Journal of Heredity 2004:95(3):185-194
© 2004 The American Genetic Association
A Marker Set for Construction of a Genetic Map of the Silver Fox (Vulpes vulpes)
From the James A. Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853 (Kukekova, Aguirre, and Acland), Institute of Cytology and Genetics, Siberian Department of the Russian Academy of Sciences, Novosibirsk, 630090, Russia (Trut, Oskina, Kharlamova, and Shikhevich), and Institute for Genomic Research, Rockville, MD 20850 (Kirkness).
Address correspondence to Anna V. Kukekova at the address above, or e-mail: avk5{at}cornell.edu.
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Abstract |
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The silver fox, a variant of the red fox (Vulpes vulpes), is a close relative of the dog (Canis familiaris). Cytogenetic differences and similarities between these species are well understood, but their genomic organizations have not been compared at higher resolution. Differences in their behavior also remain unexplained. Two silver fox strains demonstrating markedly different behavior have been generated at the Institute of Cytology and Genetics of the Russian Academy of Sciences. Foxes selected for tameness are friendly, like domestic dogs, while foxes selected for aggression resist human contact. To refine our understanding of the comparative genomic organization of dogs and foxes, and enable a study of the genetic basis of behavior in these fox strains, we need a meiotic linkage map of the fox. Towards this goal we generated a primary set of fox microsatellite markers. Four hundred canine microsatellites, evenly distributed throughout the canine genome, have been identified that amplify robustly from fox DNA. Polymorphism information content (PIC) values were calculated for a representative subset of these markers and population inbreeding coefficients were determined for tame and aggressive foxes. To begin to identify fox-specific single nucleotide polymorphisms (SNPs) in genes involved in the neurobiology of behavior, fox and dog orthologs of serotonin 5-HT1A and 5-HT1B receptor genes have been cloned. Sequence comparison of these genes from tame and aggressive foxes reveal several SNPs. The close relationship of the fox and dog enables canine genomic tools to be utilized in developing a fox meiotic map and mapping behavioral traits in the fox.
The red fox (Vulpes vulpes) and other fox-like canids last shared a common ancestor with the domestic dog (Canis familiaris) and other wolf-like canids about 12–15 million years ago (Wayne et al. 1997; Wayne and Ostrander 1999; Wayne and Vila 2001). This ancient divergence is mirrored in the extensively rearranged karyotype of the fox (34 metacentric and 0–8 B [micro] chromosomes) compared to the 78 predominantly acrocentric chromosomes of the dog (Breen et al. 1999; Graphodatsky et al. 2001; Yang et al. 1999). In further contrast to the modern dog, which represents the first animal to become fully domesticated, the red fox has, until recently, never been domesticated.
The history of animal domestication is tightly interwoven with the development of human society (Clutton-Brock 1995; Diamond 2002). To be successful, domestication involves behavioral adaptation by animals, enabling them to live in closer proximity to humans than their progenitors could. Subsequently, or simultaneously, this process is accelerated by artificial selection when breeding becomes controlled by humans and focused on retaining traits regarded as desirable. From molecular data it is evident that the modern dog originated from gray wolves (Vila et al. 1997, 1999). The calculated date of this divergence still depends on the choice of assumptions and analytic methods, but is currently estimated to be as long as 12,000–15,000 years ago (Leonard et al. 2002; Savolainen et al. 2002). Although the archaeological record reveals small canids in association with humans from about the end of this period throughout Eurasia (Clutton-Brock 1995, 1999; Davis and Valla 1978; Olsen 1985), the first unequivocal evidence of the phenotypic diversity characteristic of the modern dog dates from about 5000 years ago in China (Olsen 1985), and 2500–4500 years ago in Babylonian, Assyrian, and Egyptian records (Clutton-Brock 1995, 1999; Zeuner 1963).
Intriguingly, the morphological and physiological changes associated with domestication show similar tendencies among diverse species (Trut 1999). Domesticated animals can be easily distinguished from their wild relatives by skull shape and other skeletal features (Wayne 2001), and even by coat color. The question is, do these changes represent merely human preference for certain morphotypes, or are they consequences of genetic selection for domesticated behavior?
A scientific team from the Institute of Cytology and Genetics of the Russian Academy of Sciences (ICG) in Novosibirsk has shed light on this question by experimentally reconstructing the domestication process in the silver, farm-bred form of the red fox (Belyaev 1969; Trut 1987, 1999). When the ICG studies started in the 1960's, Belyaev and colleagues hypothesized that selection of farm foxes for less fearful and aggressive behavior would lead to development of a domesticated strain of this species. In 40 years of continuous selective breeding, about 50,000 animals were tested for amenability to domestication (Belyaev 1979; Belyaev et al. 1981; Trut 1999). The resultant population of foxes selected for tameness demonstrates emotionally friendly responses to humans from 1 month of age (Trut 1999, 2001; http://cbsu.tc.cornell.edu/ccgr/behaviour/index.html). In parallel with this selection for tameness, a second strain of fox was selectively bred for aggressive behavior (Trut 1999). Studies including experimental crossbreeding of domestic and aggressive animals, cross-fostering of newborn pups, and transplantation of embryos have demonstrated the genetic basis of tame and aggressive phenotypes (Trut 1980).
In association with increased amenability for domestication, several de novo traits appeared in the fox population selected for tame behavior without direct selection or inbreeding. In particular, coat color changes such as the appearance of a white spot (Star phenotype) on the head (Belyaev et al. 1981), floppy ears, rolled tails, shorter tails, and changes in skull shape mimic the differences between domesticated dogs and wolves (Trut 1999). Significant differences in corticosteroids and several central nervous system (CNS) neurotransmitter levels were also found between animals from the domesticated and control (unselected) populations. In particular, significantly lower density of serotonin 5-HT1A receptors and significantly higher levels of serotonin and tryptophan hydroxylase were detected in brains of domesticated strain foxes (Popova et al. 1997; Trut 2001; Trut et al. 1974).
To understand the genetic basis of tame and aggressive behavior in the silver fox, it is first essential to have a genome map of the fox. Fortunately the evolutionary relationship between the dog and fox allows extension of recent progress in canine molecular genetics (Acland et al. 1998, 1999; Breen et al. 2001; Kirkness et al. 2003; Lin et al. 1999; Mellersh et al. 1997; Sidjanin et al. 2002; Yang et al. 2000; Zhang et al. 2002) to the fox genome. Cytogenetically the relationship between the dog and fox genomes is well understood. The remarkable karyotypic differences between fox and dog represent 26 chromosomal fusion events and 4 fission events (Graphodatsky et al. 2000, 2001; Yang et al. 1999, 2000). Cross-species reciprocal chromosome painting and DAPI banding studies have clearly established the homology of chromosomal segments between domestic dog, red fox, and human (Yang et al. 1999). Thus, in attempting to create a meiotic map of the fox genome, we already know, to a first approximation, how and where the various linkage groups are arrayed, and might be able to use microsatellites from the canine genome map (Breen et al. 2001).
As a first step toward development of a fox genetic map, we have generated a primary set of 400 polymorphic markers for the fox genome based on the canine microsatellite database (Breen et al. 2001; Mellersh et al. 1997). To evaluate the informativeness of canine-derived microsatellites for the fox genome and their potential for constructing a fox meiotic map, we calculated polymorphism information content (PIC) values for 30 markers and estimated inbreeding coefficients of foxes in existing pedigrees. To optimize the map for behavioral studies, we plan to include polymorphic markers corresponding to genes involved in neurotransmitter function. As an initial step, serotonin receptor genes 5-HT1A and 5-HT1B have been selected. In man, abnormalities in serotonin metabolism are implicated in autism, anxiety, depression, obsessive-compulsive disorder, schizophrenia, and many other neuropsychiatric diseases (Cook and Leventhal 1996; Nebigil et al. 2001; Shekhar et al. 2001). In mice, the 5-HT1A receptors are implicated in the modulation of exploratory and fear-related behaviors, and aggressiveness in 5-HT1B knockout mice is greater than in wild type (Ase et al. 2000; Miczek et al. 2001; Saudou et al. 1994; Tarantino and Bucan 2000). Serotonin receptor genes 5-HT1A and 5-HT1B have been sequenced from aggressive and domestic foxes and single nucleotide polymorphisms (SNPs) identified for nonparametric linkage and association studies of behavioral trait inheritance in this fox model of domestication.
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Fox Colony and DNA Samples
Fox blood samples were collected from tame and aggressive silver foxes maintained at the experimental farm of the ICG of the Russian Academy of Sciences. Canine tissue samples were collected postmortem from animals maintained at the Retinal Disease Studies Facilities (RDSF) in Kennett Square, Pennsylvania. DNA was purified from silver fox blood and dog spleen samples by the phenol-chloroform method (Sambrook et al. 1989).
PCR Amplification of Canine Microsatellite Markers from Fox DNA
To identify genetic markers that worked robustly on fox DNA, we tested 700 previously published canine microsatellites (Breen et al. 2001; www-recomgen.univ-rennes1.fr/Dogs/maquette.html; www.fhcrc.org/science/dog_genome/dog.html) using DNA from two silver foxes and standardized conditions (initial 2 min denaturation at 96°C, followed by 30 cycles: 96°C for 20 s, 58°C for 20 s, 72°C for 20 s, and a final extension step at 72°C for 5 min). Markers that did not work robustly under these conditions were amplified with the same PCR program but with a Tm of 55°C or 61°C. PCR products were analyzed in 10% native polyacrylamide gel. Band intensity was scored by eye using a five-point scale. In parallel, a selected set of 12 fox DNA samples was genotyped by Marshfield Laboratories Mammalian Genotyping Service with a standard canine microsatellite set including 241 markers.
Estimation of Marker PIC Values and Population Inbreeding Coefficients (FIS)
Thirty microsatellites, randomly selected from 400 that robustly amplified fox DNA and representing di- and tetra- repeat microsatellites, were tested on fox DNA to evaluate their PIC value in foxes, essentially as previously reported for fluorescently labeled canine markers (Cargill et al. 2002). Each marker was amplified on DNA from 32 colony animals, including 22 domesticated foxes (13 females and 9 males) and 10 aggressive foxes (6 females and 4 males). The forward primers of each pair were labeled with one of three fluorescent dyes: 6Fam, Hex, or Tet (IDT, Coralville, IA; GIBCO BRL, Gaithersburg, MD) on the 5-end. PCR products with compatible dyes and fragment sizes were combined in multiplex sets and analyzed using the ABI 310 capillary-based genetic analyzer (Applied Biosystems, Foster City, CA). Each multiplex set included a mixture of three or four amplified markers. Collection and analysis of the multiplex sets was performed using the ABI GENESCAN version 3.1 software package (PE Applied Biosystems, Foster City, CA). The PIC value for each marker was calculated in an Excel worksheet.
Population heterozygosity was estimated for 25 of the 30 microsatellites used for PIC determination. Markers were amplified from DNA of 22 domestic and 10 aggressive foxes, and analyzed using the ABI 310. The inbreeding coefficient (FIS), which measures the reduction of heterozygosity due to nonrandom mating within a subpopulation, was estimated for domestic and aggressive fox populations using GenePop version 3.1 (http://wbiomed.curtin.edu.au/genepop/) (Weir and Cockerham 1984) and FSTAT (Goudet 1995). Hardy-Weinberg equilibrium tests were undertaken using option 1 of GenePop. Exact P values were estimated by the Markov chain method (dememorization: 1000; batches: 100; iterations per batch: 1000).
Sequencing of 5-HT1A and 5-HT1B Receptor Genes from Fox and Dog
The 5-HT1A and 5-HT1B receptor genes from fox and dog were amplified as a set of overlapping PCR fragments. PCR primers were designed partly from human sequences and partly from dog sequences retrieved from the TIGR canine genomic sequence (Kirkness et al. 2003). Fox and dog PCR products were sequenced and assembled into contigs using Sequencher 4.1. Multiple alignments between 5-HT1A and 5-HT1B receptor gene sequences from different species were performed using MegAlign, part of the DNAStar package. GENESCAN (MIT, Cambridge, MA) was utilized for open reading frame prediction.
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A Primary Microsatellite Marker Set for the Fox Genome
From 700 canine microsatellite markers tested, 400 (approximately 60%) worked robustly on fox DNA, reliably producing PCR products scored as four or better on a five-point scale (Figure 1 and Table 1). Although patterns of higher molecular weight stutter bands were observed on these gels, similar to those seen with products from canine DNA and arising from secondary structures of PCR products under nondenaturing gel conditions, they did not create problems in assigning marker genotypes. Thirty-five fox-amplified markers were sequenced to determine that the appropriate microsatellite repeats, as expected from canine marker information, were present in the fox PCR products (Table 2); in all cases the sequencing confirmed the expected result. The 400 markers that repeatedly worked well on fox DNA were selected as a primary set of genetic markers for initial mapping of the fox genome. Genotyping results on fox DNA samples analyzed by Marshfield Laboratories Mammalian Genotyping Service (MGS) confirmed the above results, and showed that approximately 55% of the canine marker set used by the MGS worked reliably on fox DNA (Table 1).
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Estimation of PIC Values of Selected Markers and Inbreeding Coefficients for Domestic and Aggressive Fox Populations
A representative multiplex set of fluorescently labeled di- and tetranucleotide microsatellites PCR amplified from fox DNA and analyzed on the ABI 310 is shown in Figure 2. Among the 30 markers tested, the calculated PIC was greater than 0.7 for 6 markers (20%); between 0.5 and 0.7 for 12 (40%); between 0.5 and 0.3 for 9 (30%); and less than 0.3 for 3 markers (10%) (Table 2). The number of fox alleles varied among the microsatellites, with a mean allele number of 5.1 for the 30 analyzed microsatellites. Ninety-two percent of these markers tested in the tame population and 88% of markers tested in the aggressive population were in Hardy-Weinberg equilibrium. Population inbreeding coefficients (FIS), calculated from data for 25 polymorphic markers, and for the same animals used for estimation of microsatellite PIC values, yielded mean values of 0.038 for 22 foxes from the tame population and 0.030 for 10 animals from the aggressive population.
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Sequencing of 5-HT1A and 5-HT1B Receptor Genes from Fox and Dog
Both the dog and fox orthologs of the 5-HT1A and 5-HT1B receptor genes were amplified as sets of overlapping fragments using primers designed from human sequence or from fragments of canine 5-HTA1 and 5-HTB1 gene sequences obtained from the TIGR 1.5X canine genome sequence (Kirkness et al. 2003). All primers used are listed in Table 3; primer positions and fragment sizes are specified relative to the corresponding fox gene sequence; GenBank accessions: AY204569 (5-HT1A); AY204571 (5-HT1B). The genomic sequences for the fox 5-HT1A and 5-HT1B receptor genes were obtained from fragments amplified from DNA of three distantly related foxes from the domestic population, and DNA of two animals from the aggressive group, and resolved by alignment of sequence data from cloned fragments. Canine 5-HT1A and 5-HT1B sequences were assembled from genomic fragments extracted from the TIGR database, and sequences of 5-HT1A and 5-HT1B receptor genes we amplified from genome DNA of a collie dog. Analysis of fox and dog gene structures predicted only one coding exon for both the 5-HT1A and 5-HT1B receptor genes of the fox and dog.
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Multiple sequence alignment of fox, dog, and human sequences for 5-HT1A, including the previously deposited canine 5-HT1A sequence (GenBank accession AY134445; Van Den Berg et al. 2003) revealed 99.5% nucleotide identity between fox and dog sequences, 89.4% between fox and human, and 89.0% between dog and human (Figure 3a). Alignment of fox, dog, and human sequences for 5-HT1B yielded identities of 97.0%, 91.3%, and 91.2%, respectively (Figure 3b).
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Sequence comparison among 5-HT1A fragments amplified from different foxes revealed one silent mutation (C/T) in the coding region in position 1184; genotypes C/C and C/T were observed. Two SNPs were identified from comparison of 5-HT1B sequences from tame and aggressive foxes in the noncoding part of the gene. Genotypes C/T and T/T were identified for the SNP located at position 174, and three genotypes (G/T, T/T, and G/G) were observed for the SNP at position 1684.
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Discussion |
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In developing this set of 400 markers for mapping the fox genome, the opportunity to exploit recent advances in canine and comparative genomics has been advantageous. Each of these markers has been previously mapped meiotically and/or by RH panels on the dog genome (Breen et al. 2001), thus the canine locations are known with confidence. As a starting point in developing this set, a marker set of 172 canine microsatellites previously developed for canine genomewide screens was exploited. For canine application, it is estimated that 42% of the genome is within 5 cM of at least one marker in this set, and 77% of the genome is within 10 cM (Richman et al. 2001). To adapt and optimize the set for application to the fox genome, several markers from this canine set have been replaced by microsatellites located closely nearby, and to improve the resolution and coverage, the overall number of markers was increased to 400. To a first approximation, the comparative location of these markers on fox chromosomes can be estimated by alignment of canine linkage groups with the results of reciprocal painting of dog and fox karyotypes (Yang et al. 1999, 2000). Thus the markers have been deliberately selected to be as uniformly and comprehensively distributed among the 34 fox metacentric chromosomes as can be predicted. It remains a possibility that, at finer resolution than is currently seen by reciprocal chromosomal painting, regions of unexpected inconsistency between the dog and fox genomes may become apparent in the process of fox map construction.
Comparative alignment of the fox genome with those of other mammals (dog, human, mouse) will allow rapid prediction of which genes are likely to be in the vicinity of each mapped marker. This latter advantage will accelerate with the recently announced high priority for sequencing the dog genome (www.nih.gov/news/pr/sep2002/nhgri-12.htm). A partially assembled 1.5X survey sequence of the dog genome has already been deposited (Kirkness et al. 2003) and installments of an even more comprehensive canine sequencing project are currently being rapidly and continuously updated in the public domain databases (www.ncbi.nlm.nih.gov/Traces/trace.cgi?).
To test the suitability of the target fox pedigrees for construction of a meiotic map of fox genome using the selected marker set, we estimated the level of heterozygosity in these populations and calculated the PIC value for 30 microsatellites. The average marker PIC value observed in the fox colony was 0.5. Over the multiple generations of selection of these foxes for specific behaviors, a deliberate effort was made to avoid inbreeding (Trut 2001). Analysis of population inbreeding coefficients (FIS) confirm that this strategy was successful in maintaining Hardy-Weinberg equilibrium in both tame and aggressive fox populations (FIS, tame = 0.038; aggressive = 0.030; overall = 0.036). The FIS 95% confidence interval (–0.040, 0.124) was estimated by the bootstrapping algorithm of FSTAT. Significant positive FIS values were observed for markers REN170E21 (0.641), FH3367 (0.554), C01.424 (0.517), FH2201 (0.449), and CPH18 (0.488) in the aggressive population, and for markers REN170E21 (0.726) and C06.636 (0.439) in tame population. As these high FIS values were observed for only a few loci, it is likely that these result from small sample sizes rather than inbreeding. Alternatively, they might represent the result of selection for specific genome regions; this will be tested by sampling more individuals and genotyping additional closely located markers.
A genomewide screen of fox families informative for both the behavioral phenotypes and the associated morphological traits that arose de novo in the domestic fox population can now be undertaken. Such a study would allow valuable insights into the molecular genetics of tame and aggressive behaviors. Because the populations of tame and aggressive foxes were created relatively quickly by selection focused only on specific behavioral traits, there are likely to be relatively few major genetic loci influencing the development of these phenotypes. It is known that a single gene mutation can cause some types of abnormal behavior. For example, mutation in the monoamine oxidase gene A (MAOA), involved in the metabolism of serotonin, dopamine, and noradrenalin, has been identified in an X-linked impulsive aggressive behavioral disorder in humans (Brunner et al. 1993).
To use the fox meiotic linkage map optimally, we will also need sequence data for identified regions of interest. Availability of comparative genomic sequence from the dog and other mammals is expected to be highly exploitable in such a situation. To test this hypothesis we cloned and sequenced the dog and fox orthologs of two genes, 5-HT1A and 5-HT1B, which are involved in serotonin metabolism. As anticipated, cloning and sequencing of the fox 5-HT1A and 5-HT1B receptor genes demonstrated very strong sequence conservation (Figure 3). Similar conservation was seen in comparative alignments of orthologous fox and dog gene sequences available from GenBank (NCBI, NIH). For example, comparison of the coding regions of the MCR1 (X90844, AF064455) and growth hormone genes (E07594, AF69071) using MegAlign demonstrated 99.1% and 92.8% similarity, respectively. These data demonstrate the high identity between coding regions of fox and dog genes and let us predict a broad potential for using canine sequences to clone fox genes.
The close evolutionary relationship between fox and dog predicts and is confirmed by the analyses of gene sequences and microsatellites reported here. This allows the application of modern tools developed for canine molecular genetics to genetic studies of the silver fox. Development of a fox genetic map and the mapping of behavioral and morphological phenotypes segregating in selected fox populations will provide insight into the mechanisms underlying canid domestication and will help to identify candidate genes potentially involved in human disorders of behavior and social interaction. Higher-resolution comparisons of the fox and dog genomes than has previously been possible will also yield insights into the chromosomal and genomic reorganizations associated with the divergence of the wolf-like and fox-like members of the Canidae.
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Acknowledgments |
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We are grateful to Irina V. Pivovarova for the excellent coordination of our experiments on the fox farm; to Irina Z. Plyusnina for her participation in fox domestication project; to Rimma G. Gulevich, Oleg V. Trapesov, Tamara N. Kuzhutova, Lyudmila V. Parafienko, Vera L. Haustova, and all animal caretakers at the ICG experimental farm for their assistance in fox sampling; to Sergey N. Borchsenius for his help in this research, to Rory J. Todhunter and Stuart P. Bliss for fluorescent primers; to Kathleen E. Whitlock, Maria Uriarte, H. Kern Reeve, Simon Klebanov, Alexander S. Graphodatsky, K. Gordon Lark, and Kevin Chase for advice and discussions; to Andrew Clark and Charles Aquadro for critiquing the manuscript; to Elaine A. Ostrander for information on unpublished canine microsatellites; and to Keith Watamura for his excellent graphics assistance. We express our gratitude to Marshfield Laboratories Mammalian Genotyping Service for genotyping fox samples with a subset of their canine microsatellite marker set. We gratefully acknowledge support from NIH grants EY06855 and EY13729 (to G.M.A. and G.D.A.); NATO grant LST CLG.979216 (to G.D.A. and L.N.T.), grant no. 02-04-48288 from the Russian Fund of Fundamental Research (to L.N.T.), and the Van Sloun Fund for Canine Genetic Research (to G.D.A.). Fox and dog 5-HT1A and 5-HT1B receptor gene sequences have been submitted to GenBank (AY204569–fox 5-HT1A receptor gene; AY204570–dog 5-HT1A receptor gene; AY204571–fox 5-HT1B receptor gene; AY204572–dog 5-HT1B receptor gene).
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Footnotes |
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Corresponding Editor: Elaine Ostrander
Received June 12, 2003
Accepted November 15, 2003
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