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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] 196 M. Switonski et al. 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 Dog genome map 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 200 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 Dog genome map 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. 202 M. Switonski et al. 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). Dog genome map 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. 204 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) 206 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 Dog genome map 207 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- 208 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. 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