The canine genome — Volkswagen Fox-Africa

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The canine genome

Abstract

The dog has as a premier species for the study of behavior, and disease. The recent of a high-quality draft sequence the dog system to a new threshold. We provide a to use the dog genome by first focusing on its history. We overview the relationship of to wild canids and discuss origin and domestication. Dogs originated from a substantial of gray wolves and dog breeds distinct genetic units can be divided into at least hierarchical groupings. We review showing that dogs high levels of linkage Consequently, given that dog express specific phenotypic and vary in behavior and the incidence of disease, genomic-wide scans for disequilibrium may allow the discovery of influencing breed-specific characteristics. we review studies that utilized the dog to understand the genetic of several traits, and we summarize resources that can be used to such studies. We suggest given these resources and the characteristics of breeds, that the dog is a valuable resource for studying the basis of complex traits.

As one of the journals in genome biology its’ 10th anniversary, the community studying dogs enjoys a year of major and milestones, particularly with to canine genomics and comparative In July of 2004, the first draft (7.5×) sequence of the dog was made publicly available et al. 2005 ). This advance on the heels of other major in the past several months, the availability of a 1.5× Poodle (Kirkness et al. 2003 ), a dense quality radiation hybrid map (Breen et al. 2004 ), a detailed map (Hitte et al. 2005 ), the localization and of several disease genes, the application of dogs for gene studies (Howell et al. 1997 ; et al. 2001 ; Mount et al. 2002 ; et al. 2002 ), and new insights into the of dogs and dog breeds (Parker et al. ).

As a result, the genome community is poised to take advantage of the system and begin to fulfill of the expectations advanced nearly 15 yr First, with the development of molecular resources, the canine was proposed to hold the power to map and disease genes that had intractable through studies of families. Second, the variation in and skeletal proportions that are into distinct breeds of dog was to provide a unique resource for genetic pathways underlying development. Finally, the range of traits that appeared associated with individual suggested a mechanism to decipher the genetic vocabulary of behavior et al. 1982 ; Ostrander et al. 1993. ; Galibert et al. 1998 ; Patterson ). At the heart of these questions a fundamental conundrum. Why has the wolf from which the dog is recently retained alleles controlling a large amount of genetic particularly as regards morphology? Is the dog somehow unique from genomes? Or would strong pressures applied to any mammalian result in a range of species a level of phenotypic variation rivals the dog? Research to date cannot readily these questions. However, we are to understand how to localize the genes regulate morphology (Chase et al. ). In so doing, we can begin to understand how variation leads to major changes. With the sequencing of the dog it may be within our grasp to localize that cause the difference Giant Mastiffs and Pekingese, and Terrier, and sight and scent

In this celebratory review, we discuss the evolutionary framework and of dogs. We then consider the accomplishments of the canine genome Finally, we highlight ongoing aimed at addressing some of the above.

The evolutionary framework

The dog is the most recently evolved in the dog family Canidae, a group has a long history spanning the 50 million years (Myr). history can be portrayed as a succession of hierarchies defined by DNA sequence (Fig. 1 ) and is a necessary structure for molecular data. Of note is dogs are the earliest divergence in the Canoidae that includes weasels, skunks, raccoons, and the (seals, sea lions, and walruses) 1A ). This kinship predicts will share more similarities with these than with cats, civets, or hyenas. However, of the early divergence of dogs all other carnivores, only evolving regions will substantial sequence similarities. A important point is that the 35 of extant canids are genetically similar, having radiated a common ancestor less about 10 Mya. The recent in a family that otherwise has a evolutionary history suggests genetic comparisons among canids will highlight evolving sequences and that all may share uniquely evolved structures such as SINE inherited from their common ancestor (Fanning et al. ; Kirkness et al. 2003 ) or rapidly genes such as olfactory immune related genes, or proteins (e.g. Clark et al. ). In fact, although the dog family has a chromosome complement ranging 36 to 78 chromosomes, they all can be reconstructed simple chromosome rearrangement a common ancestral karyotype et al. 2001 ).

Evolutionary relationships of the ( A ) The evolutionary relationships of carnivores on DNA hybridization data. (Wayne et al. ). ( B ) A neighbor-joining tree of canids on 2001 bp of mitochondrial DNA sequence b, cytochrome c oxidaes I, and cytochrome c II) (Wayne et al. 1997a ). ( C ) A neighbor-joining of wolf (W) and dog (D) haplotypes based on 261 bp of region I sequences (Vila et al. ). Dog haplotypes are grouped in four clades, numbered I to IV.

Within the Canidae, three phylogenetic groupings are apparent 1B ) (Wayne et al. 1987a ,b. 1997b ) as (1) the fox-like canids, which species closely related to the red fox Vulpes ), as well as the arctic and fox (genus Alopex and Fennecus . (2) the wolf-like canids including wolf, coyote, Ethiopian or Simien jackal, and three species of jackals (genus ), as well as the African hunting dog Lycaon ) and the dhole (genus ); and (3) the South American canids fox-sized canids such as the fox, crab-eating fox, and dog (genus Pseudolopex, Lycolopex, ) and the maned wolf (genus ) and bushdog (genus Speothos ). there are several canids have no close living and define distinct evolutionary such as the gray fox (genus ), the bat-eared fox (genus Otocyon ), and the dog (genus Nyctereutes ).


These relationships imply that the dog has close relatives within its in fact, all members of Canis can fertile hybrids and several may have genomes that hybridization in the wild (Wayne and 1991 ; Gottelli et al. 1994 ; Roy et al. ; Wilson et al. 2000 ; Adams et al. ). Furthermore, the wolf-like canids are more closely with the American canids and the red and gray fox are distinct groups whose ancestry with dogs to the beginning of the modern radiation. molecular tools developed the dog genome sequencing project are to be most applicable to the wolf-like For instance, fewer than of microsatellite primers developed in the dog DNA in the gray fox (Goldstein et al. 1999 ).

The of the dog

The essential questions about dog concern the species from the dog originated and the location, number, and of domestication or interbreeding events. data has shed some on all of these questions. First, regard to species origins, Darwin and others such as Lorenz, the renowned behavioral speculated that given the diversity in form and behavior of they might share with wolves and other such as any one of the three species of However, extensive genetic of the dog and other wolf-like canids show that the dog is derived gray wolves only, than jackals, coyotes, or wolves (Fig. 1C ; Wayne et al. ,b ; Vila et al. 1997. 2005 ; et al. 2002 ; Savolainen et al. 2002 ). the immense phenotypic diversity in the dog its origin to primarily the standing variation existing in the ancestral of gray wolves and any subsequent that occurred during the history of domestication. At least for genes, such mutations are to be few since their mutation is so low, on the order of 10 -5 mutations per per generation (Hartl and Clark ).

Mitochondrial DNA (mtDNA) sequence has shed some light on the of dog domestication as well as the number of matralines. MtDNA analysis a unique perspective on evolutionary because the mitochondrial genome is inherited, and hence, only leave a genetic legacy. because the mitochondrial genome not recombine, phylogenetic analysis of sequence data defines a bifurcating haplotype tree 1A,B,C ). Phylogenetic analysis of dog and wolf mitochondrial sequences show that dog sequences are in at least four distinct implying a single origination and at least three other or interbreeding events. The latter are to distinguish once the first had occurred, although extensive analysis of the nuclear genome be able to discriminate the two alternatives. A finding of the mtDNA analysis is one sequence clade (clade I, 1C ) contains the majority of dog sequences and the nucleotide diversity of this is high, implying an origin of the from 40 to 135 thousand years ago et al. 1997 ; Savolainen et al. 2002 ). date exceeds the 15,000-yr-old record of dogs and suggests dogs may have had a long when they were not distinct from wolf These early dogs may not been recognized as domesticated by of the archeological record before yr ago because of their physical to gray wolves. The initial to the diagnostic phenotype of domestic beginning about 15,000 yr ago may instead indicated a change in the pressures associated with the from hunter gatherer to sedentary lifestyles (Wayne et al. ).

Conceivably, a more recent can be made consistent with the record if it is assumed that were founded from matralines in clade one (Savolainen et al. ). To determine whether such a founding is likely, analysis of genes sequence data is (e.g. Parker et al. 2004 ). In recent analysis of major (MHC) genes in dogs and suggest that the origin of involved several populations and of individuals (Vila et al. 2005 ). the model emerging from DNA, MHC analysis, and microsatellite is that the dogs had a diverse in East Asia that involved multiple contributions several populations, and thereafter, may have been other of domestication and backcrossing (Vila et al. 2005 ; Leonard et al. 2002 ; et al. 2002 ; Parker et al. 2004 ). A and diverse origin model domestication in other domestic such as cattle, sheep, and (Bruford et al. 2003 ). Furthermore, domesticated, dogs rapidly around the earth and as a result, divergent populations and breeds are in Africa, Asia, the Arctic, the Middle East, and historically, the New (Leonard et al. 2002 ; Parker et al. ; Savolainen et al. 2004 ).

Breed diversity and genetic

The explosion of dog breeds over the two centuries represents perhaps one of the genetic experiments ever by humans. Distilled from the of the wild wolf are animals differ by more than in size with the ability to guard, hunt, and guide Kennel Club 1998 ). variation is surpassed by morphologic with individual breeds by dogs of every imaginable and proportion. Coats alone can be by color, texture, length, and curl. Tails can be described as curled, double curled, (upright), sickled (arching), (down and flat), whipped, screwed, or snapped (American Club 1998 ). The diversity in size and proportion of dogs is than any mammalian species and exceeds that of the entire family (Wayne 1986a ). Such variation may reflect modifications of post-natal development 1986a ,1986c ), but the specific mechanisms are not well known below).

Much of the morphologic in dogs is partitioned into 350 distinct breeds worldwide as a of the development of breed standards and breeding. In general, in order to a dog in the American Kennel Club at both parents must been registered in the same Consequently, purebred dogs are of closed breeding populations, receive little genetic beyond that existing in the founders (Ostrander and Giniger ; Galibert et al. 1998 ; Ostrander et al. ; Sutter and Ostrander 2004 ).

to the origin and development of many is a founder event involving a few dogs and, thereafter, dominance by popular sires conform most closely to the standard. These restrictive practices reduce effective size and increase genetic resulting in the loss of genetic within breeds and allele divergence among them. For in a genetic study of 85 breeds, et al. (2004 ) showed that and dogs have similar of overall nucleotide diversity, 8 × 10 -4. represent the overall number of substitutions per base/pair. However, the between dog breeds is much than the variation between populations (27.5% versus Conversely, the degree of genetic is much greater within dog breeds than within human populations (94.6% 72.5%). Furthermore, in some genetic variation has been reduced by bottlenecks associated catastrophic events such as war and depression, making them to human populations of limited variation used for disease-mapping such as the Finns, Icelanders, and As a result, the unique pattern of LD in provides an exceptional opportunity to complex traits that are to human biology using approaches that would not be in human populations.

Because breeds represent closed pools, they may define genetic clusters. Analysis of loci have strongly this notion (Koskinen ). For example, in the Parker et al. (2004 ) 96 microsatellite markers were that spanned all dog autosomes at a 30-Mb resolution (Parker et al. ). Excluding data from the related Belgian Sheepdog and Tervuren breeds, they that 99% of 414 dogs were assigned to breed. Consequently, a can be defined at the molecular level and can be correctly assigned to their with small amounts of These results strongly that breeds are distinct units and even closely breeds do not represent genetic

Breed origin and relationship

DNA studies have not been for the reconstruction of breed origins or because the origin of the vast of sequence polymorphisms found in preceded the development of modern Therefore, phylogenetic hierarchies on DNA sequences reveal the history of that occurred before were domesticated (e.g. 1C ). However, many breeds several mitochondrial DNA haplotypes, that multiple matralines involved in the founding of a dog breed. To the recent evolution and relationships of microsatellite loci provide a tool, as their high insures allele frequency through drift. Genetic trees based on the microsatellite from Parker et al. (2004 ) several distinct breed The most divergent grouping contained the most ancient but none of these nine breeds were of European The ancient breeds included from a wide geographic including the Arctic, Asia, and the Middle East. By comparison, the of breeds, including European appeared to stem from a node without significant structure, which has been a “hedge,” indicating a recent and extensive hybridization between the (Parker et al. 2004 ; Fig. 2 ). The on breeds belonging to this in past studies probably the observed lack of phylogenetic (Zajc et al. 1997 ; Koskinen and 2000 ; Irion et al. 2003 ).

analysis of 85 dog breeds. Cluster from a structure analysis of 414 from 69 breeds and based on 96 markers. Each breed was represented by five dogs, and all were unrelated to one another at the level. Structure implements a model-based clustering algorithm attempts to identify genetically subpopulations based on patterns of frequencies (Pritchard et al. 2000 ). genotyped dog is represented by a single line divided into K where K is the number of clusters in each structure analysis. The of the colored segment represents the estimated proportion of membership in cluster (Parker et al. 2004 ). At K = 4, clusters are clearly defined genetically distinct breed within the domestic dog (see

This evolutionary hierarchy breeds should cluster into groups sharing common ancestry. A genetic algorithm, deployed in the computer “structure” was used to explore the groupings within dogs et al. 2000 ). Structure assigned 335 correctly to 69 unique breed clusters that represented single breeds or sets of closely related breeds. the program could not easily a half-dozen obviously related such as the Bernese Mountain Dog and Swiss Mountain Dog or Mastiff and This lack of resolution in few breeds is predicted based on history. For instance, the Bullmastiff is to be 60% Mastiff and 40% Bulldog and was created by the two breeds in the mid-1800s (Rogers and 1995 ).

Individual breeds represented the definable cluster; however, order clusters are expected the origins of many dogs Consequently, the number of groups (K) was set to three, and finally, four. The distinct cluster to be defined at K = 2 nearly all breeds of Asian (Akita, Shiba Inu, Pei, Lhasa Apso, some sled dogs, and known ancient hounds as the Saluki (Fig. 2 ). When to the analysis, gray wolves eight countries all grouped in the cluster as well. The early of the Asian breeds on the phylogenetic and their association with the in clustering analysis (Fig. 2 ) the conclusions of mitochondrial DNA analysis domestication first took in East Asia (Savolainen et al. ). The next cluster to be defined at K = 3 was of mastiff-type dogs including the Bull-mastiff, Bulldog, Boxer, Finally, at K = 4, the third cluster to be included working dogs as the Collie and Shetland Sheepdog, with a subset of the sight such as the Greyhound. The final comprised mostly modern used in hunting and included gun hounds, and terriers. On-going is focusing on defining clusters this hedge group, more highly mutable microsatellite markers (Francisco et al. ) and less mutable markers on single nucleotide polymorphisms However, the structure analysis for the time defined groups on common ancestry and genetic rather than function hunting or herding breeds) and a genetic guide to the design of scans (see below).

promising approach toward breed history utilizes gene histories. For example, of the multidrug resistance gene ( ) and four closely linked markers was used to reconstruct the of a group of related breeds et al. 2004 ). A single MDR1 was found to segregate in nine that included seven breeds and two sight hound which were likely to at least one of the herding breeds. analysis confirmed this by revealing that the region MDR1 was identical by descent in all breeds, suggesting that inherited this haplotype an exclusive common ancestor. study of single gene in dogs will help the branching structure of “twigs” in the tree of dogs.

Mapping and the dog genome

research.nhgri.nih.gov/dog_genome/ .

www.genome.ucsc.edu ), by investigators at the Broad Institute and CanFam2.0) (Lindblad-Toh et al. 2005 ). data suggest that the portion of the dog genome is ∼18% than the human genome and 6% than the mouse genome. The difference is explained by a lower of repeat insertions in the dog genome to both human and mouse, the deletion rate of ancestral has been approximately equal the dog and human lineages. The relatively low of recent repeats in the dog genome together with high data and improved assembly to the high connectivity and quality of the dog assembly. This is well by the above-mentioned RH gene map of the dog, shows high concordance the assembled sequence as well as a set of hundred BAC ends previously by FISH (Hitte et al. 2005 ).

The sequence demonstrates that of the dog genome is contained in clear of conserved synteny relative to the and mouse genomes. The gene of ∼19,000 canine genes is lower than that considered for human, which is surprising. The accuracy of these however, is high; of the 19,000 canine genes, 14,200 1-1-1 orthologs between human, and mouse. Approximately of the orthologous nucleotides between and dog appears to be under purifying The purifying selection acting on orthologous genes appears higher in the lineage leading to dog in that leading to human, but than in the lineage leading to However, the relative constraints orthologs with different have been highly between the three lineages. genes involved in nervous function have diverged in both dog and human relative to but not relative to each other, with similar selection and possibly, convergent evolution. gene family expansions are common in dog than in human, that the dog has the most primitive content of the currently sequenced mammals.

Linkage disequilibrium and between dog breeds

To fully the unique genetic characteristics of the the architecture of linkage disequilibrium in the canine genome needs to be This knowledge would the mapping and cloning of genes to canine health, as well as the of loci regulating phenotypic The importance of this knowledge is in human studies where LD in well-defined populations has simplified heterogeneity problems associated complex traits (Kruglyak ; Sundin et al. 2000 ; Ophoff et al. ; Friedrichsen et al. 2004 ). Three questions have been First, how does the extent of LD to that which has been in humans? Second, how does LD between breeds, and finally, how does breed history the extent of LD?

These issues been addressed in two major (Sutter et al. 2004 ; Wade et al. ). Sutter et al. (2004 ) examined 189 from five unlinked in five breeds using 20 dogs from each (Fig. 3 ). They found in the Golden Retriever, LD falls to of its maximum value at about Mb. However, in the other breeds, LD is extensive, increasing to about 0.9 in the and Labrador Retriever and to 2.2 Mb in the Bernese Dog. Finally, at 3.8 Mb, LD in the Akita is 10× greater than that in the Golden Retriever. In some these observations agree with recorded breed (Fogel 1995 ; Wilcox and 1995 ; American Kennel 1998 ;). For instance, the Golden and Retriever are among the most breeds and neither breed has significant population bottlenecks 1995 ; Wilcox and Walkowicz ). By comparison, LD is expected to be greater in the as these dogs are derived a small number of founders came to the U.S. from (Fogel 1995 ; Wilcox and 1995 ). LD is predicted to be most in the Akita, a relatively rare with a restricted gene

LD in five breeds of dog. LD in 20 dogs from each of the breeds scanned for a total of 51 Kb in unlinked regions on chromosomes 1, 2, 3, 34, and 37. The revealed 189 SNPs and those a minor allele frequency then 0.2 in each breed used on LD calculations. Data averaged across the five and the D’ statistic used to the level of linkage disequilibrium. 0.5 indicates the point at which the statistic decays by 50%. are given in Mb for dog and Kb for human.

These suggest two important considerations for the of mapping and cloning studies. as there is at least a 10-fold in the extent of LD between dog breeds, selection deserves careful Second, LD in dogs is 20–50 more extensive than found in humans, where LD is reported to be about 0.28 Mb et al. 2001 ; Weiss and Clark ). More than 500,000 must be genotyped for whole-genome studies in humans (Kruglyak ; The International HapMap Consortium ). In contrast, only about SNPs are hypothesized to be needed for the dog study (Sutter et al. 2004 ). the mapping of common and complex such as epilepsy, …, disease, deafness, and heart in dogs may be more economical similar efforts in humans.

) (Lindblad-Toh et al. 2005 ) To determine how to use this resource, Sutter et al. ) examined the extent of haplotype for the five breeds described For any one breed, 80% of chromosomes examined on average, just 2.7 haplotypes. For all 100 examined, 80% of chromosomes carried 4.5 haplotypes. The overall degree of sharing, measured as the proportion of a chromosomes carrying haplotypes with another breed, from 46% to 84%. These of low haplotype diversity and high sharing, albeit with variability, suggest that a SNP set of modest size will be to successfully accomplish whole-genome studies in most breeds.

A in-depth analysis of the same questions, as well as issues the overall haplotype structure of the dog examined using ∼1300 plus resequencing data from 10 random regions 6% of the genome. The study was undertaken as of the canine genome sequencing (Lindblad-Toh et al. 2005 ) and the conclusions agree with those of et al. (2004 ). In addition to the 7.5× sequence, the genome sequencing generated 100,000 sequence from each of nine breeds representing all seven AKC and 20,000 reads from of five wild canids wolves and one coyote). The resulting SNP of 1/900 bp between breeds, bp between dogs and wolves, and bp between dogs and coyote, that all three species are closely related than and chimpanzee. The resulting set of 2.1 million have a polymorphism rate breeds of ∼72% within any breed, suggesting that SNPs discovered as part of the effort will be useful for in any breed.

Comparison of the two boxer as well as extensive resequencing and in 10 breeds by the sequencing group has illustrative for understanding the detailed structure of the dog. Such demonstrate megabase sized of the genome that are alternatively and heterozygous exist both for the boxer, as well as for 24 dogs different breeds and 20 dogs each of 10 breeds. Thus, haplotypes will be common virtually any purebred dog.

and collaborators conclude that LD any breed is actually dependent on the and duration of two bottlenecks. The first is an bottleneck occurring at the time of domestication that is common to all The second likely occurred breed formation. In combination, bottlenecks resulted in LD that for megabases in most breeds and haplotype diversity. Indeed, the dog population as a whole, ancestral blocks are roughly 5–10 kb with approximately five in each block. Thus, LD is examined carefully across breeds, typically, five are observed across each window, with one or two being and the rest rare. The recent of these haplotypes supports the that a modest number of perhaps as few as 5000, will be for genome-wide association mapping. the underlying ancestral haplotype structure implies that the rate will be high if single SNP association is used. haplotype-based association should be instead for most mapping

Canine disease gene

www.vet.cam.ac.uk/idid ) (Sargan 2004 ).

In cases, identification of canine genes has opened new avenues of for human biologists. For instance, the of a mutation in the hypocretin 2 receptor (Lin et al. 1999 ) in Doberman with inherited narcolepsy has key to understanding the molecular mechanisms regulate sleep (Nishino et al. ; Thannickal et al. 2000 ). In humans, the is associated with a progressive of hypocretin-expressing neurons and is a non-Mendelian mediated by a unique mechanism from that causing the in Dobermans. However, study of the etiology in dogs provided the tools for understanding the more disease in humans.

In other cases, study of disease genes has increased our of the interaction between genes and how interactions affect disease. interactions have proven to study in human populations, the size of even the largest studies is simply too small to anything but major effects. The of the MURR1 gene associated copper toxicosis in Bedlington (van De Sluis et al. 2002 ) an excellent example. Contrary to this disease did not map to the portion of the genome analogous to the Wilson’s locus in humans (Yuzbasiyan-Gurkan et al. ; van de Sluis et al. 1999 ). Analysis of the homolog of MURR1 in Wilson’s patients has subsequently proven as those who carry particular variants appear to present earlier onset disease et al. 2004 ), suggesting that the two or their products interact to disease.

Another significant concerns the identification of novel mechanisms through the study of dog Lohi et al. (2005 ) recently a gene for progressive myoclonic (PME) in a population of purebred wirehaired dachshunds. About 5% of the suffers from this recessive disease, which was to be analogous to the human disorder, disease. As in the human disease, individuals carry mutations in the gene. However, in contrast to the disease, the disease in dogs is due to bi-allelic expansion of a dodecamer found within the 5′ end of the genes’ large exon. Affected carry 19 to 26 copies of the repeat rather than the expected two This is the first example of a repeat expansion associated disease in any mammalian system and a potential novel mechanism for disorders.

Currently, perhaps the concentrated collaborative efforts are on the study of canine … and de Lorimier 2003 ; Ettinger ; Fan 2003 ; London and Seguin ; Porrello et al. 2004 ; Modiano et al. ). Dogs develop … twice as frequently as humans and the presentation and pathology of canine is similar to analogous human Genetic studies are ongoing to susceptibility genes for canine lymphoma, mast cell malignant histiocytosis, and kidney and a BAC CGH array resource is in development to understand somatic events to tumor growth and metastasis et al. 2003a ,b ). Of primary interest is whether different types of have unique or shared If a common origin of a particular … is established, then data from several simultaneously can facilitate the localization of the gene. Breeds of similar and sharing common ancestry as by historical record may often variants for disease phenotypes Neff et al. 2004 ). However, in cases, rigorous studies as those described below are to address the issue.

Genetics of

The genetic basis for differences in and proportion among dogs has yet to be However, both candidate and association studies are beginning to insight into the complexity morphological differentiation. For example, two candidate genes, MSX2 and . which are expressed during facial development, were in 10 different dog breeds that in cranial and face shape et al. 2001a ,b ). However, only a amino acid change in the protein showed an association short and broad skulls. greatly expanded surveys of genes may prove more for example, variation in the production of growth factor 1 (IGF-1) was to correlate with differences in the size of poodles, suggesting it may be a gene for size variation in (Eigenmann et al. 1984 ).

www.georgieproject.com/. For 460 they recorded 91 measurements a set of five x-rays taken on dog. The data were using principal component which defines independent axes based on linear of variables. Each axis is by a decreasing fraction of the total in the data set. The first axes explained 61% of the variation in the set and represented different components of and shape. For example, the first component axis reflected size variation of the skeleton, the second reflected the relationship the pelvis, head, and neck, that the size and strength of the and head–neck musculoskeletal systems are related. Quantitative Trait (QTLs) have been that are related to variation on of the above four principal Moreover, using a data set of 286 dogs, Chase et al. (2004 ) two loci on chromosome one spaced 95 Mb that appear to account for a percentage of hip dysplasia, as defined by angle in the Portuguese Water

Nonclassical genetic variation may be an important source of phenotypic in dogs. Fondon III and Garner ) suggested that highly simple tandem repeats in genes may be the source of new variation in developed lines and may explain high rate of morphologic To test this hypothesis, investigators analyzed three-dimensional of dog skulls from 20 breeds and mongrels. In representatives of 92 different they also sequenced 37 regions from 17 genes or thought to be involved in craniofacial In general, they found dogs had more perfect than humans and may be changing in length. Additionally, they that the size and the ratio of of two tandem repeats in the Runx-2 correlated with the degree of nose bend (clinorhynchy) and length in a variety of breeds. this evidence is suggestive, more detailed studies are associating repeat change specific phenotypic traits 2000 ). If such genetic are unique to the dog, they may in part, the apparent phenotypic of dogs. However, dogs have a unique skeletal whose alterations may more result in novel phenotypes 1986a ,b ,c ; Morey 1992. ).

One area of morphology we do not discuss in is that of canine coat which has been written extensively in the past. More progress on dissecting coat genetics in the dog has been done by two (Kerns et al. 2003 ; Berryere et al. ). Particular progress has been in understanding the interactions between the protein and the Melanocortin 1 receptor, control the type of pigment in mammalian hair (Berryere et al. ). Additional recent work has on black color in dogs, appears to be independent of the above (Schmutz et al. 2002 ; Kerns et al. ). Very interesting work is just beginning focuses on the of polymorphisms in coat color genes, such as the melanophilin (Philipp et al. 2005 ). With the of the canine genome sequence, is an area that will expand in the coming years.

of behavior

Dog breeds have behaviors, and dogs as a whole unique behaviors not found in wolves (Hare et al. 2002 ). the genetic basis of behavior is well understood than In general, the greatest need the development of assays to reproducibly specific behaviors. However, understanding is likely to come the study of pedigrees of dogs aberrant behaviors. For example, et al. (1998) have characterized of Bull Terriers displaying compulsive disease (OCD) such as tail chasing, in other respects is similar to OCD. As genome scans of pedigrees are completed, they may light on both the human and disease conditions.

Expression may also provide clues to the basis of behavior. Saetre et al. ) surveyed the expression pattern of genes in three different in the brains of domestic dogs and in wolves and coyotes. They that the pattern of gene in the hypothalamus of domestic dogs was from that in gray and coyotes, whereas patterns of expression in the amygdala and frontal were less differentiated. The controls specific emotional, and autonomic responses of dogs and is conserved throughout mammals. The of Saetre et al. (2004 ) suggest behavioral selection in dogs may affected this central of the brain, initiating a cascade of that result in some of the behaviors found in dogs.

The domestic dog has long fascinated biologists and geneticists because of the phenotypic diversity exhibited by the and the short time frame which this diversity has Molecular genetic evidence that dogs are indeed the domesticated species and their may have even well their first appearance in the record about 15,000 yr The dog has a diverse genetic origin likely involved multiple wolf populations and subsequently was by backcrossing with wolves their history. This input of variation from ancestors has provided the raw material for change, but unique development and mechanisms may also have the course of artificial selection. clearly have behaviors, and diseases that are not evident in wild progenitors. Finally, in the recent evolution of dog breeds, interbreeding has imposed a remarkable structure such that all breeds represent distinct pools that can be divided at least four distinct groupings.

Understanding the genetic that have given to the unique attributes of domestic may finally be within reach. A and a partial genome sequence are from a boxer and a poodle, and mapping resources are well and increasing in sophistication. The dog genome in has high levels of LD, such whole-genome association studies be facilitated and genomic scans of breeds segregating traits of may readily be found through of LD or reductions in heterozygosity due to selective (Weiss and Clark 2002 ; and Wooding 2003 ; Luikart et al. ; Pollinger et al. 2005 ). In this we have provided the evolutionary and framework for understanding the molecular of dogs with the aim of taking the step toward answering the posed in the introduction. The primary of this article was to help the enthusiasm that will to realizing the promise of the dog genome for significant problems in evolution, and human health.

Acknowledgments

We two anonymous reviewers, Kerstin Heidi Parker, Nate Ed Giniger, and Francis Galibert for comments and helpful suggestions on manuscript. We also thank Lindblad-Toh for sharing data in of publication. Finally, we thank the colleagues, dog owners, and breeders who generously shared samples and much of the work reviewed possible.

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