Download The dog genome map and its use in mammalian comparative

J. Appl. Genet. 45(2), 2004, pp. 195-214
Review article
The dog genome map and its use
in mammalian comparative genomics
Marek SWITONSKI, Izabela SZCZERBAL, Joanna NOWACKA
Department of Genetics and Animal Breeding, August Cieszkowski Agricultural University,
Poznañ, Poland
Abstract. The dog genome organization was extensively studied in the last ten years.
The most important achievements are the well-developed marker genome maps,
including over 3200 marker loci, and a survey of the DNA genome sequence.
This knowledge, along with the most advanced map of the human genome, turned out
to be very useful in comparative genomic studies. On the one hand, it has promoted
the development of marker genome maps of other species of the family Canidae
(red fox, arctic fox, Chinese raccoon dog) as well as studies on the evolution of their
karyotype. But the most important approach is the comparative analysis of human
and canine hereditary diseases. At present, causative gene mutations are known for
30 canine hereditary diseases. A majority of them have human counterparts with
similar clinical and molecular features. Studies on identification of genes having
a major impact on some multifactorial diseases (hip dysplasia, epilepsy) and cancers
(multifocal renal cystadenocarcinoma and nodular dermatofibrosis) are advanced.
Very promising are the results of gene therapy for certain canine monogenic diseases
(haemophilia, hereditary retinal dystrophy, mucopolysaccharidosis), which have
human equivalents. The above-mentioned examples prove a very important model role
of the dog in studies of human genetic diseases. On the other hand, the identification
of gene mutations responsible for hereditary diseases has a substantial impact
on breeding strategy in the dog.
Key words: Canidae, comparative genomics, dog, gene therapy, hereditary diseases,
human.
Received: March 15, 2004. Accepted: April 15, 2004.
Correspondence: M. SWITONSKI, Department of Genetics and Animal Breeding, August
Cieszkowski Agricultural University, ul. Wo³yñska 33, 60-637 Poznañ, Poland; e-mail:
[email protected]
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Introduction
Knowledge of the genome organization of a species of interest is required
for detailed genetic analyses, including the identification of genes causing
hereditary diseases and comparative genomic studies. In the recent years
extraordinary progress has been achieved in the dog genome mapping. Moreover,
numerous monogenic hereditary diseases have been characterized and molecular
tests for detection of the causative mutations have been developed. A unique
phenotype variability of dog breeds reflects differences between their gene pools,
including the distribution of gene mutations causing genetic diseases and a predisposition to develop specific cancers. These circumstances show that the dog
can be a very useful animal model for human genetic diseases and, what is very
important, for the development of gene therapy strategies. Taking into
consideration these circumstances, sequencing of the dog genome has been
undertaken (http://www.genome.gov/11007358) and a survey of the genome
sequence has been recently published (KIRKNESS et al. 2003).
Comparative genomics concerning mammalian species, including numerous
species of the order Carnivora, has benefited from the advanced human genome
map and the canine map, as well. The use of the dog whole-chromosome painting
probes, as well as locus-specific probes in FISH studies on chromosomes of other
canids, has brought new data on genome evolution in this family (NASH et al.
2001, YANG et al. 1999, SWITONSKI et al. 2003a). Establishing the dog genomic
libraries, with large inserts cloned in BAC vectors, has had a substantial impact
on the progress in genome mapping (LI et al. 1999, SCHELLING et al. 2002).
In this paper the recent advances in genomic studies in the dog are reviewed.
Three main issues are considered: (1) the dog genome organization
and comparative genomics, with special emphasis on the family Canidae,
(2) canine genetic diseases and their human counterparts with known molecular
background, and (3) progress in canine gene therapy.
Organization of the dog genome
Chromosome set
The diploid chromosome number of the dog is 78 and all the autosomes are
acrocentric, while the sex chromosomes are biarmed. The X chromosome is large,
submetacentric and the Y chromosome is metacentric, being the smallest element
in the karyotype. The high diploid number of chromosomes and their morphological similarity cause difficulties in distinguishing small autosomes. By using the
G-banding technique, only a partial standard karyotype, including 21 biggest
autosomes and the sex chromosomes, has been established (SWITONSKI et al.
1996). The application of the FISH approach with chromosome-specific paints
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197
and locus-specific probes facilitated the recognition of all the DAPI-banded chromosomes (BREEN et al. 1999a). The dog chromosomes are described by an acronym derived form the Latin name of the species (Canis familiaris) – CFA.
Marker genome map
Efforts towards establishing a marker map of the dog genome were initiated during a conference in Oslo, Norway, in 1993 (DOGMAP CONSORTIUM 1999).
At that time, three main goals were specified: (1) to develop a linkage map with
an approx. 20 cM marker density; (2) to establish the cytogenetic map with at least
two marker loci assigned to each chromosome; and (3) to standardize the dog
karyotype. So far, over 3200 markers have been mapped on the canine genome
(GUYON et al. 2003).
Cytogenetic map
There are two main strategies of the cytogenetic (physical) mapping: fluorescence
in situ hybridisation (FISH) and somatic cell hybridisation. The latter is usually
carried out on the so-called radiation hybrid panels. This means that cells of
the mapped species (the dog) were irradiated prior to the hybridization.
Such a treatment causes a fragmentation of chromosomes and rescues their fragments in the hybrid cells.
Fluorescence in situ hybridization (FISH).
The FISH technique plays a major role in the physical identification of the locus
of interest (Figure 1a and b). Until 2001, over 300 genetic markers were localized
on dog chromosomes (BREEN et al. 2001). Among them the vast majority is represented by clones harbouring microsatellites, and thus the number of physically
mapped genes is rather small – fewer than 80 (for review see: BREEN et al. 2000).
Recently, new localizations have been reported (Table 1). At present, all chromosomes have got at least one marker assigned by FISH. However, the number of the
mapped markers ranges from about 40 on the X chromosome to 1 on CFA32 and
CFA33. The smallest autosomes (CFA32-CFA38) are poorly mapped, as compared with the large ones. A map of the highest density was achieved for
autosomes CFA5 and CFA9.
Radiation map
The first step towards radiation hybrid mapping was to establish a whole-genome
radiation hybrid (WGRH) panel. The WGRH panels have become an efficient
tool for mapping and a major advantage of this strategy is the mapping
of non-polymorphic (or low-polymorphic) coding sequences, which are located in the vicinity. The first WGHR panel was developed by irradiation of
dog fibroblasts with 5000 rads and their subsequent fusion with hamster cells
Table 1. FISH-mapped markers in the dog genome
Dog
chromosome
No. of earlier
mapped markers
(BREEN et al. 2001)
Markers mapped recently (2001-2004)
Total
1
2
3
4
1
12
ERBB2 (MURUA ESCROBAR et al. 2001)
FRDA (KUIPER et al. 2002a)
EYA4 (RAK et al. 2003)
GJA1 (RAK et al. 2003)
MYB (THOMAS et al. 2003c)
17
2
11
DIAPH1 (RAK et al. 2002b)
POU4F3 (RAK et al. 2003)
13
3
11
FES (THOMAS et al. 2003c)
12
4
13
TCOF1 (HAWORTH et al. 2001b)
MSX2 (HAWORTH et al. 2001a)
CDH23 (KUIPER et al. 2002b)
5S (PIENKOWSKA et al. 2002)
NTF (KLUKOWSKA et al. 2004c)
18
5
29
TECTA (DROGEMULLER et al. 2002)
MYO15A (RAK et al. 2002a)
TP53 (THOMAS et al. 2003c)
32
6
15
ABCA4 (KLUKOWSKA et al. unpublished)
TSC2 (THOMAS et al. 2003c)
17
7
13
YES1 (THOMAS et al. 2003c)
14
8
9
TGM1 (CREDILLE et al. 2001)
COCH (RAK et al. 2003)
ESR2 (KLUKOWSKA et al. unpublished)
FOS (THOMAS et al. 2003c)
12
9
30
TUBG1 (SIDJAMIN et al. 2001)
BRCA1 (THOMAS et al. 2003c)
NF1 (THOMAS et al. 2003c)
ERBB2 (THOMAS et al. 2003c)
34
10
9
MYH9 (RAK et al. 2003)
SOX10 (RAK et al. 2003)
REL (THOMAS et al. 2003c)
SAS (THOMAS et al. 2003c)
PDGFB (THOMAS et al. 2003c)
14
11
4
12
3
COL11A2 (RAK et al. 2003)
MYOA6 (RAK et al. 2003)
5
13
4
KIT (THOMAS et al. 2003c)
MYC (THOMAS et al. 2003c)
6
14
3
DFNA5 (RAK et al. 2003)
LEP (SZCZERBAL et al. 2003b)
5
15
8
SLC25A3(DEBENHAM et al. 2001)
APAF1 (DEBENHAM et al. 2001)
CDK4 (THOMAS et al. 2003c)
11
16
17
7
6
4
OTOF (RAK et al. 2003)
NRAS (THOMAS et al. 2003c)
7
8
Dog genome map
1
2
18
17
199
3
4
SLC26A4 (RAK et al. 2003)
WT1 (THOMAS et al. 2003c)
HRAS (THOMAS et al. 2003c)
20
19
3
20
17
MITF (RAK et al. 2003)
INSR (THOMAS et al. 2003c)
RAF1 (THOMAS et al. 2003c)
20
3
21
2
PGR (ZIJLSTRA et al. 2001)
MYOA7A (RAK et al. 2003)
HBB (KLUKOWSKA et al. unpublished)
TPH (KLUKOWSKA et al. unpublished)
6
22
3
EDNRB (RAK et al. 2003)
RB1 (THOMAS et al. 2003c)
5
23
4
24
9
EDN3 (RAK et al. 2003)
10
25
11
SGCG (CONRAD et al. 2001)
GJB2 (RAK et al. 2003)
GJB6 (RAK et al. 2003)
HMGB1 (MURUA ESCOBAR et al. 2003)
15
26
7
ATPA2 (KLUKOWSKA et al. unpublished)
8
4
27
4
KRAS (THOMAS et al. 2003c)
5
28
6
RET (THOMAS et al. 2003c)
7
29
2
30
7
RAB27A (PHILIPP et al. 2003b)
MYO5A (PHILIPP et al. 2003a)
9
31
6
CLDN14 (RAK et al. 2003)
TMPRSS3 (RAK et al. 2003)
MDM2 (THOMAS et al. 2003c)
9
32
1
1
33
1
1
34
2
2
35
2
2
36
2
2
37
4
4
38
3
X
1
Y
1
Total
302
2
3
37 markers (SPRIGGS et al. 2003)
MAOA (KLUKOWSKA et al. 2004a)
ZuBeCa51-52 (KLUKOWSKA et al. 2004b)
40
1
107
409
(VIGNAUX et al. 1999). This panel, consisting of 126 hybrid cell lines, was used
to develop a first-generation WGRH map, containing 400 markers (PRIAT et al.
1998). An average distance between markers was 23 cRays. The unit, 1 cRay5000
(1cR), is defined as 1% frequency of breakage between two markers after 5000
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M. Switonski et al.
Figure 1. FISH localisation of canine-derived probes: (a) dog chromosome 14q11, BAC clone
carrying a microsatellite sequence and putatively harbouring the leptin gene, (b) dog
chromosome 17, two cosmid probes carrying microsatellite markers: ZuBeCa25 (green) –
17q19 and ZuBeCa30 (red) – 17q16, (c) red fox chromosome 10q15, BAC clone putatively
carrying the IGF-1 gene, (d) Chinese raccoon dog chromosome 3q12, cosmid clone carrying
a microsatellite marker – ZuBeCa6.
rads of gamma rays exposure. The mapped markers covered approximately 80%
of the canine genome.
The latest radiation hybrid map, composed of 3270 markers, including
1596 microsatellites, 900 genes and ESTs, 668 canine-specific BAC-ends
and 106 sequence Tagged Sites (STS), has been constructed by GUYON et al.
(2003). These markers are well distributed in the dog genome and the average
intermarker distance is 1 Mb. The authors propose a set of 325 well-spread loci to
be used in genome-wide scans.
Linkage map
The so-called third-generation linkage map, based on the typing of 114 back-cross
offspring from a Keeshond × Beagle cross, has the 10 cM density (WERNER et al.
1999). This map includes 341 loci in 38 linkage groups. The coverage of the genome reached 95% and 14 linkage groups were assigned to specific chromosomes
thanks to the available data concerning physical mapping of some of the markers
included in these groups. Within the framework of the DogMap project, a set
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201
of 222 genetic markers was typed in a reference family panel, consisting of 7 families of Beagle dogs (71 offspring) and 1 family of German Shepherd dogs (35 offspring) (LINGAAS et al. 2001). Altogether, 187 markers were assigned to
39 linkage groups, which cover 1216 cM. Fourteen groups were assigned to specific canine chromosomes. This map included 85 new markers (not previously
mapped). The density of the map is 8.9 cM.
Comprehensive map
A comprehensive map (also called an integrated map) is established by gathering
data obtained by different mapping approaches: FISH, the analysis of radiation-hybrid panels, and linkage studies. The first integrated linkage-radiation hybrid map was described by MELLERSH et al. (2000). The authors mapped
600 markers by the radiation hybrid approach and combined with data on linkage
mapping of 341 markers (WERNER et al. 1999). Finally, the integrated map was
composed of 724 markers. Since the intermarker distances were expressed in two
systems (cRay and cM), a cR/cM ratio for 119 pairs of adjacent markers was calculated. The average ratio was 6.7 (with variation from 2.4 to 18.8) and an average
intermarker distance was 24.3 cR. Thus, under the assumption that 1cM = 6.7cR,
the average genetic distance was 3.6 cM. The total map coverage was estimated at
2600 cM or 17.700 cR.
The latest version of such a map, consisting of almost 1800 markers, has been
published by BREEN et al. (2001). To construct this map, information about 302
FISH mapped markers, 1500 markers included in the radiation hybrid (RH)
groups and 354 markers included in the linkage groups were used. Since some
of the markers were mapped by two or three above-mentioned methods, the total
number of the markers was smaller – 1755. The average distance between markers
on the RH map was 17 cR or 2.5 cM (if one applied the above-mentioned equation, 1cM = 6.7cR). The total length of the map was 23.428 cR and the coverage of
the genome exceeded 90%.
Genome sequence
The most recent achievement concerns the sequencing of the dog genome. In June
2003 the National Human Genome Research Institute announced that the sequencing of the dog genome was started (http://www.genome.gov/ 11007358),
while in September 2003 two groups from Rockville, USA, i.e. The Institute
for Genomic Research and The Center for Advancement of Genomics, published
results of survey sequencing and comparative analysis of the dog genome
(KIRKNESS et al. 2003). The dog genome (2.4 Gb) appears to be smaller than
the human genome (2.9 Gb). This difference is probably caused by the lower percentage of repetitive sequences (31% of the dog genome versus 46% in the human
and 38% in the mouse genomes). It was estimated that at least 650 Mb of the dog
DNA sequence align uniquely to the sequence of the human genome.
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Comparative genomic studies
Physical map of other canid genomes
Cytogenetic maps of other species belonging to the family Canidae are in their infancy, as compared with the dog genome map. First localisations in the red fox
(Vulpes vulpes) were done with the use of somatic cell hybridisation and 35 markers were assigned to all chromosomes (SEROV, RUBSTOV 1998). Afterwards,
FISH localization of 35 markers was performed for 3 species: the red fox (Vulpes
vulpes), arctic fox (Alopex lagopus) and Chinese raccoon dog (Nyctereutes
procyonoides procyonoides) – Figure 1c and d (for review, see: SZCZERBAL et al.
2003). A set of dog-derived cosmid clones, harbouring microsatellites, was applied. Unfortunately, the FISH-mapped markers were unevenly distributed
in the studied genomes. Therefore, there are 12 chromosomes in the Chinese raccoon dog and 11 in the arctic fox genomes without any assigned marker.
Comparative chromosome mapping studies
The comparative chromosome painting (Zoo-FISH) is a well-known method
to visualize homologies between genomes of different species. This technique
facilitates the identification of the conserved chromosome segments
in the compared karyotypes and has been applied to compare the dog genome with
those of the red fox (YANG at al. 1999), arctic fox (GRAPHODATSKY et al. 2000),
cat (YANG et al. 2000), Japanese raccoon dog (GRAPHODATSKY et al. 2001),
and Chinese raccoon dog (NIE et al. 2003). The following numbers of conserved
chromosome segments were identified: 68 in the cat, 43 in the red fox, 42 in
the arctic fox, and 41 in the raccoon dog.
Reciprocal painting studies between the dog and human were also performed.
With the use of human paint probes onto dog chromosomes, different numbers
of conserved segments were detected by two research teams: 68 by BREEN et al.
(1999b) and 73 by YANG et al. (1999). This discrepancy could be caused by different sets of paint probes, derived from flow-sorted chromosomes, used in those experiments. By the reverse approach – the use of the dog paints onto human
chromosomes – 90 conserved segments were detected by YANG et al. (1999).
A comparative dog/human chromosome map was verified by SARGAN et al.
(2000), who mapped a set of type I markers and repeated the painting studies using
the dog-derived probes. The obtained results confirmed earlier data of YANG et al.
(1999).
The advanced canine linkage-radiation integrated map brings new insight into
the evolutionary conservation of chromosome segments in the dog and human
genomes. The comparison of chromosome locations of 229 RH mapped genes,
whose location in the human genome is known, revealed the presence of
65 conserved segments (BREEN et al. 2001). In recent studies, including 3270 RH
markers, 85 dog/human conserved fragments have been detected (GUYON et al.
2003).
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203
It must be pointed out that the resolution of the chromosome painting method
is limited, since it is not possible to detect minor chromosomal rearrangements.
Thus, studies with the use of locus-specific probes are required to detect
intrachromosomal mutations: inversions, duplications or deletions. Such
an approach has been applied for the dog, arctic fox and Chinese raccoon dog
genomes. A comparative analysis of FISH-mapped markers facilitated
the identification of inversion events that took place in the course of karyotype
evolution of canids (ROGALSKA-NIZNIK et al. 2003, SZCZERBAL et al. 2003a).
Canine genetic diseases and their human counterparts
Chromosome abnormalities
Cytogenetic diagnostics of the dog is not advanced due to problems with
chromosome identification. However, the recent development of molecular tools
(chromosome-specific paints and chromosome-specific BAC clones) brings new
opportunities.
Table 2. Chromosome abnormalities diagnosed in dogs (based on reviews by MELLINK,
BOSMA 1989, BREEN et al. 2001 and original papers by SWITONSKI et al. 2003b, 2003c)
Type of abnormality
Aneuploidies*
Structural rearrangements
Lymphocyte chimerism
Abnormality
Reported cases
X monosomy
5
X trisomy
2
XXY trisomy
7
Centric fusion (Robertsonian translocation)
5**
Reciprocal translocation
1
78,XY/78,XX
2
* most of aneuploidies occurred as a mosaic
** this number includes several different centric fusion types
From the dog breeders’ point of view an important issue is the chromosomal
evaluation of infertile and/or intersexual animals. Until now relatively few cases
of altered karyotypes have been reported (Table 2). The most frequent are sex
chromosome aneuploidies: X monosomy, XXY and XXX trisomies. Among
structural rearrangements almost exclusively centric fusions (Robertsonian
translocations) were found. It must be emphasized that these mutation types are
easily recognizable, due to the fact that all the autosomes are acrocentric
and the sex chromosomes are biarmed. Thus, a lack of reports precisely describing
reciprocal translocations and inversions can be caused by problems with their
identification. In the dog, also lymphocyte chimerism XX/XY was found
in infertile bitches.
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M. Switonski et al.
Monogenic diseases
Over 400 hereditary diseases have been recognized in the dog and thus the main
aim in developing the canine marker genome map is to establish a tool that may
facilitate the identification of genes responsible for those diseases. PATTERSON
(2000) in a review paper specified 21 genetic diseases for which point mutations
were identified. These include five X-linked recessive mutations, causing
haemophilia B, shaking pup demyelination of the central nervous system (CNS),
dystrophin muscular dystrophy, nephropathy, and severe combined immunodeficiency. The other 16 mutations were autosomal recessive, responsible for:
(1) elliptocytosis – abnormal red blood cell shape, (2) muscle phosphofructokinase deficiency, (3) mucopolysaccharidosis I, (4) rod-cone dysplasia I,
(5) red blood cell pyruvate kinase deficiency, (6) globoid cell leukodystrophy,
Table 3. Gene mutations causing canine hereditary diseases identified recently
(2000-2003)
Disease
Gene/ type of mutation
Mode of inheritance
Breed
References
Ivermectin sensitivity
Multi-drug-resistance gene
(MDR1)
4-bp deletion
Autosomal
recessive
Collie
MEALEY et al.
2001
Generalized retinal progressive
atrophy (gPRA)
b-subunit of cGMP
phosphodiesterase (PDE6B)
8-bp insertion
Autosomal
recessive
Sloughi
DEKOMIEN
et al. 2000
Mucopolysaccha
ridosis IIIA
Heparan sulfate sulfamidase
(HCC)
3-bp deletion
Autosomal
recessive
Dachshund
ARONOVICH
et al. 2000
Malignant
hyperthermia
Ryanodine receptor (RYR1)
T>C substitution
Autosomal
dominant
Mix-breed
ROBERTS
et al. 2001
Retinitis
pigmentosa
Rhodopsin (RHO)
C>G substitution
Autosomal
dominant
English mastiff
KIJAS et al.
2002
Nephropathy
(Alport syndrome)
Collagen type IV (COL4A5)
10-bp deletion (exon 9)
X-linked
recessive
Mixed-breed
COX et al.
2003
This disease is
also caused by
G>T substitution in exon
35 (ZHENG et
al. 1994)
Cone degeneration
(achromatopsia)
Cyclic nucleotide-gated
channel b-subunit (CNGB3)
·Deletion removing all
exons
·G>A substitution (exon 6)
Autosomal
recessive
Alaskan
Malamute
German
Shorthaired
Pointer
SIDJANIN
et al. 2002
Haemophilia A
Factor VIII
Inversion of exons 22-26
X-linked
recessive
Irish Setter
LOZIER et al.
2002
Dystrophic
epidermolysis
bullosa
Collagen type VII
G>A substitution
Autosomal
recessive
Not indicated
BALDESCHI
et al. 2003
Dog genome map
205
(7) fucosidosis, (8) glycogen storage disease type IA, (9) mucopolysaccharidosis
VII, (10) stationary night blindness, (11) complement component deficiency,
(12) Von Willebrand disease type 3, (13) rod-cone dysplasia 3, (14) narcolepsy,
(15) leukocyte adhesion deficiency, and (16) myotonia congenita. In the last
3 years, successive monogenic hereditary diseases have been characterized
(Table 3). Among the newly described 9 diseases, 3 are caused by X-linked
recessive, 2 by autosomal dominant and 4 by autosomal recessive gene mutations.
A majority of the 30 diseases described on the DNA level, have human
counterparts. Some of the canine diseases have the same name as in the human:
haemophilia B, Von Willebrand disease type 3, mucopolysaccharidosis I and VII,
narcolepsy, etc. Others have different names: dystrophin muscular dystrophy
(the human counterpart: Duchenne muscular dystrophy), stationary night
blindness (the human counterpart: Leber hereditary amaurosis), etc.
It is important to emphasize that the dog diseases are usually caused by a mutation
of the same gene as in the case of their human counterparts. It is anticipated that at
least 60% of dog diseases have a molecular background similar to that of specific
human diseases and are characterized by similar clinical abnormalities.
It is important to emphasize that at least 50% of hereditary dog diseases are
breed-specific. This means that the causative mutation segregates in 1-2 breeds
only. On the other hand, there are breeds in which 2 or more diseases have been
identified. For instance, among the above-mentioned 30 hereditary diseases,
3 were identified in Springer Spaniel (fucosidosis, muscle phosphofructokinase
deficiency, shaking pup demyelination of the central nervous system) and Irish
Setter (haemophilia A, leukocyte adhesion deficiency, rod-cone dysplasia I).
Two diseases were described in West Highland White Terrier (globoid cell
leukodystrophy, red blood cell pyruvate kinase deficiency), Cairn Terrier
(globoid cell leukodystrophy, haemophilia B) and Cardigan Welsh Corgi
(rod-cone dysplasia 3, X-linked severe combined immunodeficiency).
It can be expected that many more point mutations, causing hereditary diseases
of the dog, will be described in the near future. One of the important breeding
issues is the inherited sex reversal syndrome in female dogs (78,XX) with
an enlarged clitoris and masculinized reproductive tracts (hypoplastic testes
or ovotestes) (MEYERS-WALLEN et al. 1999). This syndrome has been diagnosed
in various breeds (SWITONSKI et al. 2004 – in press), but its molecular background
remains unclear.
Multifactorial diseases
A specific group of genetic diseases are those whose background is multifactorial.
It means that their mode of inheritance is polygenic and the effect
of environmental factors is crucial for the clinical course of the disease. This class
of diseases is well known in human genetics and includes asthma, diabetes,
epilepsy, hypertension, and many others.
In the dog there are at least 2 examples that are important both from breeders’
point of view and as a model for human diseases. The canine hip dysplasia (CHD)
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M. Switonski et al.
is one of the most common diseases, affecting large dog breeds. Due to its
multifactorial nature, a coefficient of heritability (h2) is a major parameter showing the effect of genetic variability on the development of the malformed phenotype. This parameter for the CHD varies in a wide range (0.11-0.68). The main
aim of the recent studies was an identification of genes with a major effect
(the so-called quantitative trait locus, QTL). To perform this study, a pedigree
family was developed by crossing dysplastic Labrador Retrievers and trait-free
Greyhounds (TODHUNTER et al. 2003). The family, consisting of 147 dogs,
is presently genotyped at evenly spread marker loci and the QTL for this disease is
anticipated to be detected in this way.
Another example of a complex disease is epilepsy, whose incidence in the dog
is higher than in other domestic animals. Among the dog breeds, there are some
for which epilepsy is the main genetic problem. In the Belgian Tervuren
and Sheepdog, the incidence of dogs with multiple seizures exceeds 15%. To find
a QTL for this disease, multigenerational families that showed a high or low
incidence of seizures were genotyped at 100 evenly spread loci. The results
showed that 3 chromosomal fragments may harbour the QTL associated with
the epileptic phenotype (OBERBAUER et al. 2003).
The above findings indicate that in the near future one can expect new data on
the genetic background of multifactorial diseases in dogs. This knowledge may
have an important impact on studies of similar diseases in humans.
Genetic predisposition to carcinomas
Cancer is one of the most frequent diseases of dogs. Some types of malignancies
show similarity to their human counterparts on the histopathological level
and in their response to therapy. Humans and dogs are naturally exposed to
the same environmental agents, including carcinogens, therefore the dog can be
a more suitable animal model for human cancers than rodents. Both familial
and sporadic forms of different cancers have been diagnosed in dogs
(OSTRANDER, KRUGLYAK 2000).
The frequency of a specific cancer in some breeds can be much higher than
in others. For instance, large breeds (Irish Wolfhound, St. Bernard, Great Dane,
Rottweiler, Irish Setter, Doberman Pinscher) have an increased risk
of osteosarcoma, as compared to smaller breeds (BREUR et al. 2001). Thus, canine
pedigrees can be used to search for gene mutations responsible for the predisposition to develop a breed-specific cancer. Recently, on the basis of a large
informative pedigree of German Shepherd dogs, a locus responsible for kidney
cancers (multifocal renal cystadenocarcinoma and nodular dermatofibrosis) was
mapped on dog chromosome 5 (JONASDOTTIR et al. 2000). Comparative
chromosome painting revealed that this chromosome is homologous to human
chromosomes 1p and 17p. Further studies revealed that CFA5 contains a sequence
corresponding to the human Birt-Hogg-Dube (BHD) gene, which was mapped on
human chromosome 17p11.2. Molecular studies of this locus revealed that all
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affected dogs carried an A > G substitution in exon 7, and it changed the amino
acid sequence: histidine > arginine (LINGAAS et al. 2003).
Cytogenetic studies of dog cancers are not as advanced as those of human
cancers. This is a result of difficulties in the identification of all dog chromosomes
by classical banding techniques. Some of the reports indicated that the formation
of biarmed chromosomes is a characteristic feature of mammary carcinoma cells
(REIMANN et al. 1994, TAP et al. 1998). The development of canine
whole-chromosome painting probes and locus-specific probes enabled a more
precise analysis. THOMAS et al. (2001, 2003a) applied a panel of molecular
cytogenetic techniques (CGH – comparative genome hybridization, chromosome
painting, and locus-specific FISH) to study canine lymphoma. Detailed studies
revealed that the gain of chromosome 13 was the most common aberration,
followed by the gain of chromosome 31 and the loss of chromosome 14. Canine
chromosome 13 is an evolutionary counterpart of the human chromosome 8q
and 4p. On these chromosome fragments there are two oncogenes (c-MYC
and c-KIT), which usually are activated in human non-Hodgkin lymphomas.
A recent achievement in dog cancer studies is the development of the canine
cancer-gene microarray (THOMAS et al. 2003b). Eighty-seven BAC clones were
used to design a small-scale microarray. The clones harbour dog cancer genes
and a set of chromosome-specific loci. Altogether, 22 chromosomes were represented on this microarray.
Gene therapy in the dog – a useful model for the therapy
of human diseases
The identification of point mutations causing hereditary diseases of the dog brings
an opportunity to develop gene therapy protocols. This approach is especially interesting since, as it was already mentioned, many of the dog diseases have clinical and molecular counterparts in the human. The first successful gene therapy
was applied to the stationary night blindness (hereditary retinal dystrophy),
for which the human counterpart is Leber congenital amaurosis. This disease has
been identified in some populations of Briards. The causative recessive mutation
concerns the 4bp deletion in the RPE65 gene. The therapy was performed on blind
recessive homozygous dogs by the subretinal or intravitreal injection of the recombinant adeno-associated virus carrying cDNA of the wild-type RPE65 gene.
The visual function was restored in dogs that received the subretinal injection
(ACLAND et al. 2001). A similar experiment carried out by NARFSTROM et al.
(2003) showed a long-term improvement of vision in the treated dogs.
There are other examples of gene therapies applied in the dog. PONDER et al.
(2002) administered intravenously a recombinant retroviral vector, expressing
the canine b-glucuronidase gene, to dog neonates suffering from mucopolysaccharidosis VII. The treatment was successful and prevented the clinical manifestation of this lysosomal storage disease. Another example of gene therapy of stor-
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M. Switonski et al.
age diseases is the intravenous administration of a recombinant adeno-associated
virus, carrying cDNA of the canine wild-type glucose-6-phosphatase gene, to
3 affected dogs (BEATY at al. 2002). The therapy resulted in the sustained expression of the delivered gene and improved biochemical parameters, as well as liver
histology. Also haemophilia A (SCALLAN et al. 2003) and B (EHRHARDT et al.
2003) were successfully corrected with the use of the recombinant
adeno-associated type 2 and nonintegrating helper-dependent adenoviral vectors,
respectively.
Conclusions and perspectives
In the recent years, molecular and cytogenetic tools for a detailed genetic analysis
have been developed for the dog. Progress observed in the studies of canine
hereditary diseases indicates that in the near future new diseases will
be characterized. It will have a major impact on breeding strategy in this species.
One can anticipate that the eradication of some recessive genes, causing
hereditary diseases, will be possible. It will facilitate an improvement of the dogs’
welfare, since many canine hereditary diseases are not lethal, but rather affect life
quality (blindness, deafness, hip dysplasia, epilepsy, etc.). The dog will also
be a very important model for studies of human complex genetic diseases
and cancers. Establishing reference dog families in which a disease of interest
is observed, brings a unique opportunity to identify the genes that have a major
effect on incidence of the disease. It also seems quite probable that some of
the canine genetic diseases will be corrected by gene therapy. On the other hand,
experience obtained in the dog gene therapy will be important for the development
of therapy for similar diseases in humans.
Acknowledgement. This study was supported by the Foundation for Polish
Science (contract 13/2000 – M. SWITONSKI; and 88/2004 – I. SZCZERBAL).
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