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1.  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
3.  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
4.  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
5.  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
6.  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
7.  Morphometrics within dog breeds are highly reproducible and dispute Rensch’s rule 
Using 27 body measurements, we have identified 13 breed-defining metrics for 109 of 159 domestic dog breeds, most of which are recognized by the American Kennel Club (AKC). The data set included 1,155 dogs at least 1 year old (average 5.4 years), and for 53 breed populations, complete measurement data were collected from at least three males and three females. We demonstrate, first, that AKC breed standards are rigorously adhered to for most domestic breeds with little variation observed within breeds. Second, Rensch’s rule, which describes a scaling among taxa such that sexual dimorphism is greater among larger species if males are the larger sex, with less pronounced differences in male versus female body size in smaller species, is not maintained in domestic dog breeds because the proportional size difference between males and females of small and large breeds is essentially the same. Finally, principal components (PCs) analysis describes both the overall body size (PC1) and the shape (length versus width) of the skeleton (PC2). That the integrity of the data set is sufficiently rich to discern PCs has strong implications for mapping studies, suggesting that individual measurements may not be needed for genetic studies of morphologic traits, particularly in the case of breed-defining traits that are typically under strong selection. Rather, phenotypes derived from data sets such as these, collected at a fraction of the effort and cost, may be used to direct whole-genome association studies aimed at understanding the genetic basis of fixed morphologic phenotypes defining distinct dog breeds.
doi:10.1007/s00335-008-9153-6
PMCID: PMC2748280  PMID: 19020935
8.  Canine Population Structure: Assessment and Impact of Intra-Breed Stratification on SNP-Based Association Studies 
PLoS ONE  2007;2(12):e1324.
Background
In canine genetics, the impact of population structure on whole genome association studies is typically addressed by sampling approximately equal numbers of cases and controls from dogs of a single breed, usually from the same country or geographic area. However one way to increase the power of genetic studies is to sample individuals of the same breed but from different geographic areas, with the expectation that independent meiotic events will have shortened the presumed ancestral haplotype around the mutation differently. Little is known, however, about genetic variation among dogs of the same breed collected from different geographic regions.
Methodology/Principal Findings
In this report, we address the magnitude and impact of genetic diversity among common breeds sampled in the U.S. and Europe. The breeds selected, including the Rottweiler, Bernese mountain dog, flat-coated retriever, and golden retriever, share susceptibility to a class of soft tissue cancers typified by malignant histiocytosis in the Bernese mountain dog. We genotyped 722 SNPs at four unlinked loci (between 95 and 271 per locus) on canine chromosome 1 (CFA1). We showed that each population is characterized by distinct genetic diversity that can be correlated with breed history. When the breed studied has a reduced intra-breed diversity, the combination of dogs from international locations does not increase the rate of false positives and potentially increases the power of association studies. However, over-sampling cases from one geographic location is more likely to lead to false positive results in breeds with significant genetic diversity.
Conclusions
These data provide new guidelines for association studies using purebred dogs that take into account population structure.
doi:10.1371/journal.pone.0001324
PMCID: PMC2129117  PMID: 18091995
9.  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

Results 1-9 (9)