Journal of Heredity Advance Access originally published online on April 3, 2007
Journal of Heredity 2007 98(3):221-231; doi:10.1093/jhered/esm006
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An Extended Microsatellite Set for Linkage Mapping in the Domestic Dog
From the Centre for Veterinary Science, Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK (Sargan and Aguirre-Hernandez); the Cancer Genetics Branch, National Human Genome Resources Institute, National Institutes of Health, Building 50, South Drive, Bethesda, MD 20896 (Sargan and Ostrander); and the UMR 6061 CNRS, Genetique et developpement, Faculte de Medecine, 2 avenue Pr. Léon Bernard, 35043 Rennes Cédex, France (Galibert)
Address correspondence to Dr. D. R. Sargan at the address above, or e-mail: drs20{at}cam.ac.uk.
The extremes of phenotype displayed by the domestic dog, as well as the largest number of naturally occurring inherited diseases in any mammalian species except man (>450), have generated a large interest in genomic linkage mapping in the species. Marker sets for linkage mapping should ideally show both high levels of polymorphism among the target group of animals and an even spacing of markers across the whole genome. Currently a microsatellite marker set known as Minimal Screening Set 2 (MSS2) is widely used. Here, we have extended this marker set by filling in gaps as noted from the marker positions in the CanFam genome assembly (1.0) and the 5000cR radiation hybrid (RH) map. An additional 183 markers have been positioned to increase the coverage of the MSS2 set wherever it contains a gap >9 mb or 10005000 RH units. We have called the marker set derived from the MSS2 set and these 183 markers, MSS3. The average physical spacing of markers in the complete 507 marker MSS3 set is 5 mb, whereas average heterozygosity of the 183 new markers on a panel of 10 dogs of differing breeds is 0.74. This marker group will allow genome-wide scans in the dog to be conducted at close to 5 cM resolution.
The domestic dog Canis familiaris was the first species domesticated by man and has been under selection for suitability to many different roles in human societies for several tens of thousands of years (Wayne 1993; Ostrander and Wayne 2007). This has led to a greater variation of adult body size, conformation, pelage, and behavioral repertoire than is seen in any other mammalian species (Wayne 1986; Fondon and Garner 2004). The species has been stratified into approximately 400 purebred or pedigree breeds, most of which are now maintained as genetically isolated subpopulations, in the developed world (Fogel 1995; Wilcox and Walkowicz 1995; American Kennel Club 1998). As a consequence of such genetic isolation, founder effects, and coselection of undesired mutations with desired characteristics, as well as of the heavy veterinary surveillance and high degree of investigative medicine in the dog, more naturally occurring genetic diseases (>450) have been described in the dog than any other species except man (Sargan 2004).
The dog shows enormous similarities in physiology to humans, and has therefore been widely adopted as a model both for the genetic analysis of inherited quantitative and qualitative traits and for disease studies (Ostrander and Kruglyak 2000; Chase et al. 2002; Starkey et al. 2005). In the past 3 years, tools available for genetic analysis in the dog have developed rapidly (Sutter and Ostrander 2004), and include a third generation meiotic map (Mellersh et al. 2000), bacterial artificial chromosome libraries (Li et al. 2001), 2 radiation hybrid (RH) mapping panels (Vignaux et al. 1999; Hitte et al. 2005), and the localization of many loci by both RH mapping and fluorescence in situ hybridization (FISH) (Breen et al. 2001, 2004). An RH map of 4249 markers, including 1596 microsatellite markers (Breen et al. 2004) has been described, together with a high resolution 10 000 gene RH map (Hitte et al. 2005). The availability of both a 1.5x survey sequence of the poodle (Kirkness et al. 2003) and an assembled 7.5x boxer sequence (Lindblad-Toh et al. 2007) can be expected to facilitate the rate at which disease genes can and will be identified.
With the help of these tools, microsatellite mapping sets have been developed to allow a rational approach to linkage mapping in the dog (Richman et al. 2001; Cargill et al. 2002, 2004; Clark et al. 2004). The most complete set previously described, Minimal Screening Set 2 (MSS2) (Guyon, Lorentzen, et al. 2003; Clark et al. 2004), consisted of primers for 325 microsatellite-based markers, which were evenly spaced across chromosomes based on positioning using the 5000-rad RH map, and have average heterozygosity of 0.73 when analyzed using a panel of 10 purebred dogs representing distinct breeds. MSS2, or derivations thereof, has been used with great success in parametric linkage analysis studies of monogenic disorders, as well as in some studies in which traits segregate at more than one locus (Chase et al. 2004, 2005; Park et al. 2004; O'Brien et al. 2005). Thus, it is clear that whole-genome mapping studies using microsatellite markers, which have been the mainstay of the mammalian genome mapping community, will continue to be of importance for the identification of genes associated with developmental and behavioral traits as well as many complex diseases. On the other hand, a number of studies with existing microsatellite marker sets have not been successful in trait mapping (most are unpublished, see review by Dukes-McEwan and Jackson 2002). If markers are widely spaced, older mutations may not be in strong linkage disequilibrium (LD) with any marker in the mapping set. In some cases, there has been too little heterozygosity in the marker set used given the population under study. Nonuniformity in genotype underlying a phenotype or misclassification of a variable phenotype both diminish power to detect a mutation. In order to increase the power of mapping studies, better coverage of evenly spaced and well-characterized markers is needed. Here, we describe a marker set with an average physical spacing of about 5 mb and whose average genetic spacing is predicted to be approximately 5.5 cM, which we term Minimal Screening Set 3, MSS3.
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Materials and Methods |
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Primer Design
Major gaps in the MSS2 primer set were identified by comparison of the whole-genome assembly (CanFam 1.0. Lindblad-Toh et al. 2007) and the RH map of Guyon, Lorentzen, et al. (2003). (For more detail, see Results.) Where possible, markers that had already been characterized and localized on the RH map and/or in the genome assembly were used to fill gaps. Three of these (FH2107, CPH16, and FH2144) are markers from the MSS1 marker set of Richman et al. (2001), not used in MSS2. When marker heterozygosity was available, only markers with heterozygosities above 0.5 were used. Where no previously characterized marker was available, long dinucleotide repeat and tetranucleotide repeat elements were identified in the CanFam 1.0 assembly (Lindblad-Toh et al. 2007) within 0.6 mb of each desired new location. After screening with RepeatMasker (http://repeatmasker.org), primers were designed to amplify microsatellite repeats within unique sequences using Primer 3 (Rozen and Skaletsky 2000). Forward primers were fused to an upstream 19 bp M13-specific element (CACGACGTTGTAAAACGAC) to allow indirect labeling (Neilan et al. 1997). The marker sequences, locations, product sizes, and repeat types are summarized in Table 1.
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DNA Samples, PCR, and Genotyping
Heterozygosity analysis was performed using a panel of DNA samples from 10 unrelated purebred dogs representing distinct breeds as has been described previously in the development of MSS1 and MSS2 (Richman et al. 2001; Guyon, Lorentzen, et al. 2003; Clark et al. 2004) marker sets, with the exception that one beagle sample in the panel had been exhausted, and was thus substituted by another DNA sample from the same breed. Touchdown PCR was performed after denaturing 10 min at 95 °C, using 10 cycles of 95 °C, 20 s, annealing starting at 65 °C reducing by 1 degree per cycle to 55 °C for a further 30 cycles, extension 72 °C for 30 s. Genotyping of reaction products was performed by capillary electrophoresis using an Applied Biosystems 3730 and GENEMAPPER v3.5 software.
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Results |
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In MSS2, the physical spacing of markers was calculated based on RH mapping distances, and assuming a constant scaling between RH map and sequence for each individual chromosome. By these criteria, markers are placed at an average of 9 mb with a largest gap of 17.1 mb. The availability of the genome sequence has allowed us to check the actual chromosomal position of these microsatellites. As judged by the sequence assembly, the 17.1 mb gap predicted from the RH map is only 11.7 mb, but several larger gaps exist, with the largest of 33.9 mb on the X chromosome. Seventeen markers in the MSS2 marker set have no matches in the CanFam 1.0 assembly, emphasizing that this assembly is not yet fully completed. When considering the whole genome, the genetic spacing of MSS2 markers is estimated to be between 7 and 8 cM. Many MSS2 markers have not been placed on the canine meiotic map, so this figure represents an average spacing based on total genetic length, rather than a direct measurement.
To create a more complete and evenly spaced marker set, primers were designed to amplify microsatellites in order to add markers to the MSS2 set wherever it contains a physical gap of more than 9 mb based on the CanFam 1.0 genome assembly (Lindblad-Toh et al. 2007). Additional markers were also designed wherever the RH map of Guyon, Lorentzen, et al. (2003) showed a gap of more than 10005000 units. Further markers were placed close to the boundaries of major discrepancies between the RH map and the CanFam 1.0 assembly, to allow for added mapping quality at these positions.
Details of the new markers in the panel are shown in Table 1. Markers were rejected 1) if PCR failed to produce products within the 80 bp of the size range expected from the canine sequence assembly; 2) when the product genotypes were very weak; 3) when there were multiple products; or 4) when amplicon product sizes were difficult to assess because of excessive stutter. In general, markers were also rejected when heterozygosity measured on the panel was less than 0.5 (although in 5 cases markers with lower heterozygosity were retained, as there were no other suitable microsatellite repeat to cover the region in question). For each marker that was rejected, a new marker was selected that was as close as possible to the original. This yielded to a panel of 183 additional markers.
The average heterozygosity for those markers with no previously published polymorphic information content or heterozygosity measurement is 0.74, and average spacing across the whole 507 marker set is 5.00 mb, based on the CanFam 1.0 assembly, and excluding the 3 markers on the Y chromosome. Figure 1 shows the arrangement of all markers, both on the CanFam 1.0 assembly and on the RH map of Guyon, Kirkness, et al. (2003). A small number of markers do not have matches in CanFam 1.0. The RH map predicts that an MSS2 marker, FH2993, from MSS2, is located centrally in this gap, but no match was found to this marker anywhere in the CanFam 1.0 assembly. Subsequent publication of CanFam 2.0 places FH2993 distal to FH4076, so that this gap is not closed. A further marker, Ren216N05, has been added to bridge this gap in CanFam 2.0. Most of the other primer pairs without matches to Canfam 1.0 also have matches at the expected locations in CanFam 2.0. The longest gap without any marker prediction is 10.6 mb (chromosome 1), and there are 5 other gaps of greater than 8 mb.
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Discussion |
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Purebred dog populations segregate large numbers of both monogenic and polygenic traits that are suitable for mapping studies aimed at facilitating both canine and human health (Ostrander and Comstock 2004; O'Rourke 2005). Pedigree records allow both parametric linkage analysis and nonparametric methods based on identity by descent. But purebred dog populations have often been through profound genetic bottlenecks at breed foundation and also show high levels of inbreeding, with major popular sire effects, and resulting in predictably high selective indices (Ostrander and Kruglyak 2000; Sutter et al. 2004; Lindblad-Toh et al. 2007). This leads to a within-breed reduction in polymorphism as measured by both microsatellites and single nucleotide polymorphism (SNP)-based markers. Indeed, several studies of canine microsatellites have shown reductions in heterozygosity within breeds of 22–30% compared with the canine population as a whole (Fredholm and Wintero 1995; Pihkanen et al. 1996; Zajc et al. 1997; Koskinen and Bredbacka 2000; Parker et al. 2004). This level of heterozygosity loss is typical when only 3–4 genomes are sampled from the whole population (Wright's F-statistic). Marker sets for genetic screening need to be sufficiently polymorphic within single breeds to allow for mapping. Based on the figures above, the average heterozygosity of MSS3 in a single breed will usually be above 0.5, so that microsatellite screening remains an attractive first option for disease and trait mapping.
For nonparametric analysis, markers should ideally be positioned densely enough to fully exploit the relatively long LD regions in purebred dog populations. Typically, LD extends in dogs for 0.5–2.0 mb (Sutter et al. 2004; Lindblad-Toh et al. 2007). This marker set does not have sufficient density to allow identification of disease-associated haplotypes by LD mapping, which would require several thousand additional markers. SNP-based mapping tools, are currently under construction in the dog to facilitate such studies (Lindblad-Toh K, personal communication). But SNP chips are typically expensive, ranging in price from a few hundred to more than a thousand dollars a chip. Thus, whereas SNP chips will likely be a first line mapping tool for whole-genome association studies, mapping panels composed of well-characterized microsatellite repeats will remain a useful and sufficient tool for initial localization of disease genes in large pedigrees such as are frequently available for mapping of canine disease genes. Such pedigrees yield sufficient power to pursue IDB-based techniques more than 10–20 meioses. This will be sufficient for many canine genome mapping projects where large extended families, derived from few founders, are available for study (Yuzbasiyan-Gurkan et al. 1997; Acland et al. 1998; Acland, Ray, Mellersh, Langston, et al. 1999; Lingaas et al. 1998; Jonasdottir et al. 2000; Lowe et al. 2003; Lohi et al. 2005). For example, microsatellite-based genome scans on such families have been used successfully to map genes for a variety of diseases including vision disorders (Acland et al. 1998; Acland, Ray, Mellersh, Gu, et al. 1999; Sidjanin et al. 2002; Lowe et al. 2003), canine narcolepsy (Lin et al. 1999), kidney cancer (Jonasdottir et al. 2000), metabolic diseases (Yuzbasiyan-Gurkan et al. 1997), ceroid lipofucinosis (Lingaas et al. 1998), and a host of others (Galibert et al. 2004; Ostrander and Wayne 2007).
Based on the canine genome assembly and RH map, MSS3 will allow screening of virtually the whole genome, including areas previously not close to any marker. As demonstrated by Figure 1, and reported previously from the 10 000 gene mapping project (Hitte et al. 2005), there is strong colinearity between the RH map of the dog and the assembly of the 7.5x canine genome sequence (Lindblad-Toh et al. 2007) for most chromosomes. Exceptions include a part of chromosome 9 (as assessed by RH mapping) that appears in the sequence assembly on chromosome 18, with local rearrangement of order of chromosome 18 markers adjacent to this insertion. Local reversals of marker order in short sections of chromosomes 2, 9, 11, 16, and 37 and for pairs of markers on chromosomes 23 and 31 reflect minor discrepancies between the whole-genome assembly and both the 5000 and 9000cR versions of the RH map. Chromosomes 19 and 21 are oriented in opposite directions in the 2 maps. The previous FISH analysis of Breen et al. (2001) would support the marker order found in sequence assembly for chromosome 2, and that in the RH map for chromosomes 19 and 18. Minor discrepancies between meiotic map and RH map for chromosomes 11 and 16 are resolved if markers on these chromosomes are ordered as in the genome assembly.
In summary, building on previous resources we have developed a well-characterized resource that should continue to facilitate mapping of disease genes in dogs using microsatellite-based approach. The 508 microsatellite-based marker set MSS3 provides the needed information to conduct genome-wide scans at about 5 cM resolution. Because not all new markers appear on the meiotic linkage map and have been selected based on their position in the sequence assembly, fine mapping to localize recombinants and reduce regions of linkage for selection of candidate genes will still require construction of local linkage maps using publicly available mapping resource families. But the high concordance between existing RH map and genome assembly resources (Hitte et al. 2005; Lindblad-Toh et al. 2007) suggests that investigators are not likely to be led far astray if they choose to utilize the 5 cM mapping set at face value. The integration of the newly described MSS3 mapping panel with SNP-based resources as they become available should further serve the canine community in their efforts to understand the genetic basis of both simple and complex traits.
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Acknowledgments |
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We acknowledge the American Kennel Club Canine Health Foundation and NIH R01 CA92167 (E.A.O. and F.G.). E.A.O. was supported by K05 CA90754 and is the recipient of a Burroughs Wellcome Award in Functional Genomics; F.G. is supported by the Centre National Recherche Scientifique, the Université de Rennes, and Conseil Régional de Bretagne (France); and J.A.-H. and D.R.S. are supported by Cancer Research UK (CRUK) grant C8876/A4012. This research was supported (in part) by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health
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Footnotes |
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Corresponding Editor: Robert Wayne
Received November 28, 2005
Accepted December 22, 2006
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