Journal of Heredity Advance Access originally published online on August 31, 2005
Journal of Heredity 2005 96(5):475-484; doi:10.1093/jhered/esi092
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Evaluation of Candidate Genes in the Absence of Positional Information: A Poor Bet on a Blind Dog!
From the Centre for Veterinary Science, University of Cambridge, Cambridge CB3 0ES, UK (Aguirre-Hernández and Sargan), and Hospital Infantil de México ‘Federico Gómez’, Dr. Márquez 162, México, D.F. 06720, México (Aguirre-Hernández)
Address correspondence to J. Aguirre-Hernández, Centre for Veterinary Science, University of Cambridge, Cambridge CB3 0ES, UK, or e-mail: ja248{at}cam.ac.uk.
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Abstract |
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 Top Abstract Canine Retinal DiseasesFCG StudiesLinkage AnalysisConclusionSupplementary DataReferences |
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More than 350 inherited diseases have been reported in dogs and at least 50% of them have human counterparts. To remove the diseases from dog breeds and to identify canine models for human diseases, it is necessary to find the mutations underlying them. To this end, two methods have been used: the functional candidate gene approach and linkage analysis. Here we present an evaluation of these in canine retinal diseases, which have been the subject of a large number of molecular genetic studies, and we show the contrasting outcomes of these approaches when dealing with genetically heterogeneous diseases. The candidate gene approach has led to 377 published results with 23 genes. Most of the results (66.6%) excluded the presence of a mutation in a gene or its coding region, while only 3.4% of the results identified the mutation causing the disease. On the other hand, five linkage analysis studies have been done on retinal diseases, resulting in three identified mutations and two mapped disease loci. Mapping studies have relied on dog research colonies. If this favorable application of linkage analysis can be extended to dogs in the pet population, success in identifying canine mutations could increase, with advantages to veterinary and human medicine.
Dogs were domesticated more than 15,000 years ago and subgroups have been selected for particular traits ever since (Savolainen et al. 2002). More than 350 inherited diseases have been reported in this species (Nicholas 2003), and a recent survey of the literature suggests that the number of diseases with major inherited components may considerably exceed this figure (Sargan 2004). This places dogs as the species with the second largest number of known genetic diseases, surpassed only by humans. Particular diseases occur with a high incidence in specific breeds, which may be thought of as genetically isolated and inbred subgroups within the entire species. This large number of reported inherited diseases has two main causes: the close surveillance to which dogs are subjected, and the founder effect and inbreeding practiced in pure-bred dogs that uncovers recessive disease alleles. The frequency of these alleles may increase by "popular sire" effects, whereby a very small proportion of the available males (those successful in dog shows or in competition events for working breeds) contribute disproportionately to the next generation. Thus over the last 30 years, only 3%–5% of registered dogs were used to produce the current Dutch pure-bred dog population (Ubbink et al. 1998).
To reduce the incidence of canine recessive diseases, which account for about 70% of all inherited diseases with a known mode of inheritance (Brooks and Sargan 2001), carriers of the mutant allele, as well as affecteds, have to be identified before they reach sexual maturity. Carriers and affecteds are then either removed from breeding or mated only to individuals with the wild-type allele (Petersen-Jones et al. 1995).
In addition, more than 50% of canine inherited diseases are shared with humans (Nicholas 2001; Ostrander et al. 2000; Sargan 2004) and the coding sequences of dogs and humans show an overall greater similarity to each other than to mouse coding sequences (Kirkness et al. 2003), even though mouse and human share a more recent common ancestor. Thus dogs can be used as models to understand many diseases and to develop therapies before they are tested in humans, as is being done with muscular dystrophy (Bartlett et al. 2000), Leber congenital amaurosis (Acland et al. 2001; Narfstrom et al. 2003), clotting disorders (Mount et al. 2002), lysosomal storage diseases (Ponder et al. 2002), dystrophic epidermolysis bullosa (Baldeschi et al. 2003), hemophilia A (Chuah et al. 2003), and hemophilia B (Mount et al. 2002), among others. For this to be done, the first step is to find the mutations.
Two approaches have predominated in the search for mutations involved in dog diseases: the functional candidate gene (FCG) approach and linkage analysis (LA). In the former, the mutation is pursued in genes that have been implicated in a similar disease in another species or in genes implicated by their known normal activity or by their distribution among cells or tissues. In LA, on the other hand, the procedure consists of three steps. First, the segregation of genetic markers and the disease are analyzed in families with affected individuals to identify those markers that cosegregate with the disease. This indicates the region where the disease locus is found. Then, fine mapping with additional markers in the region of interest is performed to increase the resolution. Finally, candidate genes within the region of interest, chosen by their role, structure, or transcript distribution, are analyzed, hence the terms positional cloning and positional candidate genes used in this context (Collins 1992).
A large number of genetic studies have been done on canine retinal diseases, so in this article we use those results to show the contrasting outcomes of using the FCG approach and LA to find genes involved in canine diseases, particularly those with genetic heterogeneity.
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Canine Retinal Diseases |
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TopAbstractCanine Retinal DiseasesFCG StudiesLinkage AnalysisConclusionSupplementary DataReferences |
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These comprise, among others, progressive retinal atrophy (PRA), cone dystrophy (cd), and retinal dystrophy, diseases that impair the normal functioning of dog photoreceptors or the retinal pigment epithelium, leading to partial or total blindness (Clements et al. 1996; Lin et al. 2002; Petersen-Jones 1998b). The age of onset varies for these diseases, depending on the nature of the mutation and, to a lesser extent, on the genetic background of affected individuals. These diseases have human counterparts (Petersen-Jones 1998a). For example, PRA, cd (Sidjanin et al. 2002), and retinal dystrophy (Aguirre et al. 1998; Veske et al. 1998, 1999) are homologous to retinitis pigmentosa (RP), achromatopsia (Sundin et al. 2000), and Leber congenital amaurosis (Gu et al. 1997; Marlhens et al. 1997; Morimura et al. 1998), respectively.
Studies to identify the mutations underlying dog retinal diseases have been numerous for three reasons. First, these diseases affect many breeds (e.g., PRA has been reported for more than 100 breeds) (Clements et al. 1996; Petersen-Jones 1998b). Second, they are comparatively easy to detect. Third, they show genetic heterogeneity, which means that the identification of a mutation or the exclusion of a gene in one breed may tell nothing about that gene in other breeds. In addition to this genetic heterogeneity among breeds, there is also genetic heterogeneity within some breeds (e.g., Briard and Labrador retriever; see supplementary information in Table S1). The opposite situation may also exist: progressive rod-cone degeneration (prcd) is allelic in at least six breeds (Narfstrom and Wrigstad 1999; Ray et al. 1999) and cd is allelic in two (Sidjanin et al. 2002), and two breeds with X-linked PRA (XLPRA) share the same mutation (Zhang et al. 2002).
To date, 10 mutations causing canine retinal diseases have been found, affecting 11 breeds plus a single individual of mixed breed (Table 1). In addition, two PRA loci have been mapped, but the genes have not yet been identified (Table 2).
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FCG Studies |
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Using the candidate gene approach, 377 results have been published on 23 genes addressing 72 breed diseases in 64 breeds plus a mongrel individual (Table S1). We define a breed disease as each disease present in one breed. For example, prcd and retinal degeneration, both seen in Labrador retrievers, are two different breed diseases (Kommonen and Karhunen 1990); likewise, prcd in the poodle and the English cocker spaniel are considered different breed diseases inasmuch as they occur in different breeds, even though it is known that they are allelic (Aguirre and Acland 1988).
Most of the results (60.2%) have excluded the presence of mutations in particular genes (Table S1). The exclusions have been derived from the distribution of intragenic polymorphisms in functional candidate genes (FCGs) among affected and nonaffected individuals. In this approach, it is assumed that the mutation underlying each disease occurred only once in the breed, and it appeared in the context of a particular haplotype, so all affected individuals in a breed disease must share that haplotype, while nonaffecteds may have several different haplotypes. However, instead of analyzing complete haplotypes, usually individual intragenic polymorphisms are studied separately. If the recessive mutation lies in the gene being studied, all affected individuals are expected to be homozygous for the same allele, while nonaffecteds may have any of a number of different combinations of alleles in homozygous and heterozygous genotypes. Thus heterozygosity in intragenic polymorphisms of a particular gene in affected dogs, or the presence of two or more different homozygous genotypes, excludes that gene as the cause of the disease. For this procedure to be applied, it is important to have clear evidence regarding the recessive inheritance of the disease.
In 6.4% of the results, exon or cDNA sequencing excluded the presence of a mutation in the coding region of candidate genes or their transcripts. The sequences were compared in affected and nonaffected dogs, and no differences were found. Nevertheless, strictly speaking, the possibility remains for a mutation to be present in noncoding regions of the gene. For this reason, the analysis of intragenic polymorphisms is more powerful than merely sequencing the coding regions.
In a third category representing 8.22% of the results, instead of sequencing coding regions, intragenic polymorphisms in coding or noncoding regions were searched for. However, results were uninformative since no intragenic polymorphisms were found among the dogs studied—affected and nonaffected—so no information could be obtained regarding the segregation of these genes and their possible involvement in causing the disease.
In 14.6% of the results, the exclusion of a previously known mutation or any other mutation in that same exon was derived. For these results, the exclusion of a known mutation was obtained by restriction fragment length polymorphism (RFLP) analysis or by sequencing a small region covering the site of a known mutation; this does not tell if a mutation exists in that gene outside the small region studied.
Some results (7.2%) have been equivocal, meaning that the distribution of intragenic polymorphisms among affected and nonaffected dogs was consistent with the presence of a mutation in the gene. However, a very small sample of affected dogs was studied (one to three), so the observed distribution of polymorphic alleles could be due to chance, thus a larger sample needs to be studied or the gene must be screened for mutations.
Finally, only 3.4% of the results identified the mutation. This strikingly low success suggests that the FCG approach tends to be very inefficient.
Most of the 23 FCGs studied to date are involved in the phototransduction cascade or have mutations causing human retinal diseases. Surprisingly, fulfillment of these criteria does not often lead to the identification of the mutations causing canine retinal diseases. It could be argued that many other genes fulfilling the criteria remain to be studied and that mutations may be found in them. Unfortunately, however, including more FCGs would only perpetuate, and in fact exacerbate, the problem of having a low success rate with the FCG approach.
Half (50.4%) of the results correspond to studies on just five genes (Table S2)—PDE6B, RHO, PDC, RPE65, RDS—and mutations have been found in four of them (Table 1): a nonsense mutation in PDE6B in Irish setters with PRA (Clements et al. 1993; Dekomien et al. 2000; Ray et al. 1994; Suber et al. 1993), a missense mutation in RHO in English mastiffs and some Bull mastiffs, a missense mutation in PDC responsible for some cases of photoreceptor dysplasia (PD) in miniature schnauzers (Zhang et al. 1998), and a 4 bp deletion in RPE65 in briards with retinal dystrophy (Aguirre et al. 1998; Veske et al. 1998, 1999). RDS is the other most intensively studied gene, and it codes for a structural protein on the photoreceptor membrane; it is involved in a digenic retinal disease in humans (Kajiwara et al. 1994), but no mutations have been found in dogs.
To date, half (50.1%) of all the FCG results correspond to only 13 breed diseases (19% of all breed diseases; Table S3), but interestingly, in only 3 of them has the mutation been found (retinal dystrophy in the Briard, PD in some miniature schnauzers, and early onset PRA in the Irish setter), again underscoring the difficulties encountered with the FCG approach. For the six most intensively studied breed diseases, mutations have not yet been found.
Pooling together the results on prcd, which has been shown to be allelic among six breeds, they represent one-fifth (19.6%) of all the results.
As shown in the section on LA, the lack of success with the FCG approach in some of these most intensively studied diseases is due to the fact that they seem to be caused by genes that have not yet been associated with retinal diseases in humans or any other species.
Finally, the level of redundancy in the FCG studies (Table S1) constitutes a strong argument in favor of publishing in a rapid manner negative results obtained with this approach in order to avoid further redundant experiments.
The analysis of intragenic polymorphisms or the comparison of the sequence of the gene in affected and nonaffected individuals generates very detailed information on the genes. For example, all FCG studies have reported gene or cDNA sequences, except TTR, and all have been mapped to particular canine chromosomes, except GCE and TTR.
Intragenic polymorphisms have been observed in the laboratory for all FCGs except four: CNGB3, CRX, GNBT1, and GNGT2; polymorphisms have also been reported for two positional candidate genes—APOH (Gu et al. 1999) and TIMP1 (Zeiss et al. 1998)—giving a total of 154 intragenic polymorphisms. In addition, for some genes and cDNAs, or parts of them, more than one sequence has been deposited in the databases. By comparing them, 104 additional polymorphisms have been found, corresponding to 13 genes. These in silico polymorphisms still need to be validated.
Of the polymorphisms observed in the laboratory, 132 correspond to single nucleotide polymorphisms (SNPs) belonging to 19 FCGs, resulting in 1.19 SNP/kb. Here, SNPs are defined in the narrow sense, as a change of one base for another, thus excluding indels (Brookes 1999). Coding SNPs (cSNPs) constitute 37.1% of the 132 observed SNPs, with missense cSNPs representing 13.6%. On the other hand, in silico polymorphisms contain 78 additional SNPs in 13 genes (37.2% cSNPs, with 15.4% missense cSNPs). If these in silico SNPs turn out to be real, there would be 1.89 SNP/kb. Previously a SNP density of 2.56 SNP/kb was obtained by a pooling and sequencing approach from 12 canine genes from 10 different breeds (Brouillette et al. 2000), while the analysis of the canine genome sequence of a single male poodle resulted in a value of 0.67 SNP/kb (Kirkness et al. 2003). The average density of SNPs in the human genome has been estimated at 0.53 SNP/kb (Sachidanandam et al. 2001) and 0.83 SNP/kb (Zhao et al. 2003).
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Linkage Analysis |
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Only four canine retinal diseases have been studied with this technique (Table 2). Three mutations have been found and two additional disease loci have been mapped.
One of the advantages of LA is that it determines the region containing the disease locus, thus limiting the study of candidate genes to those within that region. Once the locus has been mapped, and fine mapped, three outcomes are possible.
The first possible outcome is that the region where the canine disease locus has been mapped may contain a known gene causing a similar disease in another species, making it the obvious positional candidate and leading to the identification of the mutation, as happened with XLPRA in the Siberian husky (Zeiss et al. 2000) and cd in Alaskan malamutes. The former was mapped to an X chromosome region homologous to that containing RPGR in humans (OMIM 300389 [OMIM] ), which is a known X-linked RP gene (Meindl et al. 1996; Roepman et al. 1996; Zhang et al. 2001). When this gene was studied in affected dogs, a deletion was found (Zhang et al. 2002). For cd, a whole-genome scan (WGS) was undertaken to map the disease locus (Sidjanin et al. 2002). The result pointed to a region homologous to a human chromosome location harboring the CNGB3 gene, which is involved in achromatopsia (OMIM 262300 [OMIM] ), the equivalent human disease (Sundin et al. 2000). This gene was shown to be absent in affected malamutes, pointing to a microdeletion as the cause of the disease.
The second possible outcome of LA mapping is that it may point to a region containing a disease locus that has already been mapped, but not yet identified, in another species. Suitable candidate genes have to be studied within that region in both species until the mutations are found. Canine prcd and human RP17 loci (OMIM 600852 [OMIM] ) may be an example of this situation. With a WGS, the prcd locus was mapped to the centromeric portion of CFA9 (Acland et al. 1998), a region homologous to part of the short arm of human chromosome 17, where the RP17 locus had been mapped, but whose identity was unknown (Bardien et al. 1995, 1997; Bardien-Kruger et al. 1999; den Hollander et al. 1999). It was suggested that the prcd and RP17 loci might be homologous, although the canine disease is recessive, while human RP17 is dominant (Acland et al. 1998). Since the gene involved in RP17 has recently been identified as CA4 (Rebello et al. 2004), it should now be possible to determine if mutations in this gene also account for canine prcd.
The third possible outcome when mapping canine disease loci is that the locus mapped may be in a region where no genes implicated in a similar disease are known in humans or other species, so the search for suitable candidates has to proceed without reference to known disease genes or mapped disease loci. This seems to be the case with early retinal degeneration (erd) in the Norwegian elkhound. The locus has been mapped to a region of CFA27 with homology to human 12p13-12q13 and to mouse chromosome 6 (Acland et al. 1999). Two human retinal disease loci (COL2A1, OMIM 120140 [OMIM] ; RDH5, OMIM 136880 [OMIM] ) have been identified on HSA12 (Gonzalez-Fernandez et al. 1999; Yamamoto et al. 1999), but the characteristics of the diseases differ from erd, so they are unlikely candidates.
If this review of LA studies is expanded to include not only retinal diseases, but any canine disease, it emerges that only two LA studies have failed to map the disease locus: canine conotruncal heart defect and dilated cardiomyopathy (Table 2). In the first case, the failure may be attributed to the fact that only the telomeric end of CFA26 was studied instead of performing a WGS (Werner et al. 1999). In the second case, there seems to have been difficulties in assigning the correct phenotypes to some individuals, and a number of markers were uninformative, thus leaving large gaps of the genome inadequately covered (Dukes-McEwan and Jackson 2002); it is also possible that this disease may have a complex genetic basis. An interesting characteristic of canine LA studies is that almost all of them have relied on research colonies of affected dogs, and in some cases the structure of the pedigrees has been tailored to maximize their usefulness for LA. In total, LA has led to the identification of seven disease loci and an additional nine have been mapped. This is still a relatively small number, but the success rate is high. The number of success stories is expected to increase dramatically because of the availability of both a high-density map (Guyon et al. 2003) and a rough draft sequence of the canine genome (Kirkness et al. 2003).
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Conclusion |
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TopAbstractCanine Retinal DiseasesFCG StudiesLinkage AnalysisConclusionSupplementary DataReferences |
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A large number of FCG studies have been done to identify the mutations causing canine retinal diseases, but only a minimal proportion of them (3.4%) have been successful. This problem with the FCG approach is likely to be most acute in diseases with heterogeneous genetic etiologies.
On the other hand, few studies have used LA, but the results obtained are encouraging. Assuming an adequate number of cases, the best strategy to find canine disease loci seems to consist of performing a WGS to map the disease locus. Then, if the region points to a previously known FCG, the information already amassed for these genes will lead rapidly to the mutation. If no obvious candidate disease genes are located in that region, LA nevertheless provides information on where to search for them and what remains to be done; for example, study positional candidates with appropriate expression patterns that have been identified in homologous chromosome regions in other species.
The immediate task for LA studies on canine disease loci is to extend its application to individuals in the general population (as opposed to breeding research colonies). The difficulty here lies in collecting complete multigenerational families, particularly for diseases of late onset. A partial solution to this problem may reside in using nonparametric forms of linkage analysis. Another possibility is to use association studies not requiring pedigree information (Hyun et al. 2003), and which would take advantage of the genetic homogeneity of many breed-specific diseases. Success in developing such methods will have a great impact on reducing the incidence of genetic diseases in affected breeds and will also open up a large pool of models to study human diseases and for testing therapies against them.
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Supplementary Data |
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TopAbstractCanine Retinal DiseasesFCG StudiesLinkage AnalysisConclusionSupplementary DataReferences |
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Supplementary tables are available at Journal of Heredity online (www.jhered.oxfordjournals.org).
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Acknowledgments |
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J. Aguirre-Hernández was supported by grants from the Consejo Nacional de Ciencia y Tecnología de México (CONACYT), and Pembroke College, Cambridge; this work was supported by grants from the Kennel Club and The Wellcome Trust for progressive retinal atrophy studies (Sargan)
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Footnotes |
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Corresponding Editor: Stephen J. O'Brien
Received October 26, 2004
Accepted May 12, 2005
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References |
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