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Origin, genetic diversity,and genome structureof the domestic dogRobert K. Wayne1* and Elaine A. Ostrander2

Summary

C om p arative analysis ofm am m alian g enom es p rovid es im p ortantinsig htinto the

struc ture an d fun ction of g en es. H ow ever, the co m p arative an alysis of g en e

seq ue nc es from ind ivid ua ls of the sam e an d d ifferen t spe cies also p rovid es

insig htinto the e volution o fg enes,p op ulations,and sp ecies.W e e xem p lify these

tw o use s of g en om ic inform ation . First, w e d oc um en t the evo lution ary relation -

ship s of the d om estic d og to other ca rnivores b y using a variety of D N A -b ase d

inform ation .A p hylog en etic co m p arison ofm itoc ho nd rialD N A seq ue nc es in d og s

an d g ray w olves sho w s tha td og s m ay ha ve orig ina ted from m ultip le w olfp op ula-

tion s at a tim e m uch ea rlier tha n sug g ested b y the archae olog ic rec ord . W e

d iscu ss p reviou s the ories ab ou td og d evelop m en tan d evo lution in lig hto fthe ne w

g en etic d ata.S econ d ,w e review rec en tp rog ress in d og g en etic m ap p ing d ue to

the d eve lop m en t of hyp ervariab le m arkers and sp ec ific ch rom o som e p aints.

E xtensive g enetic hom olog y in g ene ord er and function b etw een hum an s and

do gs has be en discovered . The do g prom ises to b e a valuab le m od el for

id entifying g enes thatc ontrolm orp holog ic d ifferen ces b etw een m am m als as w ell

as und erstand ing g ene tically b ased d isease. B ioE ssays 21 :247257,

1999. 19 99 John W iley & S ons,Inc.

Introduction

We will review recent studies of genetic diversity and genome

mapping of dogs to demonstrate the use of genome informa-

tion in evolutionary and biomedical studies. Initially, we will

discuss the evolutionary history of dogs and their relationship

to other canines and carnivores as revealed by DNA-based

research. These results show that canines belong to a very

unique and long distinct genetic lineage of carnivores. There-

after, we will describe new genetic studies suggesting that

dogs were domesticated over 100,000 years ago. Although

all dogs appear to have been derived from the gray wolf,

origination or interbreeding events may have occurred sev-

eral times over human history. Gray wolves may continue to

influence the genetic diversity of dogs through the interbreed-

ing of dog-wolf hybrids and domestic dogs. We will conclude

with an overview of dog genome mapping studies and their

relationship to similar studies in humans and other mammals.

Progress in the physical map of genes has been slow

because dogs have a high numbered karyotype (2n 78)

and the smallest chromosome elements are difficult to iden-

tify. However, recent advances in banding studies and the

development of hypervariable markers and chromosome

paints have resulted in more extensive syntenic and physical

maps.

Evolutionary relationships of the domestic dog

The domestic dog is a species in the family Canidae, order

Carnivora, and superfamily Caniodea that includes seals,

bears, weasel-, and raccoon-like carnivores (Fig. 1). The dog

family is sometimes considered representative of the super-

family, but the Canidae is, in actuality, the most phylogeneti-

cally distinct family, diverging from other carnivores over 50

million years ago (Fig. 1). In fact, the canine karyotype holds

1Department of Biology, University of California, Los Angeles, CA.2Clinical Research Division, Fred Hutchinson Cancer Research Cen-

ter, Seattle, WA.

*Correspondence to: Robert K. Wayne, Department of Biology, 621

Circle Drive South, University of California, Los Angeles, CA 90095

1606. E-mail [email protected]

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little similarity to those in any other carnivore family,(1,2)

suggesting large blocks of chromosome may not be con-

served. However, conserved syntenic gene groups have

been found throughout Carnivora.(3) Nonetheless, extrapola-

tions about gene structure and function from one carnivore

family to another may be dubious because of the ancient

evolutionary divergence between dogs and other carni-

vores.(4)

Although dogs belong to an ancient lineage, the 35 extant

species are all very closely related (Fig. 2). The radiation of

recent lineages probably began about 12 to 15 million years

ago and diversified into three distinct groups: (1) the redfox-like canids, including red, kit, and Arctic foxes; (2) the

South American foxes; and (3) the wolf-like canids, including

the domestic dog, gray wolf, coyote, and jackals. The gray

fox, raccoon dog, and bat-eared fox do not fit into these

categories and represent long-distinct lineages. The raccoon

dog appears to have the most primitive chromosome comple-

ment and may have some large chromosome blocks that are

homologous to those in cats.(2) However, chromosome num-

ber and structure vary widely among canid species, from 36

metacentric chromosomes (red fox) to 78 acrocentric chromo-

somes (wolves, coyotes, and jackals) (Fig. 2). This degree of

variation contrasts sharply with most other carnivore families

in which chromosome number and structure are well con-

served.(1)

Origin of the domestic dog

Domestic animals are used widely as models for genetic

investigations ranging from classic breeding studies to de-

tailed molecular genetic examinations.(5) However, the origin

of genetic diversity in domesticated varieties is seldom wellknown. Often, the number, timing, and geographic origin of

founding events is unclear from historical records or the

domestication event was so ancient that no records were

kept. This uncertainty is well exemplified by the domestic dog

(Canis familiaris). Theories of dog origin range from those

maintaining that dogs originated once from a limited founding

pool to those suggesting multiple origins, from possibly more

than one species, over the course of human history. (6,7) Most

Figure 1. Relationship of carnivores based on DNA hybridization data.(69) Family and superfamily groupings are indicated. Time scale

based on comparisons of molecular divergence to first appearance times in the fossil record.

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of the several hundred extant dogs breeds have been

developed in the last few hundred years, but even for these,

the specific crosses that led to their establishment often have

not been recorded.(8) The genetic diversity of the founding

populations is essential knowledge for understanding the

immense phenotypic diversity of dogs. A diverse gene pool

suggests that gene diversity is critical to phenotypic diver-

gence, whereas a limited gene pool suggests development

plasticity is more important in breed evolution. Moreover, an

understanding of genetic diversity is needed in order that

genome mapping studies can document and use efficiently

the genetic diversity that exists in the dog.All species in the dog genus Canis are phylogenetically

closely related and can potentially interbreed. Charles Darwin

felt that domestic dogs were phenotypically so diverse that

they likely had originated from two or more wild canine

species.(9) Similarly, Konrad Lorenz initially suggested that

traits from wolves and jackals could be observed in dogs.(10)

However, such polyphyletic theories of dog origin are uncom-

mon, and most researchers maintain that dogs were derived

from one or more populations of gray wolves.(6,7) Molecular

genetic data clearly support the origin of dogs from wolves;

dogs have protein alleles in common with wolves, (11,12) share

highly polymorphic microsatellites,(13) and have mitochondrial

DNA sequences similar or identical to those found in gray

wolves.(14,15) Recently, a comprehensive survey of several

hundred gray wolves and dogs found that the two species had

only slightly divergent mitochondrial DNA control region

sequences.(16) For example, the average divergence be-

tween dogs and wolves was about 1.5% in comparison to

7.5% between dogs and coyotes, their next closest relation.

More controversial is the specific number of domestication

events and their timing and location. The archeologic record

suggests that the first domestic dogs are found in the Middle

East approximately 14,000 years ago.(6,7) However, remains

close to this age are known from Europe, and 8,000-year-old

specimens are known from North America.(6,7,17) Morphologic

comparisons suggest that dogs are closest phenotypically to

Chinese wolves.(18) The phenotypic plasticity of dogs is a

problem when attempting reconstructions of their origin.Some dogs approach closely the phenotype of wild wolves,

whereas others do less so.(19) Consequently, the first appear-

ance in the fossil record of domestic dogs, as marked by their

phenotypic divergence from wolves, may be misleading.

Rather than the first domestication event, the appearance of

the first differentiated dogs in the fossil record instead may

have recorded a change in artificial selection associated with

a cultural change in human societies.(16)

An independent assessment of dog domestication is

provided by mitochondrial control region sequence data (Fig.

3).(16) Phylogenetic analysis of control region sequences

reveals four divergent sequence clades. The most diverse of

these clades contain sequences that differ by at most 1% in

DNA sequence (Fig. 3, clade 1). Therefore, because wolves

and coyotes diverged about 1 million years ago and have

control region sequences that are 7.5% different, dogs and

gray wolves may have diverged 1/7.5 as long ago or about

135,000 years before present. Consequently, the molecular

results suggest an ancient origin of domestic dogs from

wolves. In fact, wolves and humans lived in the same habitats

for as much as 500,000 years.(6) Therefore, they may have

been domesticated earlier and have only recently changed in

conformation with changing conditions associated with the

shift from hunter-gather cultures to more agrarian societies

about 12,000 years ago.

(6)

The role that dogs played insocieties before this period may have been dramatically

different, perhaps restricted more to protection and hunting

and living less closely with humans. Alternatively, dogs may

have had a more recent origin, but are descended from a now

extinct species of canid whose closest living relative was the

gray wolf.

At least four origination or interbreeding events are implied

by the genetic results because dog sequences are imbedded

Figure 2. Maximum parsimony tree of 26 canid species

based on analysis of 2,001 bp of DNA sequence from

mitochondrial protein-coding genes.(70) Diploid number indi-

cated in parentheses for species or groupingsof canids.(2) The

nine remaining species not surveyed genetically have been

classified with the red fox-like or wolf-like canids.(71)

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in four distinct groupings or clades, each with a separate

ancestry with wolves (Fig. 3). In clade 4, a wolf sequence is

identical to a dog sequence, suggesting a very recentinterbreeding or origination event. Unfortunately, domestica-

tion events are difficult to distinguish from interbreeding

events. Once dogs were domesticated, they may have

spread over a widearea and,thereafter, occasional interbreed-

ing with wild wolves would have transferred wolf mtDNA to

them. The number of origination/interbreeding events is likely

much more than that implied by the tree for several reasons.

First, because mitochondrial DNA is maternally inherited,

interbreeding events between male wolves and female dogs

would not be preserved. In fact, such crosses may be more

successful than female wolf/male dog crosses because the

female wolf might tend to raise her offspring in the wild where

conditions are more difficult.(20) Second, by chance, the

mitochondrial DNA from dog/wolf interbreeding events may

have been lost during the history of domestication. Because

mitochondrial DNA is clonally inherited from the female

parent, by chance, female offspring may not reproduce

although nuclear genes are transmitted through male prog-

eny.

Within breeds, the sequence diversity also is high. Most

well-sampled breeds have at least three to six distinct

sequences, suggesting that many females were involved in

the development of the breed.(16) For the reasons above, the

number of founding females for each breed may be much

greater than suggested by the number of different sequences

alone. Few breeds have unique sequences, and the genea-

logic relationship among breeds is not apparent in the

sequence tree. Most breeds have originated too recently,within the past few hundred years, such that unique breed-

defining mutations have not occurred in the control region.

Therefore, the relationship of sequences among breeds

reflects divergence in the ancestral common gene pool of

dogs rather than specific ancestor-descendent relationships

of recently diverged breeds. Ample genetic diversity within

breeds also is supported by analysis of protein alleles (12,21)

and hypervariable microsatellite loci. Microsatellite loci have

values of average expected heterozygosity within breeds

ranging from 36% to 55%,(22,23) whereas pure wild popula-

tions of wolves have an average value of 53%.(13,24) Conse-

quently, the moderate to high genetic diversity of dog breeds

indicates that they were derived from a diverse gene pool andoften have not been intensively inbred.

Ancient dog breeds

The genetic results suggest that the majority of breeds are

genetically diverse and are not well differentiated (Fig. 3).(20)

These results are expected because most breeds have been

developed very recently and apparently were derived from a

diverse and well-mixed gene pool. However, more ancient

breeds, such as the dingo, the New Guinea singing dog,

greyhounds, and mastiffs were developed when human

populations were more isolated. Some of these breeds may

have been independently domesticated from wolves. In fact,the Norwegian breeds in our study have sequences that

define a highly divergent clade, suggesting an ancient and

perhaps independent origin from wolves (Fig. 3, Clade 2). To

determine whether other ancient breeds with a long history of

isolation were independently derived from wolves, a survey of

the Mexican hairless, or Xolo, was undertaken.(25) The Xolo

is a breed of hairless dogs developed in Mexico over 1,000

years ago. A survey of 26 Xolos showed that they contained

Figure 3. Neighbor-joining relationship tree of wolf (W) and

dog (D) control region sequences.(16) Dog haplotypes are

grouped in four clades, I to IV. Boxes indicate haplotypes

found in the 19 Mexican hairless dogs.(25) Bold charac-

ters indicate haplotypes found in New World wolves (W20 to

W25).

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sequences identical to those found in other dogs breeds.

Moreover, representatives of all four sequence clades were

found in the Xolo (Fig. 3), indicating that the population of

dogs that migrated with humans into the New World over

10,000 years ago was large and diverse and had a recent

common ancestry with dogs of the Old World. None of the

Xolo sequences were similar to New World wolves, suggest-

ing that they were not independently domesticated from

them.

Wolf-dog hybridization

Wolves continue to influence the genetic diversity of dogs. In

the United States, over 100,000 wolf-dog hybrids exist.

Wolf-dog hybrids are frequently interbred with dogs, and the

progeny of hybrids, by having a lower proportion of wolf

genes, may be more docile. Consequently, wolf genes will

diffuse into the dog population at large. Dog genes may also

be influencing the genetic composition of wild wolves. In Italy

and Spain, gray wolves interact and may interbreed with

semi-feral populations of domestic dogs.(20) Such hybridiza-tion can threaten the genetic integrity of wild wolf populations,

although the frequency of occurrence may not be as high as

previously thought.(20)

Implications for genome mapping

The implication of these results for genetic studies of dogs is

that despite intense selection for phenotypic uniformity within

breeds, the genetic diversity within many dog breeds is

similar to that in wild gray wolf populations. Consequently,

breeds without a closely controlled history of inbreeding

should not be considered genetically uniform, except as

regarding specific genes affecting conformation and breed

defining traits. Additionally, these results suggest that the

diversity of functional genes in dogs should be systematically

explored to complement efforts in genome mapping. A ge-

nome map based on studies from a limited sample of dogs

will not adequately represent the genetic diversity of dogs.

However, crosses between distinct dog breeds to create

highly heterozygous individuals for mapping studies may not

be very useful because of the low level of divergence among

breeds. Crosses between dogs and coyotes may be more

informative in this regard (Fig. 2).

Developmental and genetic diversity

An intriguing question concerns the origin of phenotypicdiversity in domestic dogs. Dogs are clearly the most diverse

domestic species. The range in size and conformation is

exemplified by the petite Chihuahua (0.5 kg) and the massive

Great Dane (80 kg). This two orders of magnitude difference

in size has no parallel in other domesticated animals. Past

theories to explain the origin of phenotypic diversity in dogs

have hypothesized that it is related to the profound develop-

mental alterations that occur from neonate to adult.(19) Neona-

tal dogs have an extremely broad and foreshortened cranium,

whereas an adult German Shepard has a long tapered face

and cranium (Fig. 4). Developmental alterations that truncate,

accelerate, or retard aspects of this ontogenetic transforma-

tion create dramatically divergence skull morphologies that

can readily be selected by breeders. Puppy-like features in

adult animals are often cultivated by humans.(26) In contrast,

neonatal and adult domestic cats vary little in proportion and,

thus, changes in growth rate or timing will not cause such a

dramatic change in conformation (Fig. 4). Breed diversity is

reflected by ontogenetic diversity in other domestic mammals

as well.(19) This finding suggests that the difference in diver-

sity between dogs and other domestic animals reflects the

degree to which neonates and adults differ in conformation.

The action of only a few development genes on growth will

cause more dramatic change in dogs than in other domestic

animals. However, this conclusion was based on the assump-

tion that dogs and other domestic species had similar initial

levels of genetic variation. The finding that dogs have had a

diverse and ancient origin suggests that genetic variationmay be an important prerequisite for phenotypic variation in

dogs and other domestic species.

The canine genome: Genome organization

and cytogenetics

Among the many methods for studying genetic variation are

those based on cytogenetic analyses, comparative studies of

gene families, and molecular genetic analyses. The first of

these, cytogenetic analysis, has been extremely difficult to

perform in the dog due to the large number of small acrocen-

tric chromosomes (2n 78). Based on high-resolution

banding of metaphase chromosomes from dog fibroblasts, an

ideogram of 460 numbered bands and landmarks has only

recently been proposed.(27) But standards for chromosome

identification by G-banding have been established for only

the largest 22 canine autosomes by the Committee for the

Standardized Karyotype of the Dog.(27,28) Thus, efforts to

reproducibly distinguish canine chromosomes have had to

rely largely on newer molecular approaches, such as chromo-

some painting after isolation of flow-sorted single canine

chromosomes.(29) This particular approach has worked well;

application of dual-laser flow cytometry has allowed high-

resolution sorting of canine chromosomes in 32 distinct

peaks. This flow sorted material can be amplified by using the

polymerase chain reaction (PCR) and then used as a probe incytogenetic analyses on metaphase spreads of dog chromo-

somes. Twenty-two of the canine chromosome paints allow

the identification of a single canine chromosome; the remain-

der identify two chromosomes that are similar in size. Re-

agents such as canine chromosome paints are expected to

play a key role in unraveling the organization of the canine

genome and determining the relationship between closely

related mammalian genomes.

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two best strategies for linking the evolving canine genetic

map with those of the human and mouse is through identifica-

tion of gene-containing cosmids that can then be used for

fluorescence in situ hybridization (FISH) mapping and by the

development of resources for physical mapping such as

interspecies hybrid cell lines or radiation hybrid panels.

The first approach is best illustrated by the mapping of

several loci from human chromosome 17q to the centromeric

two-thirds of dog chromosome 9, where FISH has been usedto localize cosmids containing genes from 17q.(57) Subse-

quent isolation of microsatellite-based markers from each

cosmid followed by linkage analyses that use multiple large

outbred families has allowed the placement of these gene-

linked markers on the canine microsatellite map. Both FISH

and linkage analysis now suggest that the gene order on

canine chromosome 9 is similar to that of human 17q and

mouse chromosome 11. All genes mapped between the

neurofibromatosis gene (NF1) and the thymidine kinase gene

(TK1) appear to be present, although the gene order is

inverted with respect to the centromere in the dog 9. In

addition, two loci, GLUT4 and PMP22, which are located on

human chromosome 17p, have been mapped by FISH

analysis of gene containing cosmids to dog chromosome 5 in

a region also identified by the whole human chromosome 17

paint, thus indicating a breakage of human chromosome 17

syntenic homology at the centromere. This finding is con-firmed by the previous placement of the canine p53 gene on

canine chromosome 5.(58) Consequently, other loci on human

chromosome 17q may be localized to canine chromosome 9,

whereas loci on 17p are likely localized to canine chromo-

some 5. Genes or expressed sequence tags (ESTs) mapped

to human chromosome 17, therefore, serve as candidates for

linkage to loci mapped to canine chromosome 9 and 1,

respectively. This finding is likely to facilitate mapping of

Figure 6. Canine genetic map of four canine chromosomes. Linkage groups 1, 2, 3, and 4 are based on analyses of over 350 distinct

microsatellite markers (4849, and Mellersh and Ostrander, unpublished results). Markers are indicated to the right of each vertical line.

The distance between the markers is calculated in centimorgans and is indicated to the left of the line. All markers have been assignedwith Lod score greater or equal to 5.0. Markers underlined are ordered with a Lod score greater or equal to 3.0.

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canineprcdgene, which lies close to the TKgene on canine

chromosome 9, and studies of a number of genes such as

BRCA1, her2, and RARA which have a role in growth and

regulation of malignant tumors.

In addition to studies of autosomes, a number of cosmids

that hybridize to the canine X chromosome also have been

localized.(59,60) Together with data provided in an earlier study

by Deschenes, these data suggest that the canine X chromo-

some has been evolutionarily maintained between humans

and dogs.(61) For instance, the genes for SCID, AR, PGK, and

CHM are localized to the proximal region of Xq in the dog, in

this case in Xq13-q21, as they are in the human.(61) Similarly,

factor VIII and IX are localized to Xq28 and Xq26.3, similar to

their placement on the human map.(59) Karyotypic studies of

the canine X predicted these results. Linkage mapping

studies of additional X-linked disorders are likely to be one of

the quickest ways in which the canine map will assist in

studies of human disease, because a significant number of

informative meioses can be more quickly collected in canine

families than in human families.A second approach for undertaking comparative studies of

all mammalian genomes can be quickly undertaken if com-

mon sets of genes are placed on all mammalian genome

maps. Toward this goal, a comprehensive panel of canine-

rodent hybrid cell lines has been constructed and character-

ized.(62) Groups of microsatellite markers or cloned canine

genes can now be assigned to putative syntenic groups by

testing markers against this panel of cell lines in which each

complete canine chromosome appears to be represented at

least once (Fig. 7). In the example provided, several genes

from human chromosome 6 were analyzed on 46 of the

canine-rodent hybrid cell lines. PCR primers defining several

genes from the central and telomeric regions of human

chromosome 6 amplified the same subset of cell lines,

suggesting these genes are likely on the same canine

chromosome. Similar patterns of conservation are observed

in mice. Until final nomenclature is established, this chromo-

some has tentatively been referred to as dog chromosome F.

Genes DLA-79 and PLN amplified a distinct subset of cell

lines (dog chromosomes A and E), suggesting that this region

of human 6 has not been evolutionarily conserved.

Due to the recent availability of a panel of 106 canine-

hamster radiation hybrids containing the entire canine ge-

nome, this approach will be largely superseded by radiation

hybrid mapping.

(63)

This panel has been used to construct apreliminary radiation hybrid map of the canine genome, which

is composed of 182 microsatellite markers and 218 genes.(64)

By integrating the resulting 56 RH groups with the 40 linkage

groups that define the linkage map, it is expected that a

high-density map of the canine genome, coordinated

with the syntenic dog and human chromosomes, will be

generated quickly. The more densely mapped mouse and

human genomes, thus, will provide a resource of candidate

genes after a discovery of linkage between any microsatellite

and a phenotype of interest.

Several sets of anchored reference loci have been devel-

oped to further facilitate these comparative mapping stud-

ies.(58,6567) The genes selected as anchor loci are evolution-

arily conserved, are members of important gene families, and

have been characterized in several mammalian species such

as the cow, pig, and cat. Primer pairs that define each gene in

the anchor set have been designed to span introns, thus

maximizing the opportunity for development of polymorphic

markers as well.(67) A concerted effort is under way for the

developers of maps of all mammalian genomes to place the

same set of 300400 genes on their maps. In this way,

analyses of a locus on any single mammalian chromosome

will be enhanced by a wealth of data from the comparative

chromosomes of other mammals.

Finally, a canine bacterial artificial chromosome (BAC)

library of 8.2-fold density, averaging 145 KB inserts recently

has been constructed.(68)

In regions where linkage has beendefined already, such as the localization of the prcdlocus to

canine chromosome 9,(56) BACs are being used to construct a

physical map across the small chromosomal region defined

by linkage analysis. Once a minimal tiling path of BACs is

made that spans the region of interest, BACs will be individu-

ally studied for genes in the region by either screening cDNA

libraries developed from canine-specific tissues, or by exon

trapping methods. Once specific genes are identified in the

Figure 7. Comparative mapping of human chromosome 6.

Several genes from human chromosome 6 were analyzed on

a panel of canine-rodent hybrid cell lines. Genes TNFA, RDS,

CGA, and TBP amplified the same subset of cell lines,suggesting that they are on the same canine chromosome.

Genes DLA-79 and PLN amplified a distinct subset of cell

lines, suggesting this region of human 6 has not been

evolutionarily conserved.

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region of linkage, the sequence of affected and unaffected

dogs can be compared to determine which gene is most likely

disease-associated. Thus, BACs provide the bridge that

moves the identification of disease genes from genetic to

physical mapping. The entire process is aided by the fact that

the human and canine genomes share synteny. For example,

because canine chromosome 9 and human 17q share their

chromosomal organization, information from human chromo-

some 17q can be used to target selected candidate genes

from canine chromosome 9 for additional study.

One additional resource that is just emerging is the

availability of databases of ESTs. Sequencing large numbers

of cDNA clones to develop databases of partial genes of

unknown function provides a resource of enormous potential.

Examination of such databases after partial cloning of a gene

can provide researchers with additional DNA sequence, as

well as information about tissue-specific expression.

Summary remarks

The development of dogs as a model for analysis of inheriteddisorders and gene expression and regulation has been

hampered by an inadequate genetic map. However, progress

over the past few years in better defining the genetic map of

dogs has been considerable. The high incidence of behav-

ioral and physiologic disorders and genetic disease within

specific dogs breeds as well as the available of multigenera-

tion genealogies, now make the dog a tangible and attractive

genetic model. Together will population level and evolutionary

studies reveal that dog is swiftly becoming one of the

genetically best-defined domestic species.

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Genes and genomes

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