PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-24 (24)
 

Clipboard (0)
None

Select a Filter Below

Year of Publication
1.  Genomic Analyses of Modern Dog Breeds 
A rose may be a rose by any other name, but when you call a dog a poodle it becomes a very different animal than if you call it a bulldog. Both the poodle and the bulldog are examples of dog breeds of which there are >400 recognized world-wide. Breed creation has played a significant role in shaping the modern dog from the length of his leg to the cadence of his bark. The selection and line-breeding required to maintain a breed has also reshaped the genome of the dog resulting in a unique genetic pattern for each breed. The breed-based population structure combined with extensive morphologic variation and shared human environments have made the dog a popular model for mapping both simple and complex traits and diseases. In order to obtain the most benefit from the dog as a genetic system, it is necessary to understand the effect structured breeding has had on the genome of the species. That is best achieved by looking at genomic analyses of the breeds, their histories, and their relationships to each other.
doi:10.1007/s00335-011-9387-6
PMCID: PMC3559126  PMID: 22231497
2.  Canine Genomics and Genetics: Running with the Pack 
PLoS Genetics  2005;1(5):e58.
ABSTRACT
The domestication of the dog from its wolf ancestors is perhaps the most complex genetic experiment in history, and certainly the most extensive. Beginning with the wolf, man has created dog breeds that are hunters or herders, big or small, lean or squat, and independent or loyal. Most breeds were established in the 1800s by dog fanciers, using a small number of founders that featured traits of particular interest. Popular sire effects, population bottlenecks, and strict breeding programs designed to expand populations with desirable traits led to the development of what are now closed breeding populations, with limited phenotypic and genetic heterogeneity, but which are ideal for genetic dissection of complex traits. In this review, we first discuss the advances in mapping and sequencing that accelerated the field in recent years. We then highlight findings of interest related to disease gene mapping and population structure. Finally, we summarize novel results on the genetics of morphologic variation.
doi:10.1371/journal.pgen.0010058
PMCID: PMC1287952  PMID: 16311623
3.  Canine Genomics and Genetics: Running with the Pack 
PLoS Genetics  2005;1(5):e58.
ABSTRACT
The domestication of the dog from its wolf ancestors is perhaps the most complex genetic experiment in history, and certainly the most extensive. Beginning with the wolf, man has created dog breeds that are hunters or herders, big or small, lean or squat, and independent or loyal. Most breeds were established in the 1800s by dog fanciers, using a small number of founders that featured traits of particular interest. Popular sire effects, population bottlenecks, and strict breeding programs designed to expand populations with desirable traits led to the development of what are now closed breeding populations, with limited phenotypic and genetic heterogeneity, but which are ideal for genetic dissection of complex traits. In this review, we first discuss the advances in mapping and sequencing that accelerated the field in recent years. We then highlight findings of interest related to disease gene mapping and population structure. Finally, we summarize novel results on the genetics of morphologic variation.
doi:10.1371/journal.pgen.0010058
PMCID: PMC1287952  PMID: 16311623
4.  A Copy Number Variant at the KITLG Locus Likely Confers Risk for Canine Squamous Cell Carcinoma of the Digit 
PLoS Genetics  2013;9(3):e1003409.
The domestic dog is a robust model for studying the genetics of complex disease susceptibility. The strategies used to develop and propagate modern breeds have resulted in an elevated risk for specific diseases in particular breeds. One example is that of Standard Poodles (STPOs), who have increased risk for squamous cell carcinoma of the digit (SCCD), a locally aggressive cancer that causes lytic bone lesions, sometimes with multiple toe recurrence. However, only STPOs of dark coat color are at high risk; light colored STPOs are almost entirely unaffected, suggesting that interactions between multiple pathways are necessary for oncogenesis. We performed a genome-wide association study (GWAS) on STPOs, comparing 31 SCCD cases to 34 unrelated black STPO controls. The peak SNP on canine chromosome 15 was statistically significant at the genome-wide level (Praw = 1.60×10−7; Pgenome = 0.0066). Additional mapping resolved the region to the KIT Ligand (KITLG) locus. Comparison of STPO cases to other at-risk breeds narrowed the locus to a 144.9-Kb region. Haplotype mapping among 84 STPO cases identified a minimal region of 28.3 Kb. A copy number variant (CNV) containing predicted enhancer elements was found to be strongly associated with SCCD in STPOs (P = 1.72×10−8). Light colored STPOs carry the CNV risk alleles at the same frequency as black STPOs, but are not susceptible to SCCD. A GWAS comparing 24 black and 24 light colored STPOs highlighted only the MC1R locus as significantly different between the two datasets, suggesting that a compensatory mutation within the MC1R locus likely protects light colored STPOs from disease. Our findings highlight a role for KITLG in SCCD susceptibility, as well as demonstrate that interactions between the KITLG and MC1R loci are potentially required for SCCD oncogenesis. These findings highlight how studies of breed-limited diseases are useful for disentangling multigene disorders.
Author Summary
Domesticated dogs offer a unique mechanism for disentangling complex genetic traits, such as cancer. Over 300 breeds exist worldwide, each selected for particular morphologic and behavioral traits. Unfortunately the breeding programs used to generate such diversity are associated with breed-specific increase in disease. Squamous cell carcinoma of the digit (SCCD) is a locally aggressive cancer that causes lytic bone lesions and, occasionally, death. Among the breeds with the highest risk is the Standard Poodle (STPO), where the disease is found only in dark-coated dogs. We show that the KITLG locus is highly associated with SCCD and that a 5.7-Kb copy number variant is likely causative for the disease when in an expanded form. Interestingly, light-colored STPO carry the putative causal variant at the same frequency as black STPOs, but are protected from SCCD. We show this is likely due to a compensatory mutation in the well-known coat color locus, MC1R. This work demonstrates the utility of dog breeds for understanding the genetic causes of complex diseases of interest to both human and animal health.
doi:10.1371/journal.pgen.1003409
PMCID: PMC3610924  PMID: 23555311
5.  Myxomatous mitral valve disease in dogs: Does size matter? 
Myxomatous mitral valve disease (MMVD) is the most commonly diagnosed cardiovascular disease in the dog accounting for more than 70% of all cardiovascular disease in dogs. As are most canine diseases with genetic underpinnings, risk of MMVD is greatly increased in a subset of breeds. What is uncommon is that the vast majority of the breeds at elevated risk for MMVD are small or toy breeds with average adult weights under 9 kg. These breeds appear to have little in common other than their diminutive size. In the following review we propose a number of mechanisms by which relatively unrelated small breeds may have developed a predisposition for chronic valvular disorders. Although factors such as age are key in the expression of MMVD, taking a comprehensive look at the commonalities, as well as the differences, between the susceptible breeds may assist in finding the causal variants responsible for MMVD and translating them to improved treatments for both dogs and humans.
doi:10.1016/j.jvc.2012.01.006
PMCID: PMC3307894  PMID: 22356836
Canine genetics; degenerative valve disease; canine phenotype; dog breeds
6.  Finding Cardiovascular Disease Genes in the Dog 
Recent advances in canine genomics are changing the landscape of veterinary biology, and by default, veterinary medicine. No longer are clinicians locked into traditional methods of diagnoses and therapy. Rather major advances in canine genetics and genomics from the past five years are now changing the way the veterinarian of the 21st century practices medicine.
First, the availability of a dense genome map gives canine genetics a much needed foothold in comparative medicine, allowing advances made in human and mouse genetics to be applied to companion animals. Second, the recently released 7.5x whole genome sequence of the dog is facilitating the identification of hereditary disease genes. Finally, development of genetic tools for rapid screening of families and populations at risk for inherited disease means that the cost of identifying and testing for disease loci will significantly decrease in coming years.
Out of these advances will come major changes in companion animal diagnostics and therapy. Clinicians will be able to offer their clients genetic testing and counseling for a myriad of disorders. Such advances are certain to generate healthier and more long lived dogs, improving quality of life for owner and pet alike. The clinician of the 21st century, therefore, faces incredible opportunities as well as challenges in the management of genetic disease. In this review we summarize recent findings in canine genomics and discuss their application to the study of canine cardiac health.
doi:10.1016/j.jvc.2006.04.002
PMCID: PMC3559124  PMID: 19083345
inherited disease; genome; canine; cardiac; heart
7.  Molecular Genetic Analysis of a Putative Domestic Dog Clone 
Nature  2006;440(7081):E1-E2.
doi:10.1038/nature04685
PMCID: PMC3559127  PMID: 16525421
8.  Subcutaneous 5-Azacitidine Treatment of Naturally Occurring Canine Urothelial Carcinoma: A Novel Epigenetic Approach to Human Urothelial Carcinoma Drug Development 
The Journal of urology  2011;187(1):302-309.
Purpose
We determined the efficacy, biological activity, pharmacokinetics and safety of the hypomethylating agent 5-azacitidine (Celgene Corp., Summit, New Jersey) in dogs with naturally occurring invasive urothelial carcinoma.
Materials and Methods
We performed a preclinical phase I trial in dogs with naturally occurring invasive urothelial carcinoma to examine once daily subcutaneous administration of 5-azacitidine in 28-day cycles at doses of 0.10 to 0.30 mg/kg per day according to 2 dose schedules, including days 1 to 5 (28-day cohort) or days 1 to 5 and 15 to 19 (14-day cohort). Clinical efficacy was assessed by serial cystosonography, radiography and cystoscopy. Urinary 5-azacitidine pharmacokinetic analysis was also done. Pretreatment and posttreatment peripheral blood mononuclear cell and invasive urothelial carcinoma DNA, respectively, was analyzed for global and gene specific [CDKN2A (p14ARF)] methylation changes.
Results
Enrolled in the study were 19 dogs with naturally occurring invasive urothelial carcinoma. In the 28-day cohort the maximum tolerated dose was 0.20 mg/kg per day with higher doses resulting in grade 3 or 4 neutropenia in 4 of 6 dogs. In the 14-day cohort the maximum tolerated dose was 0.10 mg/kg per day with grade 3 or 4 neutropenia seen in 2 of 3 dogs treated at higher doses. No grade 3 or 4 nonhematological toxicity was observed during either dosing schedule. Of 18 dogs evaluable for tumor response partial remission, stable disease and progressive disease were observed in 4 (22.2%), 9 (50.0%) and 4 (22.2%), respectively. Consistent 5-azacitidine levels (205 to 857 ng/ml) were detected in urine. Pretreatment and posttreatment methylation analysis revealed no significant correlation with clinical response.
Conclusions
Subcutaneous 5-azacitidine showed promising clinical activity in a canine invasive urothelial carcinoma model, thus meriting further development in humans with urothelial carcinoma.
doi:10.1016/j.juro.2011.09.010
PMCID: PMC3508763  PMID: 22099988
urinary bladder; urothelium; carcinoma; azacitidine; dogs
9.  Genome-wide SNP and haplotype analyses reveal a rich history underlying dog domestication 
Nature  2010;464(7290):898-902.
Advances in genome technology have facilitated a new understanding of the historical and genetic processes crucial to rapid phenotypic evolution under domestication1,2. To understand the process of dog diversification better, we conducted an extensive genome-wide survey of more than 48,000 single nucleotide polymorphisms in dogs and their wild progenitor, the grey wolf. Here we show that dog breeds share a higher proportion of multi-locus haplotypes unique to grey wolves from the Middle East, indicating that they are a dominant source of genetic diversity for dogs rather than wolves from east Asia, as suggested by mitochondrial DNA sequence data3. Furthermore, we find a surprising correspondence between genetic and phenotypic/functional breed groupings but there are exceptions that suggest phenotypic diversification depended in part on the repeated crossing of individuals with novel phenotypes. Our results show that Middle Eastern wolves were a critical source of genome diversity, although interbreeding with local wolf populations clearly occurred elsewhere in the early history of specific lineages. More recently, the evolution of modern dog breeds seems to have been an iterative process that drew on a limited genetic toolkit to create remarkable phenotypic diversity.
doi:10.1038/nature08837
PMCID: PMC3494089  PMID: 20237475
10.  Man’s Best Friend Becomes Biology’s Best in Show: Genome Analyses in the Domestic Dog* 
Annual Review of Genetics  2010;44:309-336.
In the last five years, canine genetics has gone from map construction to complex disease deconstruction. The availability of a draft canine genome sequence, dense marker chips, and an understanding of the genome architecture has changed the types of studies canine geneticists can undertake. There is now a clear recognition that the dog system offers the opportunity to understand the genetics of both simple and complex traits, including those associated with morphology, disease susceptibility, and behavior.
In this review, we summarize recent findings regarding canine domestication and review new information on the organization of the canine genome. We discuss studies aimed at finding genes controlling morphological phenotypes and provide examples of the way such paradigms may be applied to studies of behavior. We also discuss the many ways in which the dog has illuminated our understanding of human disease and conclude with a discussion on where the field is likely headed in the next five years.
doi:10.1146/annurev-genet-102808-115200
PMCID: PMC3322674  PMID: 21047261
GWAS; linkage disequilibrium; genomics; canine; domestication; complex traits
11.  Breed-Specific Ancestry Studies and Genome-Wide Association Analysis Highlight an Association Between the MYH9 Gene and Heat Tolerance in Alaskan Sprint Racing Sled Dogs 
Mammalian Genome  2011;23(1-2):178-194.
Alaskan sled dogs are a genetically distinct population shaped by generations of selective interbreeding with purebred dogs to create a group of high performance athletes. As a result of selective breeding strategies, sled dogs present a unique opportunity to employ admixture-mapping techniques to investigate how breed composition and trait selection impact genomic structure. We used admixture mapping to investigate genetic ancestry across the genomes of two classes of sled dogs, sprint and long distance racers, and combined that with genome wide association studies (GWAS) to identify regions correlating with performance enhancing traits. The sled dog genome is enhanced by differential contributions from four non-admixed breeds (Alaskan Malamute, Siberian Husky, German Shorthaired Pointer, and Borzoi). A principle components analysis (PCA) of 115,000 genome-wide SNPs clearly resolved the sprint and distance populations as distinct genetic groups, with longer blocks of linkage disequilibrium (LD) observed in the distance versus sprint dogs (7.5–10 and 2.5–3.75 kb, respectively). Further, we identified eight regions with the genomic signal either from a selective sweep or an association analysis, corroborated by an excess of ancestry when comparing sprint and distance dogs. A comparison of elite and poor performing sled dogs identified a single region significantly association with heat tolerance. Within the region we identified seven SNPs within the myosin heavy chain 9 gene (MYH9) that were significantly associated with heat tolerance in sprint dogs, two of which correspond to conserved promoter and enhancer regions in the human ortholog.
doi:10.1007/s00335-011-9374-y
PMCID: PMC3320045  PMID: 22105876
canine; admixture; attributes; GWAS
12.  An Insertion in the RSPO2 Gene Correlates with Improper Coat in the Portuguese Water Dog 
Journal of Heredity  2010;101(5):612-617.
We recently showed that genes at 3 loci account for the majority of variation in canine fur. Allelic variation at genes controlling length of fur, texture, and curl is responsible for the striking phenotypic variety observed among purebred dogs in the United States today. In this paper, we investigate the phenomenon of “improper coat” (IC) or a coat that is not typical of the breed. IC is occasionally observed among specific breeds, such as the Portuguese Water Dog (PWD), and is characterized by short hair on the head, face, and lower legs, rather than a thick and even coat covering the whole body. The IC is reminiscent of that observed on the curly or flat-coated retriever, thus making such dogs unable to compete effectively in conformation events. We have found that the presence of the wild-type allele, rather than the expected variant allele at the R-spondin 2 (RSPO2) gene, accounts for this phenotype. The development of a genetic test that distinguishes these 2 allelic types would allow breeders to easily avoid producing PWD with ICs.
doi:10.1093/jhered/esq068
PMCID: PMC2908740  PMID: 20562213
fur; furnishings; genetics; morphology; mutation
14.  A genetic dissection of breed composition and performance enhancement in the Alaskan sled dog 
BMC Genetics  2010;11:71.
Background
The Alaskan sled dog offers a rare opportunity to investigate the development of a dog breed based solely on performance, rather than appearance, thus setting the breed apart from most others. Several established breeds, many of which are recognized by the American Kennel Club (AKC), have been introduced into the sled dog population to enhance racing performance. We have used molecular methods to ascertain the constitutive breeds used to develop successful sled dog lines, and in doing so, determined the breed origins of specific performance-related behaviors.
One hundred and ninety-nine Alaskan sled dogs were genotyped using 96 microsatellite markers that span the canine genome. These data were compared to that from 141 similarly genotyped purebred dog breeds. Sled dogs were evaluated for breed composition based on a variety of performance phenotypes including speed, endurance and work ethic, and the data stratified based on population structure.
Results
We observe that the Alaskan sled dog has a unique molecular signature and that the genetic profile is sufficient for identifying dogs bred for sprint versus distance. When evaluating contributions of existing breeds we find that the Alaskan Malamute and Siberian Husky contributions are associated with enhanced endurance; Pointer and Saluki are associated with enhanced speed and the Anatolian Shepherd demonstrates a positive influence on work ethic.
Conclusion
We have established a genetic breed profile for the Alaskan sled dog, identified profile variance between sprint and distance dogs, and established breeds associated with enhanced performance attributes. These data set the stage for mapping studies aimed at finding genes that are associated with athletic attributes integral to the high performing Alaskan sled dog.
doi:10.1186/1471-2156-11-71
PMCID: PMC2920855  PMID: 20649949
15.  Coat Variation in the Domestic Dog Is Governed by Variants in Three Genes 
Science (New York, N.Y.)  2009;326(5949):150-153.
Coat color and type are essential characteristics of domestic dog breeds. Although the genetic basis of coat color has been well characterized, relatively little is known about the genes influencing coat growth pattern, length, and curl. We performed genome-wide association studies of more than 1000 dogs from 80 domestic breeds to identify genes associated with canine fur phenotypes. Taking advantage of both inter- and intrabreed variability, we identified distinct mutations in three genes, RSPO2, FGF5, and KRT71 (encoding R-spondin–2, fibroblast growth factor–5, and keratin-71, respectively), that together account for most coat phenotypes in purebred dogs in the United States. Thus, an array of varied and seemingly complex phenotypes can be reduced to the combinatorial effects of only a few genes.
doi:10.1126/science.1177808
PMCID: PMC2897713  PMID: 19713490
16.  Epidemiology, Pathology, and Genetics of Histiocytic Sarcoma in the Bernese Mountain Dog Breed 
Journal of Heredity  2009;100(Suppl 1):S19-S27.
Histiocytic sarcoma (HS) refers to a highly aggressive and frequently disseminated neoplastic disease belonging to the class of canine histiocytic proliferative disorders. Disseminated HS (previously called malignant histiocytosis) is highly breed specific, with Bernese mountain dogs (BMDs), rottweilers, and retrievers having a high prevalence with a frequency of approximately 25% in the BMD breed. We collected DNA samples and clinical information from 800 BMDs, of which 200 are affected by HS. To better characterize the physiopathology and epidemiology, an in-depth analysis of 89 BMD cases has been performed. The mean age of onset was 6.5 years, males and females being equally affected. The clinical features, biochemical parameters, and pathological features have been determined. The life span after diagnosis has been estimated to be 49 days. A large BMD pedigree of 327 dogs, 121 of which are affected, was assembled. Using a subset of 160 BMDs, encompassing 21 complete sibships, we now propose an oligogenic transmission mode of the disease. Whole-genome linkage scans as well as association studies using a case/control analysis, in parallel with expression profiling of neoplastic versus normal histiocytes, are all underway. Altogether, these complementary approaches are expected to localize the genes for HS in the BMD, leading to advances in our knowledge of histiocyte diseases in dogs and humans.
doi:10.1093/jhered/esp039
PMCID: PMC3139364  PMID: 19531730
Bernese mountain dogs; cancer; dog; genetics; histiocytic sarcoma
17.  An Expressed Fgf4 Retrogene Is Associated with Breed-Defining Chondrodysplasia in Domestic Dogs 
Science (New York, N.Y.)  2009;325(5943):995-998.
Retrotransposition of processed mRNAs is a frequent source of novel sequence acquired during the evolution of genomes. The vast majority of retroposed gene copies are inactive pseudogenes that rapidly acquire mutations that disrupt the reading frame, while precious few are conserved to become new genes. Utilizing a multi-breed association analysis in the domestic dog, we demonstrate that a recently acquired fgf4 retrogene causes chondrodysplasia, a short-legged phenotype that defines several common dog breeds including the dachshund, corgi and basset hound. The discovery that a single evolutionary event underlies a breed-defining phenotype for 19 diverse dog breeds demonstrates the importance of unique mutational events in constraining and directing phenotypic diversity in the domestic dog.
doi:10.1126/science.1173275
PMCID: PMC2748762  PMID: 19608863
18.  A Single IGF1 Allele Is a Major Determinant of Small Size in Dogs 
Science (New York, N.Y.)  2007;316(5821):112-115.
The domestic dog exhibits greater diversity in body size than any other terrestrial vertebrate. We used a strategy that exploits the breed structure of dogs to investigate the genetic basis of size. First, through a genome-wide scan, we identified a major quantitative trait locus (QTL) on chromosome 15 influencing size variation within a single breed. Second, we examined genetic variation in the 15-megabase interval surrounding the QTL in small and giant breeds and found marked evidence for a selective sweep spanning a single gene (IGF1), encoding insulin-like growth factor 1. A single IGF1 single-nucleotide polymorphism haplotype is common to all small breeds and nearly absent from giant breeds, suggesting that the same causal sequence variant is a major contributor to body size in all small dogs.
doi:10.1126/science.1137045
PMCID: PMC2789551  PMID: 17412960
19.  Population genomics of the inbred Scandinavian wolf 
Molecular ecology  2009;18(7):1341-1351.
The Scandinavian wolf population represents one of the genetically most well characterized examples of a severely bottlenecked natural population (with only two founders), and of how the addition of new genetic material (one immigrant) can at least temporarily provide a “genetic rescue”. However, inbreeding depression has been observed in this population and in the absence of additional immigrants, its long-term viability is questioned. To study the effects of inbreeding and selection on genomic diversity, we performed a genomic scan with approximately 250 microsatellite markers distributed across all autosomes and the X chromosome. We found linkage disequilibrium (LD) that extended up to distances of 50 Mb, exceeding that of most outbreeding species studied thus far. LD was particularly pronounced on the X chromosome. Overall levels of observed genomic heterozygosity did not deviate significantly from simulations based on known population history, giving no support for a general selection for heterozygotes. However, we found evidence supporting balancing selection at a number of loci and also evidence suggesting directional selection at other loci. For markers on chromosome 23, the signal of selection was particularly strong indicating that purifying selection against deleterious alleles may have occurred even in this very small population. These data suggest that population genomics allows the exploration of the effects of neutral and non-neutral evolution on a finer scale than what has previously been possible.
doi:10.1111/j.1365-294X.2009.04120.x
PMCID: PMC2747086  PMID: 19368642
heterozygosity; genome scan; linkage disequilibrium; inbreeding; conservation genetics
20.  A Mutation in the Myostatin Gene Increases Muscle Mass and Enhances Racing Performance in Heterozygote Dogs 
PLoS Genetics  2007;3(5):e79.
Double muscling is a trait previously described in several mammalian species including cattle and sheep and is caused by mutations in the myostatin (MSTN) gene (previously referred to as GDF8). Here we describe a new mutation in MSTN found in the whippet dog breed that results in a double-muscled phenotype known as the “bully” whippet. Individuals with this phenotype carry two copies of a two-base-pair deletion in the third exon of MSTN leading to a premature stop codon at amino acid 313. Individuals carrying only one copy of the mutation are, on average, more muscular than wild-type individuals (p = 7.43 × 10−6; Kruskal-Wallis Test) and are significantly faster than individuals carrying the wild-type genotype in competitive racing events (Kendall's nonparametric measure, τ = 0.3619; p ≈ 0.00028). These results highlight the utility of performance-enhancing polymorphisms, marking the first time a mutation in MSTN has been quantitatively linked to increased athletic performance.
Author Summary
An individual's genetic profile can play a role in defining their natural skills and talents. The canine species presents an excellent system in which to find such associative genes. The purebred dog has a long history of selective breeding, which has produced specific breeds of extraordinary strength, intelligence, and speed. We have discovered a mutation in the canine myostatin gene, a negative regulator of muscle mass, which affects muscle composition, and hence racing speed, in whippets. Dogs that possess a single copy of this mutation are more muscled than normal and are among the fastest dogs in competitive racing events. However, dogs with two copies of the same mutation are grossly overmuscled, superficially resembling double-muscled cattle known to possess similar mutations. This result is the first to quantitatively link a mutation in the myostatin gene to athletic performance. Further, it emphasizes what is sure to be a growing area of research for performance-enhancing polymorphisms in competitive athletics. Future implications include screening for myostatin mutations among elite athletes. However, as little is known about the health issues and potential risks associated with being a myostatin-mutation carrier, research in this arena should proceed with extreme caution.
doi:10.1371/journal.pgen.0030079
PMCID: PMC1877876  PMID: 17530926
21.  Genome Sequencing Highlights the Dynamic Early History of Dogs 
PLoS Genetics  2014;10(1):e1004016.
To identify genetic changes underlying dog domestication and reconstruct their early evolutionary history, we generated high-quality genome sequences from three gray wolves, one from each of the three putative centers of dog domestication, two basal dog lineages (Basenji and Dingo) and a golden jackal as an outgroup. Analysis of these sequences supports a demographic model in which dogs and wolves diverged through a dynamic process involving population bottlenecks in both lineages and post-divergence gene flow. In dogs, the domestication bottleneck involved at least a 16-fold reduction in population size, a much more severe bottleneck than estimated previously. A sharp bottleneck in wolves occurred soon after their divergence from dogs, implying that the pool of diversity from which dogs arose was substantially larger than represented by modern wolf populations. We narrow the plausible range for the date of initial dog domestication to an interval spanning 11–16 thousand years ago, predating the rise of agriculture. In light of this finding, we expand upon previous work regarding the increase in copy number of the amylase gene (AMY2B) in dogs, which is believed to have aided digestion of starch in agricultural refuse. We find standing variation for amylase copy number variation in wolves and little or no copy number increase in the Dingo and Husky lineages. In conjunction with the estimated timing of dog origins, these results provide additional support to archaeological finds, suggesting the earliest dogs arose alongside hunter-gathers rather than agriculturists. Regarding the geographic origin of dogs, we find that, surprisingly, none of the extant wolf lineages from putative domestication centers is more closely related to dogs, and, instead, the sampled wolves form a sister monophyletic clade. This result, in combination with dog-wolf admixture during the process of domestication, suggests that a re-evaluation of past hypotheses regarding dog origins is necessary.
Author Summary
The process of dog domestication is still poorly understood, largely because no studies thus far have leveraged deeply sequenced whole genomes from wolves and dogs to simultaneously evaluate support for the proposed source regions: East Asia, the Middle East, and Europe. To investigate dog origins, we sequence three wolf genomes from the putative centers of origin, two basal dog breeds (Basenji and Dingo), and a golden jackal as an outgroup. We find that none of the wolf lineages from the hypothesized domestication centers is supported as the source lineage for dogs, and that dogs and wolves diverged 11,000–16,000 years ago in a process involving extensive admixture and that was followed by a bottleneck in wolves. In addition, we investigate the amylase (AMY2B) gene family expansion in dogs, which has recently been suggested as being critical to domestication in response to increased dietary starch. We find standing variation in AMY2B copy number in wolves and show that some breeds, such as Dingo and Husky, lack the AMY2B expansion. This suggests that, at the beginning of the domestication process, dogs may have been characterized by a more carnivorous diet than their modern day counterparts, a diet held in common with early hunter-gatherers.
doi:10.1371/journal.pgen.1004016
PMCID: PMC3894170  PMID: 24453982
22.  The MTAP-CDKN2A Locus Confers Susceptibility to a Naturally Occurring Canine Cancer 
Background
Advantages offered by canine population substructure, combined with clinical presentations similar to human disorders, makes the dog an attractive system for studies of cancer genetics. Cancers that have been difficult to study in human families or populations are of particular interest. Histiocytic sarcoma is a rare and poorly understood neoplasm in humans that occurs in 15–25% of Bernese Mountain Dogs (BMD).
Methods
Genomic DNA was collected from affected and unaffected BMD in North America (NA) and Europe. Both independent and combined genome wide association studies (GWAS) were used to identify cancer-associated loci. Fine mapping and sequencing narrowed the primary locus to a single gene region.
Results
Both populations shared the same primary locus, which features a single haplotype spanning MTAP and part of CDKN2A and is present in 96% of affected BMD. The haplotype is within the region homologous to human chromosome 9p21, which has been implicated in several types of cancer.
Conclusions
We present the first GWAS for HS in any species. The data identify an associated haplotype in the highly cited tumor suppressor locus near CDKN2A. These data demonstrate the power of studying distinctive malignancies in highly predisposed dog breeds.
Impact
Here, we establish a naturally-occurring model of cancer susceptibility due to CDKN2 dysregulation, thus providing insight regarding this cancer-associated, complex, and poorly understood genomic region.
doi:10.1158/1055-9965.EPI-12-0190-T
PMCID: PMC3392365  PMID: 22623710
Genome Wide Association Study; Dogs; p16; Cancer; Histiocytic sarcoma
23.  A Simple Genetic Architecture Underlies Morphological Variation in Dogs 
PLoS Biology  2010;8(8):e1000451.
The largest genetic study to date of morphology in domestic dogs identifies genes controlling nearly 100 morphological traits and identifies important trends in phenotypic variation within this species.
Domestic dogs exhibit tremendous phenotypic diversity, including a greater variation in body size than any other terrestrial mammal. Here, we generate a high density map of canine genetic variation by genotyping 915 dogs from 80 domestic dog breeds, 83 wild canids, and 10 outbred African shelter dogs across 60,968 single-nucleotide polymorphisms (SNPs). Coupling this genomic resource with external measurements from breed standards and individuals as well as skeletal measurements from museum specimens, we identify 51 regions of the dog genome associated with phenotypic variation among breeds in 57 traits. The complex traits include average breed body size and external body dimensions and cranial, dental, and long bone shape and size with and without allometric scaling. In contrast to the results from association mapping of quantitative traits in humans and domesticated plants, we find that across dog breeds, a small number of quantitative trait loci (≤3) explain the majority of phenotypic variation for most of the traits we studied. In addition, many genomic regions show signatures of recent selection, with most of the highly differentiated regions being associated with breed-defining traits such as body size, coat characteristics, and ear floppiness. Our results demonstrate the efficacy of mapping multiple traits in the domestic dog using a database of genotyped individuals and highlight the important role human-directed selection has played in altering the genetic architecture of key traits in this important species.
Author Summary
Dogs offer a unique system for the study of genes controlling morphology. DNA from 915 dogs from 80 domestic breeds, as well as a set of feral dogs, was tested at over 60,000 points of variation and the dataset analyzed using novel methods to find loci regulating body size, head shape, leg length, ear position, and a host of other traits. Because each dog breed has undergone strong selection by breeders to have a particular appearance, there is a strong footprint of selection in regions of the genome that are important for controlling traits that define each breed. These analyses identified new regions of the genome, or loci, that are important in controlling body size and shape. Our results, which feature the largest number of domestic dogs studied at such a high level of genetic detail, demonstrate the power of the dog as a model for finding genes that control the body plan of mammals. Further, we show that the remarkable diversity of form in the dog, in contrast to some other species studied to date, appears to have a simple genetic basis dominated by genes of major effect.
doi:10.1371/journal.pbio.1000451
PMCID: PMC2919785  PMID: 20711490
24.  An integrated 4249 marker FISH/RH map of the canine genome 
BMC Genomics  2004;5:65.
Background
The 156 breeds of dog recognized by the American Kennel Club offer a unique opportunity to map genes important in genetic variation. Each breed features a defining constellation of morphological and behavioral traits, often generated by deliberate crossing of closely related individuals, leading to a high rate of genetic disease in many breeds. Understanding the genetic basis of both phenotypic variation and disease susceptibility in the dog provides new ways in which to dissect the genetics of human health and biology.
Results
To facilitate both genetic mapping and cloning efforts, we have constructed an integrated canine genome map that is both dense and accurate. The resulting resource encompasses 4249 markers, and was constructed using the RHDF5000-2 whole genome radiation hybrid panel. The radiation hybrid (RH) map features a density of one marker every 900 Kb and contains 1760 bacterial artificial chromosome clones (BACs) localized to 1423 unique positions, 851 of which have also been mapped by fluorescence in situ hybridization (FISH). The two data sets show excellent concordance. Excluding the Y chromosome, the map features an RH/FISH mapped BAC every 3.5 Mb and an RH mapped BAC-end, on average, every 2 Mb. For 2233 markers, the orthologous human genes have been established, allowing the identification of 79 conserved segments (CS) between the dog and human genomes, dramatically extending the length of most previously described CS.
Conclusions
These results provide a necessary resource for the canine genome mapping community to undertake positional cloning experiments and provide new insights into the comparative canine-human genome maps.
doi:10.1186/1471-2164-5-65
PMCID: PMC520820  PMID: 15363096
canine; dog; radiation hybrid; microsatellites; ESTs; BAC-ends

Results 1-24 (24)