Total impact
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Article: Rethinking dog domestication by integrating genetics, archeology, and biogeography.
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ABSTRACT: The dog was the first domesticated animal but it remains uncertain when the domestication process began and whether it occurred just once or multiple times across the Northern Hemisphere. To ascertain the value of modern genetic data to elucidate the origins of dog domestication, we analyzed 49,024 autosomal SNPs in 1,375 dogs (representing 35 breeds) and 19 wolves. After combining our data with previously published data, we contrasted the genetic signatures of 121 breeds with a worldwide archeological assessment of the earliest dog remains. Correlating the earliest archeological dogs with the geographic locations of 14 so-called "ancient" breeds (defined by their genetic differentiation) resulted in a counterintuitive pattern. First, none of the ancient breeds derive from regions where the oldest archeological remains have been found. Second, three of the ancient breeds (Basenjis, Dingoes, and New Guinea Singing Dogs) come from regions outside the natural range of Canis lupus (the dog's wild ancestor) and where dogs were introduced more than 10,000 y after domestication. These results demonstrate that the unifying characteristic among all genetically distinct so-called ancient breeds is a lack of recent admixture with other breeds likely facilitated by geographic and cultural isolation. Furthermore, these genetically distinct ancient breeds only appear so because of their relative isolation, suggesting that studies of modern breeds have yet to shed light on dog origins. We conclude by assessing the limitations of past studies and how next-generation sequencing of modern and ancient individuals may unravel the history of dog domestication.Proceedings of the National Academy of Sciences 05/2012; 109(23):8878-83. · 9.68 Impact Factor -
Article: Efficient mapping of mendelian traits in dogs through genome-wide association.
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ABSTRACT: With several hundred genetic diseases and an advantageous genome structure, dogs are ideal for mapping genes that cause disease. Here we report the development of a genotyping array with approximately 27,000 SNPs and show that genome-wide association mapping of mendelian traits in dog breeds can be achieved with only approximately 20 dogs. Specifically, we map two traits with mendelian inheritance: the major white spotting (S) locus and the hair ridge in Rhodesian ridgebacks. For both traits, we map the loci to discrete regions of <1 Mb. Fine-mapping of the S locus in two breeds refines the localization to a region of approximately 100 kb contained within the pigmentation-related gene MITF. Complete sequencing of the white and solid haplotypes identifies candidate regulatory mutations in the melanocyte-specific promoter of MITF. Our results show that genome-wide association mapping within dog breeds, followed by fine-mapping across multiple breeds, will be highly efficient and generally applicable to trait mapping, providing insights into canine and human health.Nature Genetics 12/2007; 39(11):1321-8. · 35.53 Impact Factor -
Article: The dog as a cancer model.
Nature Biotechnology 10/2006; 24(9):1065-6. · 23.27 Impact Factor -
Article: A high-resolution comparative map of canine Chromosome 5q14.3-q33 constructed utilizing the 1.5x canine genome sequence.
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ABSTRACT: A high-density map of the region of canine Chromosome 5 (CFA5) surrounding the evolutionary breakpoint between human Chromosomes 1p32 and 17pll was constructed by integrating a radiation hybrid map including 41 microsatellites, 10 BACs, and 59 genes and a linkage map including 18 markers. A collection of canine genomic survey sequences providing 1.5x coverage was used to identify dog orthologs of human genes, proving instrumental in the development of this map. Of particular interest is the canine BHD gene, within which we have previously described a single nucleotide polymorphism associated with Hereditary Multifocal Renal Cystadenocarcinoma and Nodular Dermatofibrosis (RCND) in German Shepherd dogs. The corresponding region of the human genome is particularly gene rich, containing genes involved in development, metabolism, and cancer that are likely to be of interest in future mapping studies. This current mapping effort on CFA5 expands the degree to which initial findings of linkage in canine families can be followed by successful positional cloning efforts and increases the value of the human genome sequence for defining candidate genes. Moreover, this study demonstrates the utility of genomic survey sequences when combined with accurate genome maps for rapid mapping of disease susceptibility loci.Mammalian Genome 08/2004; 15(7):544-51. · 2.89 Impact Factor -
Article: A high-resolution comparative map of canine Chromosome 5q14.3–q33 constructed utilizing the 1.5× canine genomesequence
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ABSTRACT: A high-density map of the region of canine Chromosome 5 (CFA5) surrounding the evolutionary breakpoint between human Chromosomes 1p32 and 17p11 was constructed by integrating a radiation hybrid map including 41 microsatellites, 10 BACs, and 59 genes and a linkage map including 18 markers. A collection of canine genomic survey sequences providing 1.5 coverage was used to identify dog orthologs of human genes, proving instrumental in the development of this map. Of particular interest is the canine BHD gene, within which we have previously described a single nucleotide polymorphism associated with Hereditary Multifocal Renal Cystadenocarcinoma and Nodular Dermatofibrosis (RCND) in German Shepherd dogs. The corresponding region of the human genome is particularly gene rich, containing genes involved in development, metabolism, and cancer that are likely to be of interest in future mapping studies. This current mapping effort on CFA5 expands the degree to which initial findings of linkage in canine families can be followed by successful positional cloning efforts and increases the value of the human genome sequence for defining candidate genes. Moreover, this study demonstrates the utility of genomic survey sequences when combined with accurate genome maps for rapid mapping of disease susceptibility loci.Mammalian Genome 06/2004; 15(7):544-551. · 2.89 Impact Factor -
Article: The domestic dog genome.
Current Biology 03/2004; 14(3):R98-9. · 9.65 Impact Factor -
Article: A mutation in the canine BHD gene is associated with hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis in the German Shepherd dog.
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ABSTRACT: Hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis (RCND) is a naturally occurring canine kidney cancer syndrome that was originally described in German Shepherd dogs. The disease is characterized by bilateral, multifocal tumors in the kidneys, uterine leiomyomas and nodules in the skin consisting of dense collagen fibers. We previously mapped RCND to canine chromosome 5 (CFA5) with a highly significant LOD score of 16.7 (theta=0.016). We have since narrowed the RCND interval following selection and RH mapping of canine genes from the 1.3 x canine genome sequence. These sequences also allowed for the isolation of gene-associated BACs and the characterization of new microsatellite markers. Ordering of newly defined markers and genes with regard to recombinants localizes RCND to a small chromosomal region that overlaps the human Birt-Hogg-Dubé locus, suggesting the same gene may be responsible for both the dog and the phenotypically similar human disease. We herein describe a disease-associated mutation in exon 7 of canine BHD that leads to the mutation of a highly conserved amino acid of the encoded protein. The absence of recombinants between the disease locus and the mutation in US and Norwegian dogs separated by several generations is consistent with this mutation being the disease-causing mutation. Strong evidence is provided that the RCND mutation may have a homozygous lethal effect (P<0.01).Human Molecular Genetics 12/2003; 12(23):3043-53. · 7.64 Impact Factor -
Article: Amplifying Nuclear and Mitochondrial DNA from African Elephant Ivory: a Tool for Monitoring the Ivory Trade
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ABSTRACT: The ability to extract DNA from ivory provides the basis for genetically tracking the origin of poached ivory and thus has important implications for elephant conservation and management. We describe a method to isolate and amplify both genomic and mitochondrial DNA from African elephant ivory that requires very small amounts of ivory taken from any location on the tusk. We pulverized ivory and isolated DNA with a modified QIAamp kit. Ivory as old as 10 to 20 years, stored at ambient conditions, was amenable to DNA isolation with this method. The isolated DNA was robustly amplified at 16 elephant microsatellite loci and two mitochondrial DNA loci. This method has important applications for the forensic analysis of poached African elephant ivory. It enables determination of where stronger antipoaching efforts are needed and provides the basis for monitoring the extent of the trade as well as the consequences of future international trade decisions.Resumen: La habilidad para extraer ADN del marfil proporciona la base para rastrear genéticamente el origen de marfil furtivo y por tanto tiene implicaciones importantes para la conservación y el manejo de elefantes. Describimos un método para aislar y amplificar ADN genómico y mitocondrial de marfil de elefante africano que requiere de cantidades muy pequeñas de marfil tomadas de cualquier parte del colmillo. Pulverizamos el marfil y aislamos el ADN con un equipo QIAamp modificado. Con este método, fue posible aislar el ADN de marfil de 10 a 20 años, conservado en condiciones ambientales. El ADN aislado fue amplificado robustamente en 16 loci microsatélite y dos loci de ADN mitocondrial. Este método tiene aplicaciones importantes para el análisis forense de marfil de elefantes africanos cazados furtivamente. Permite la identificación de sitios donde se requieren mayores esfuerzos para combatir la cacería furtiva y proporciona la base para monitorear la extensión del comercio así como las consecuencias de decisiones futuras de comercio internacional.Conservation Biology 11/2003; 17(6):1840 - 1843. · 4.69 Impact Factor -
Article: Patterns of molecular genetic variation among African elephant populations.
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ABSTRACT: The highly threatened African elephants have recently been subdivided into two species, Loxodonta africana (savannah or bush elephant) and L. cyclotis (forest elephant) based on morphological and molecular studies. A molecular genetic assessment of 16 microsatellite loci across 20 populations (189 individuals) affirms species level genetic differentiation and provides robust genotypic assessment of species affiliation. Savannah elephant populations show modest levels of phylogeographic subdivision based on composite microsatellite genotype, an indication of recent population isolation and restricted gene flow between locales. The savannah elephants show significantly lower genetic diversity than forest elephants, probably reflecting a founder effect in the recent history of the savannah species.Molecular Ecology 01/2003; 11(12):2489-98. · 5.52 Impact Factor -
Article: A bioluminescent orthotopic mouse model of human osteosarcoma that allows sensitive and rapid evaluation of new therapeutic agents In vivo.
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ABSTRACT: Osteosarcoma (OSA) is the most common primary malignant bone tumor in children, 30% of whom develop lung metastases despite aggressive treatment. Our objective was to develop a mouse model of OSA for preclinical studies that (i) incorporates the natural history of OSA including tumor growth in bone and development of lung metastasis and (ii) is amenable to non-invasive detection methods. A human OSA cell line that expresses high levels of luciferase was created. Following subcutaneous injection, nine out of ten mice showed tumor growth. Eight out of ten mice showed tumor growth following orthotopic injection into the proximal tibia. Thirty percent of mice showed pulmonary metastasis by bioluminescent imaging eight to 10 weeks following orthotopic injection. Animals receiving cisplatin treatment showed reduced tumor volume compared to animals treated with vehicle alone. This model allows real-time detection of tumors and can be used to study mechanisms of OSA metastasis and test new therapeutic agents.In vivo (Athens, Greece) 23(5):661-8. · 1.17 Impact Factor
Top co-authors
Top Journals
- Mammalian Genome (2)
- In vivo (Athens, Greece) (1)
- Current Biology (1)
- Molecular Ecology (1)
- Human Molecular Genetics (1)
Institutions
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2003–2004
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Fred Hutchinson Cancer Research Center
- Division of Clinical Research
Seattle, WA, USA -
Norwegian School of Veterinary Science
Oslo, Oslo, Norway
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