The Journal of Heredity 2001:92(4)
© 2001 The American Genetic Association 92:322-326
Mapping of a QTL for Serum HDL Cholesterol in the Rabbit Using AFLP Technology
From the Department of Laboratory Animal Science, Faculty of Veterinary Medicine, Graduate School of Animal Health, Utrecht University, P.O. Box 80.166, NL-3508 TD Utrecht, The Netherlands (Van Haeringen, Bieman, Gillissen, Lankhorst, Van Zutphen, and Van Lith) and KeyGene N.V., Wageningen, The Netherlands (Kuiper). W. A. Van Haeringen is currently at the Dr. Van Haerigen Laboratorium B.V., Wageningen, The Netherlands, and M. T. R. Kuiper is currently at Aventis CropScience N.V., Gent, Belgium.
Address correspondence to H. A. Van Lith, Ph.D. at the address above or e-mail: lith{at}las.vet.uu.nl.
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The amplified fragment length polymorphism (AFLP) technique is a DNA technology that generates the so-called AFLP markers. These markers are genomic restriction fragments detected after two rounds of polymerase chain reaction (PCR) without prior knowledge of nucleotide sequence. Here we describe the first application of the AFLP technique in the rabbit. We have tested two primer combinations. The results obtained with the DNA from rabbits of different breeds justify the conclusion that AFLP analysis is an effective tool for genetic studies in the rabbit. In addition, we contribute to the linkage map of the rabbit by localizing two AFLP markers on rabbit linkage group VI (LG VI). For this purpose the progeny of a IIIVO/JU x [IIIVO/JU x AX/JU1 backcross were genotyped for 12 AFLP markers and 3 LG VI classical markers [one coat color marker (e) and two biochemical markers (Es-1 and Est-2)]. AX/JU is a dietary cholesterol-susceptible (hyperresponding) inbred strain and IIIVO/JU is a dietary cholesterol resistant (hyporesponding) inbred strain. Moreover, it is possible to evoke dietary cholesterol-induced aorta atherosclerosis in a relatively short time period in AX/JU rabbits, in contrast to IIIVO/JU rabbits. A significant cosegregation was found between basal serum HDL cholesterol level (i.e., the level on a low-cholesterol, control diet) and an AFLP marker on LG VI. It is concluded that one or more genes of LG VI are regulating the basal serum HDL cholesterol level in rabbits. Thus the present study with rabbits clearly illustrates the value of AFLP markers for the construction of linkage maps and mapping of quantitative trait loci (QTL).
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Introduction |
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The rabbit (Oryctolagus cuniculus) is frequently used as a model in biomedical research. In particular, the laboratory rabbit is an extremely valuable animal model for the study of human diseases such as hypercholesterolemia and atherosclerosis (Mortensen et al. 1994). Furthermore rabbits are bred for several other purposes: as an animal model to study skin papillomas and carcinomas (Breitburd et al. 1997), for exhibition, or for the production of meat, wool, and fur (Korstanje et al. 2000).
To detect the quantitative trait loci (QTL) that are involved in the pathogenesis of complex diseases or that control economically relevant phenotypes, identification and chromosomal localization of genetic markers exhibiting variation among different breeds is highly desirable (Lander and Schork 1994). Unfortunately the rabbit gene map is still rudimentary (Fox 1993, 1994; RABBITMAP, http://locus.jouy.inra.fr/cgi-bin/lgbc/mapping/common/main.pl?BASE = rabbit). In the rabbit, mapping information is limited to 88 loci. The chromosomal location is known for 68 loci, whereas the other 20 loci have only been assigned to one of the autosomal linkage groups that have been described in this species (Korstanje 2000). Thus to maximize the likelihood of finding genes associated with complex multifactorial diseases or production traits, it is necessary to further increase the number of genetic markers and to develop a rather dense genetic map of polymorphic markers spaced at regular intervals over the rabbit genome.
Until now, only markers that were detectable by conventional biochemical, immunological, and morphological methods have been used for linkage studies in the rabbit (references cited in Fox 1993, 1994; Korstanje 2000). Although these classical markers have proven their value and some of them might still be useful for gene mapping, as will be demonstrated in this study, there are also some disadvantages (technique is laborious; low degree of polymorphism; posttranslational variation). Therefore we intend to further extend the genetic map of the rabbit by using DNA markers, which clearly have several advantages over the conventional markers.
Until now only a limited number of simple sequence length polymorphisms (SSLPs) have been described (Mougel et al. 1997; Rico et al. 1994; Surridge et al. 1997; Van Haeringen et al. 1997), but it is anticipated that more effort will be put into the development of these types of DNA markers in the rabbit (Korstanje et al. 2000). However, the amplified fragment length polymorphism (AFLP) fingerprinting technique has the potential to become a valuable genome mapping tool (Mueller and LaReesa Wolfenbarger 1999). The technique rapidly generates hundreds of highly replicative markers from the DNA of any organism. Some years ago we experimented with AFLP technology in the rat (Otsen 1995; Otsen et al. 1996).
To test the feasibility of using this method in rabbit genetic studies, we studied the polymorphism rate of AFLP markers in rabbit by using DNA of various breeds. In addition, we also contribute to the linkage map of the rabbit by localizing two AFLP markers on rabbit linkage group VI (LG VI).
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Materials and Methods |
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Animals and Samples
DNA samples were prepared from rabbits of different breeds (2–8 rabbits/breed; Korstanje et al. 2000). Serum and DNA samples were also obtained from a backcross progeny. A total of 57 backcross animals from IIIVO/JU x [IIIVO/JU x AX/JU]F1 were available for genetic analysis. The two parental inbred strains for this cross (AX/JU and IIIVO/JU) are maintained by brother-sister mating at the Department of Laboratory Animal Science, Utrecht University. AX/JU is a dietary cholesterol-susceptible (hyperresponding) strain and IIIVO/JU is a dietary cholesterol resistant (hyporesponding) strain. Furthermore, IIIVO/JU and AX/JU rabbits have high and low basal serum HDL cholesterol levels (i.e., the level on a low-cholesterol, control diet), respectively (Van Lith et al. 1996). The strains originated from The Jackson Laboratory colony (Bar Harbor, ME; Fox 1975). In 1983 The Jackson Laboratory stopped research on rabbits. Breeding pairs of IIIVO/J (F > 0.99) and AX/J (F > 0.80) were taken over by Van Zutphen, who continued inbreeding at the Department of Laboratory Animal Science, Utrecht University. Since their arrival in Utrecht the two strains are indicated as IIIVO/JU and AX/JU, and have been propagated by strictly brother x sister mating. From 1983 to 2000, AX/JU and IIIVO/JU were inbred for more than 15 generations. For each backcross animal the basal serum HDL cholesterol level was determined. Details on the experimental procedures for the backcross animals (production, housing, diet, blood sampling, and serum HDL cholesterol determinations) are described elsewhere (Van Lith et al. 1996).
DNA was isolated from liver, kidney, or spleen using a standard isolation procedure involving overnight proteinase K digestion and subsequent phenol/chloroform extractions (Ausubel et al. 1987). DNA was resuspended in TE buffer (10 mM Tris, 0.2 mM EDTA, pH 8.0) at a concentration of 1 µg/µl. DNA samples were stored at 4°C.
Coat Color Variation and Serum Esterase Genotypes of Backcross Rabbits
AX/JU inbred rabbits have a medium chinchilla coat and brown eyes, whereas IIIVO/JU inbred rabbits are albino. The differences in coat and eye color between these two rabbit inbred strains are due to three coat color loci: c (albino; located in LG I), e (extension; located in LG VI), and w (width of subterminal agouti band; located in LG IV). AX/JU rabbits have the genotype cchmcchmEEww. The genotype for the IIIVO/JU rabbits is ccEDEDWW (Fox 1975).
Serum esterase (Es-1 and Est-2) genotypes were determined by discontinuous horizontal starch-gel electrophoresis. Electrophoresis of serum was carried out as previously described (Van Zutphen 1974). After electrophoresis the gels were stained for esterase activity using the azo dye procedure; 
-naphthylacetate was used as a substrate and Fast Blue BB as the coupling salt. IIIVO/JU rabbits display the EST-2f' zone and are homozygous for the Es-1a genotype, whereas AX/JU rabbits have no fast anodal serum esterase zone and are homozygous for the Es-1b genotype (Korstanje 2000).
AFLP Protocol
The AFLP procedure was developed by the company KeyGene N.V. (Wageningen, The Netherlands), which has filed property rights on this technology (Zabeau and Vos 1993). The main steps of the AFLP procedure have been described in Vos et al. (1995). A detailed description of the procedure has been described by Vos and Kuiper (1997). The present AFLP analysis was performed with the restriction enzyme combination SseI/MseI according to the protocol described in Otsen (1995) and Otsen et al. (1996). Two different SseI/MseI primer combinations were tested: S12/M61 and S13/M51. After two rounds of polymerase chain reaction (PCR) the products were separated on sequencing gels and visualized by exposure to X-ray films. The same PCR products were run with different running times. The running times were chosen in such a way that three size ranges (0–200 bp, 250–500 bp, and 500–1000 bp) were visible on the gels. The mobility of the fragments in the gel is estimated relative to DNA markers of known length (10-base DNA ladder; Allele Sizing Set, Boehringer Mannheim GmbH, Mannheim, Germany). All PCR amplifications and electrophoretic separations were performed twice. By comparing the results it was concluded that the AFLP patterns are highly reproducible.
Linkage and Statistical Analyses
For genetic analysis of the backcross and mapping of AFLP markers to LG VI, we used the JoinMap computer package (version 1.4; Stam 1993). For the establishment of linkage groups we used a critical minimal LOD score of 3.0 (linklod). For calculation of map distances and estimating most likely gene orders we used a critical LOD score of 0.05 (maplod). The Kosambi mapping function was used for the construction of the map of LG VI, as presented in this article (see Figure 1).
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Comparison of the basal serum HDL cholesterol level of the backcross animals after grouping by genotype has also been performed. For this purpose 2 biochemical (Es-1 and Est-2) and 12 AFLP markers were used. If the Es-1, Est-2, or an AFLP locus and the basal serum HDL cholesterol level segregate independently, the basal serum HDL cholesterol values will be equally distributed among the homozygote and heterozygote genotypes. The results for the basal serum HDL cholesterol level are presented as means ± SD (see Table 1). The Kolmogorov–Smirnov one-sample test was used to check the normality of these data. All results within groups were found to be normally distributed. The significance of difference between the segregating genotype groups was calculated by two-way analysis of variance (ANOVA) with gender and genotype as factors. Homogeneity of variance was tested using Bartlett's test. The variances were similar. For the two-way ANOVA P = .0036 (0.05/14; Bonferroni adjusted P value, correction for 14 different marker genotypes) was chosen as a critical limit for detection of linkage in order to reduce type I error (false-positive linkage). In all other cases the probability of a type I error less than 0.05 was taken as a criterion of significance. All statistical analyses were carried out according to Steel and Torrie (1981) using the SPSS PC+ computer program (SPSS Inc. 1990).
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Results and Discussion |
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Genomic DNA from different rabbit breeds (Korstanje et al. 2000) was restricted using the octamer cutter SseI and the tetramer cutter MseI. For amplification of the fragments, two different primer combinations were used: SseI + AC/MseI + CTG (S12-M61) and SseI + AG/MseI + CCA (S13-M51). Selection procedures as used in this study resulted in high-density fingerprints. More than 100 amplified fragments in the range of 50–700 bases were visible on the gels. Figure 2 shows a section of such a fingerprint.
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With the S12-M61 and S13-M51 primer combinations, 21 and 23 bands, respectively, appeared to be clearly polymorphic (Tables 2 and 3). These polymorphisms were based on the presence/absence of a specific band. Furthermore, the band intensity from the amplified DNA fragments varied between the noninbred rabbit samples. This is mainly due to the difference in the heterozygote and homozygote "band present" genotype. One main limitation of the AFLP technology is that these two genotypes cannot be distinguished without the help of specialized software. Therefore KeyGene N.V. has developed such software (AFLP-Quantar). By using a phosphor imaging system and quantification of band intensities, the AFLP fragments can be converted into codominant markers. This has been demonstrated by Ajmone-Marsan et al. (1997) for cattle.
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For the AX/JU and IIIVO/JU strain, the calculated coefficient of inbreeding (F) is greater than 0.98. The calculated F at the time samples were collected for OS/J, WH/J, and X/J is between 0.70 and 0.90. Despite the fact that the Fs for these five rabbit strains are high, there was within-strain variation for several AFLP markers: E[S12-M61] (IIIVO/JU), G[S12-M61] (WH/J), H[S12-M61] (AX/JU), K[S12-M61] (WH/J), U[S12-M61] (IIIVO/JU), H[S13-M51] (IIIVO/JU), I[S13-M51] (WH/J), P[S13-M51] (WH/J), R[S13-M51] (WH/J) (Tables 2 and 3). It is well known that the rabbit is a species with a severe degree of inbreeding depression (Altman and Katz 1979). Thus it must be kept in mind that due to this inbreeding depression, there is a simultaneous selection for heterozygosity. Therefore the calculated inbreeding coefficient in rabbits might be an overestimation of the actual homozygosity attained.
To be useful as genetic markers, alleles must be inherited in a Mendelian fashion. Until now, AFLPs that have been characterized have fulfilled this criterion (Vos et al. 1995). Analysis of the lanes containing AX/JU, IIIVO/JU, and the corresponding F1 offspring showed no evidence of non-Mendelian inheritance of the parental presence/absence polymorphisms (see also Tables 2 and 3).
Twelve bands (S12-M61: bands B, D, G, K, N, T; S13-M51: bands D, G, J, M, P, W), which are absent in IIIVO/JU rabbits but present in AX/JU rabbits (see Tables 2 and 3), were used for genetic analysis of the IIIVO/JU x [IIIVO/JU x AX/JU]F1 backcross progeny. Two of the 12 polymorphic bands could be assigned to LG VI by linkage to the e locus: B[S12-M61], recombination = 6.8%; M[S13-M51], recombination = 21.2%. In order to conform rabbit gene and locus symbols to those of other mammalian species, we decided to give the bands B[S12-M61] and M[S13-M51] the gene symbols D0Utr1 and D0Utr2, respectively (see Figure 1). The basic rules (of, e.g., rat gene nomenclature) have been described by Levan et al. (1995).
Two biochemical markers (Es-1 and Est-2) and the 12 AFLP markers were also tested for association with basal serum HDL cholesterol level of the IIIVO/JU x [IIIVO/JU x AX/JU]F1 backcross animals. Two-way ANOVA applied to the genotype groups revealed that one LG VI AFLP marker (D0Utr1) was significantly associated with the basal serum HDL cholesterol level (Table 1 and Figure 1). Comparative gene mapping in the human, mouse, rat, and rabbit has revealed evidence for considerable conservation of gene order during mammalian evolution (Lyons et al. 1994). Linkage homology has been shown for rabbit LG VI, rat chromosome 19 (RNO 19), mouse chromosome 8 (MMU 8) and human chromosome 16 (HSA16) (Van Zutphen and Den Bieman 1988). Of interest, human chromosome 16, rat chromosome 19, and mouse chromosome 8 contain the gene LCAT. This gene codes for the enzyme lecithin-cholesterol acyltransferase (LCAT), which plays a major role in HDL cholesterol metabolism (Jonas 1991). Human chromosome 16 also contains the cholesteryl ester transfer protein gene (CETP). This gene is also involved in HDL cholesterol metabolism (Yamashita et al. 1996). Meijer et al. (1993) found that serum LCAT and CETP activities in AX/JU rabbits fed on a low-cholesterol control diet were lower than in IIIVO/JU rabbits. Based on homology, one might speculate that in the rabbit the LCAT and CETP loci are also on LG VI and thus one or both genes (or transcription factors in the vicinity of these genes) might be the responsible genetic factors for the different basal serum HDL cholesterol levels in rabbits. Mehrabian et al. (2000) and Bottger et al. (1996) described for mouse and rat a QTL that affects serum HDL cholesterol levels on chromosomes 8 (MMU 8) and 19 (RNO 19), respectively. As pointed above, these chromosomes are homologous to rabbit LG VI.
In summary, the results obtained with the DNA from rabbits of different breeds justify the conclusion that the AFLP technique is suitable for the genetic characterization of rabbits. Several markers are generated simultaneously and can be tested in two rounds of PCR without prior sequence knowledge. This makes the AFLP technique very efficient for the construction of genetic linkage maps, especially in species such as the rabbit, where limited information on genomic sequences is available. Thus the possibility of generating a saturated genetic map of the rabbit genome within a few years seems to be achievable. Such a map is indispensable for the study of complex traits controlled by QTL.
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Footnotes |
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Corresponding Editor: Muriel T. Davisson
Received November 17, 2000
Accepted April 30, 2001
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