Journal of Heredity Advance Access originally published online on March 10, 2005
Journal of Heredity 2005 96(4):329-338; doi:10.1093/jhered/esi044
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Mapping and Exclusion Mapping of Genomic Imprinting Effects in Mouse F2 Families
From the Institut für Tierzucht und Tierhaltung, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, 24098 Kiel, Germany (Mantey, Kalm, and Reinsch); Forschungsinstitut für die Biologie landwirtschaftlicher Nutztiere, 18196 Dummerstorf, Wilhelm-Stahl-Allee 2, Germany (Brockmann and Reinsch); and Institut für Nutztierwissenschaften, Humboldt-Universität zu Berlin, Invalidenstrasse 42, 10115 Berlin (Brockmann)
Address correspondence to Gudrun A. Brockmann, Institut für Nutztierwissenschaften, Züchtungsbiologie und Molekulare Genetik, Invalidenstrasse 42, D-10115 Berlin, Germany, or e-mail: gudrun.brockmann{at}agrar.hu-berlin.de.
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Abstract |
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Parent-of-origin effects were mapped by multimarker regression analysis in a cross between a high body weight selected line (DU6) and a control line (DUKs). The difference between F2 progeny being heterozygous Qq and qQ (first allele is paternally derived) for grandpaternal Q and grandmaternal q alleles was genome-wide significant for the traits liver weight and spleen weight with a paternal imprinting effect at 1 cM on proximal chromosome 11. Suggestive imprinting effects (chromosome-wide error probability less than 0.05) were found for the traits body weight, liver weight, and kidney weight, and were located on chromosome 14 at 25 cM, 23 cM, and 32 cM, respectively. A genome-wide significant quantitative trait locus (QTL) for spleen weight at 26 cM slightly failed the suggestive significance level for imprinting. The effect was consistently maternal for all these traits on chromosome 14. Further suggestive imprinting effects were found for abdominal fat percentage on chromosome 3, for spleen weight on chromosome 5, and for liver weight on chromosome X. Our results are supported by a likely imprinting in a human genome region with homology to mouse chromosome 14 and agree well with the known imprinting of proximal chromosome 11 in the mouse.
For a number of genes, the allele inherited from one parent is inactivated, so that the expression of an allele depends on having been paternally or maternally transmitted. This parent-of-origin effect on allele activity and on the phenotype is controlled by an epigenetic process called genomic imprinting.
The nonequivalence of parental genomes and the differential imprinting of nuclear genes was postulated from the results of nuclear transfer experiments with parthenogenetic activation of mammalian oocytes (Barton et al. 1985; McGrath and Solter 1984; Surani et al. 1984). By breeding mice with uniparentally disomic chromosome segments, phenotypic imprinting effects, mainly on growth and viability of the embryo, could be mapped (Beechey et al. 2004; Cattanach 1986; Cattanach and Beechey 1990). Currently more than 70 imprinted genes have been identified in humans and mouse (Morison et al. 2001; Peters and Beechey 2004).
On the molecular level, genomic imprinting is mediated by parent-specific heritable epigenetic modifications during gametogenesis. More specifically, the presence or absence of methyl groups at CpG dinucleotides or acetylation and methylation modifications to core histones on chromosomal elements regulating imprinting is thought to block or unblock the access of an allele to binding sites for enhancers or transcription factors (Fournier et al. 2002; Reik and Walter 2001). Genomic imprinting plays a role in fetal growth and development (Hitchins and Moore 2002), tumorigenesis (e.g., Rainier et al. 1993; Reik et al. 1995), and in the transmission of several human diseases, such as Prader-Willi syndrome (Nicholls et al. 1989) and Russell-Silver syndrome (Kotzot et al. 1995).
Recent research in livestock species has shown that genomic imprinting is also important for juvenile growth and development of healthy individuals. The callipyge locus on ovine chromosome 18 causes a double muscling phenotype only in heterozygous individuals that inherited the mutant allele from the sire. The mutation has been found within the DLK1-GTL2 imprinted domain (Georges et al. 2003).
Significant variance components (roughly 10% of the total phenotypic variance) due to paternally expressed genes were found for back fat thickness and daily gain in commercial pigs by de Vries et al. (1994) in a quantitative genetic study. Engellandt and Tier (2002) found significant variance components for paternally derived genes for fatness traits (11% and 22% for kidney and pelvic fat, respectively) and estimated lean meat content (14%) in 1.5-year-old bulls.
Genome-wide scans for body composition in pigs revealed an important role of imprinting. A paternally expressed quantitative trait locus (QTL) affecting muscle mass and fat deposition was detected at the IGF2 locus on porcine chromosome 2 in two independent experiments (Jeon et al. 1999; Nezer et al. 1999). Parent-of-origin QTL effects were also mapped to other locations of porcine chromosomes 2, 6, and 7 (de Koning et al. 2000; Rattink et al. 2000).
In an effort to enhance the current knowledge of imprinting effects in the mouse genome, we present an extended analysis of a previously published mouse QTL experiment on growth and body composition traits (Brockmann et al. 1998). Two founders from different outcross lines, 24 F1 animals and 338 F2 progeny, were genotyped in a genome-wide scan for parent-of-origin effects on six different traits related to body composition and juvenile growth.
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Materials and Methods |
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Pedigree and Phenotypic Characterization
An F2 intercross design (Figure 1) was generated by mating a single mouse of the high body weight selected line DU6 and one animal of the unselected control line DUKs (pedigree 8 in Brockmann et al. [1998]). These lines descend from original crosses of four base (NMRI orig., Han: NMRI, CFW, CFI) and four inbred (CBA/Bln, AB/Bln, C57BL/Bln, XVII/Bln) populations at the Research Institute for the Biology of Farm Animals, Dummerstorf, Germany (Bünger et al. 1983; Schüler 1985).
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The level of inbreeding expected from the pedigrees of both lines was estimated to be about 40%. The population size in both lines was 80 pairs per generation. Full-sib matings of 24 F1 individuals resulted in 338 F2 progeny. The litter size was standardized to nine individuals. Offspring were weaned at 21 days. All phenotypic data (Table 1)—quantitative measurements of body weight (BW), abdominal fat weight (AFW), and the mass of the liver (LW), kidney (KW), and spleen (SW)—were recorded at the age of 42 days (Brockmann et al. 1998). Abdominal fat percentage (AFP) was estimated as the ratio of abdominal fat weight to body weight.
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Markers and Maps
Previous genotyping results of 84 markers (Brockmann et al. 1998) were supplemented with 12 additional markers. These additional markers have been selected to be heterozygous for at least one of the founder parents. Primers were purchased from Research Genetics (Huntsville, AL).
All marker data were collected in the ADRDB database (Reinsch 1999). After checking for genotyping errors, pedigree-specific sex-averaged marker maps were calculated using the option BUILD in the CRIMAP program (Green et al. 1990).
Regression Model
Both founder animals were assumed to be homozygous QQ and qq for alternative QTL alleles. Consequently, four different QTL genotypes can be expected to occur in the F2 generation: QQ, Qq, qQ, and qq, where the first allele is paternally transmitted and Q and q indicate grandparental origin. Three QTL parameters were estimated (Falconer and Mackay 1996; Knott et al. 1998): the additive effect a, defined as half of the phenotypic difference between homozygotes QQ and qq; the dominance effect d, that is, the difference between the joint mean of both heterozygotes and the mean of both homozygotes; and the imprinting effect i, the difference between heterozygotes Qq and qQ. In matrix notation, the phenotypic means (indicated by a bar) of the four possible genotypes in the F2 generation of a single family can be written as
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Family-specific means µj account for possible polygenic variability between families. Under the assumption of the line-cross model (founder lines homozygous QQ and qq), there is no between-family variation due to the QTL since all F1 parents are heterozygous Qq. The QTL parameters a, d, and i can therefore be estimated across families and describe the variability within families caused by segregating QTL in the F2.
Hypothesis Tests
Under the null hypothesis of no linked QTL, there are no phenotypic differences between genotypes and all three QTL parameters have an expectation of zero. With ß' = [a d i], the null hypothesis can be written as [2 1 1]ß = 0. Alternatively, the existence of a linked QTL, regardless of its mode of inheritance, means that at least one element of ß must be different from zero and is tested by the corresponding F value (FQTL). A parent-of-origin effect is observed if the impact of an allele on the phenotype depends on its maternal or paternal transmission or, equivalently, if the Qq and qQ genotypes differ in their mean phenotype. The absence or presence of such an effect can thus be tested by calculating an F value (FIMP) for the null hypothesis [0 0 1]ß = 0.
Special cases of genomic imprinting can be further investigated by exclusion mapping: The complete silencing of one parental allele may be termed "complete imprinting," in contrast to "partial imprinting," where both alleles are active, but differ in the size of their effects depending on their origin. If either the paternal or maternal allele is completely silenced, then the phenotypic mean of the heterozygotes is expected to coincide with the homozygote with the same active allele. When the maternal allele is completely silenced (complete maternal imprinting) and only the paternal allele is expressed, then 
and 
or in terms of the QTL parameters, 2a = i and d = 0. By considering the F value (FPEX) for the null hypothesis
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The opposite situation of complete silencing of the paternal allele (complete paternal imprinting) means that 
and 
that is, 2a = –i and d = 0. A significant F value (FMEX) for the corresponding null hypothesis
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Chromosome-wide and genome-wide significance thresholds were calculated from a permutation test (Churchill and Doerge 1994) with 10,000 permutations for each trait. All four hypothesis tests described above were performed on each permutation. All map positions with test statistics FQTL or FIMP with less than a 5% chromosome-wide error probability are reported as suggestive for a linked QTL or a parent-of-origin effect, respectively. For all these map positions, we also report the test statistics FPEX and FMEX and their corresponding 5% chromosome-wide error probabilities for the exclusion of a complete imprinting of the maternal or paternal allele.
Confidence Intervals
Approximate 1 LOD drop support intervals (Lander and Botstein 1989) were constructed for genome-wide significant QTLs and imprinting effects. For this purpose approximate LOD scores were computed according to Haley and Knott (1992) at each map position as
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Information Content Mapping for Imprinting Effects
In general, the ability to detect QTLs depends on the precision of the probability statements on the QTL genotypes derived from the markers. The ability to distinguish between Qq and qQ heterozygotes is especially essential for the recognition of parent-of-origin effects. As a measure for this ability, a value for the entropy (Kruglyak et al. 1996) was calculated for every F2 animal j with a positive probability to have the genotype of Qq or qQ:
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Results |
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Linkage Maps
The genome-wide scan was performed across 1178 cM, based on 96 informative markers. Map positions and the number of alleles for the 12 additional markers of this study are given in Table 2. For details on all other markers, see the related article by Brockmann et al. (1998). The marker maps of all chromosomes were based on pedigree-specific analyses. The average distance of adjacent loci was 12.3 cM (range 0.8–42.0 cM). For the majority of markers, only two different alleles were found, but 27 markers had three different alleles and one marker had four. The latter situation is optimal for distinguishing between Qq and qQ heterozygotes in the F2 generation and thus is also optimal for an imprinting analysis. Markers with more than two alleles covered 567 cM, that is, 48% of the total genome (30 cM per marker minus overlap). There was at least one marker with more than two alleles in every region where genome-wide significant QTLs for body weight had been found previously in the analysis of Brockmann et al. (1998).
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QTL Detection
Genome-wide significance thresholds are shown in Table 3 for all traits. The number and localization of the detected QTLs (Table 4) were in good agreement with the results presented by Brockmann et al. (1998). All genome-wide highly significant QTLs from the previous study were redetected at genome-wide significance levels. Slight deviations in the size of the F value and the position and effects of detected QTLs result from the inclusion of 12 additional markers into the linkage analysis, which were located close to previously identified QTLs. Slightly different error probabilities from this and the previous study are expected due to different marker maps, different calculation of error probabilities (permutation test instead of simulation), and different models (three instead of two QTL parameters).
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Parent-of-Origin Effects
Significant imprinting effects (Table 4) on the development of liver and spleen were detected on chromosome 11 at 1 cM. The imprinting effect for liver weight was highly significant genome-wide (P < .01; FIMP = 16.6; Figure 2B) and an imprinting effect for spleen weight was genome-wide significant (P < .05; FIMP = 11.3; Figure 2D). Both detected imprinting effects were positive with higher organ weights when the Q allele was paternally inherited. This can be seen from Table 5, which shows estimates for the average phenotypic deviations of all different genotypes from the family mean (–a, d – 0.5i, d + 0.5i, a) computed from the estimates for the QTL parameters. The estimated phenotypic difference between heterozygotes at the imprinted locus at 1 cM on chromosome 11 was 0.24 g for liver weight and 0.026 g for spleen weight (Table 4). The differences between homozygotes (2a) were estimated as 0.126 g and 0.006 g, and the solutions for the dominance effects were –0.014 g and 0.002 g for liver and spleen weights, respectively. The 1 LOD drop interval for the genome-wide significant imprinting effect had a size of 8 cM for liver weight and 10 cM for spleen weight at the centromere region of chromosome 11.
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On chromosome 14, three traits showed a chromosome-wide significant (P < .05) imprinting effect: body weight at 25 cM, liver weight at 23 cM, and kidney weight at 32 cM (Table 4). In all cases, the position was close to the suggestive QTL effect on liver weight at 21 cM and the genome-wide significant QTL for spleen weight at 26 cM on the same chromosome. The signs of the average phenotypic deviations from the family mean for all genotypes consistently showed a maternal imprinting pattern of the Q allele for all three significant imprinting effects on chromosome 14 (Table 5). Moreover, at the genome-wide significant QTL for spleen weight at 26 cM on the same chromosome, the deviations from the family mean were –0.014, –0.011, 0.011, and 0.014 for the genotypes qq, qQ, Qq, and QQ, respectively. Obviously these values also agree fairly well with a maternal imprinting effect, and the test for imprinting close at this QTL at 28 cM (chromosome-wide error probability 0.0642) only slightly failed to be significant.
Suggestive imprinting effects were also found for abdominal fat percentage on chromosome 3 at 5 cM, for spleen weight on chromosome 5 at 48 cM, and for liver weight on the X chromosome at 30 cM. From Table 5, a paternal imprinting effect can be deduced on chromosomes 3 and X, and a maternal imprinting effect on chromosome 5.
Exclusion Mapping of Purely Uniparental Imprinting Effects
A purely uniparental imprinting effect (complete imprinting of an allele) can be distinguished from partial imprinting (incomplete imprinting of an allele) by exclusion mapping of imprinting effects. All exclusion mapping results for map positions with significant QTLs or imprinting effects are summarized in Table 6. In the more distal part of chromosome 11 at the genome-wide highly significant QTLs for body weight, liver weight, and spleen weight (at 58, 69, and 70 cM, respectively), both an exclusively paternal and an exclusively maternal imprinting could be excluded at a genome-wide significance level of P < .01 (Table 6). The FMEX ratio for the exclusion of a purely maternal imprinting was significant over the entire chromosome for the traits body weight (Figure 3A) and liver weight (Figure 2A). However, the pattern of a purely paternal imprinting was not significantly violated for any trait (Figures 2 and 3) in the proximal region of chromosome 11, where the highly significant parent-of-origin effects for liver and spleen weight were found together with a QTL for abdominal fat weight. This is in good agreement with paternal imprinting, which can be deduced for the traits liver weight and spleen weight from the average phenotypic deviations from the family mean of the four QTL genotypes shown in Table 5.
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At the QTL for spleen weight on chromosome 14 at 26 cM, a purely paternal imprinting could be excluded with a genome-wide error probability of 0.0295, and also for liver weight at 21 cM with a chromosome-wide error probability of 0.0177. Exclusion mapping for purely paternal imprinting was not significant for other traits on chromosome 14. For all traits, the exclusion of a purely maternal imprinting was not significant on chromosome 14. Thus the exclusion mapping results were also in good agreement with a maternal imprinting pattern for body weight, liver weight, and kidney weight at the respective map positions of 25, 23, and 32 cM on chromosome 14 (Table 5). On the other three chromosomes (3, 5, and X) with chromosome-wide suggestive imprinting effects, neither kind of exclusion mapping was significant. For four QTLs on chromosomes 11 and 9 (Table 6), the activity of both parental alleles could be proven by highly significant exclusion mapping of both types of complete imprinting.
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Discussion |
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The whole-genome scan for imprinting effects was significant for liver weight and spleen weight on chromosome 11, and, on a suggestive level, for the three traits body weight, liver weight, and kidney weight on chromosome 14. Further suggestive parent-of-origin effects were found on chromosomes 3, 5, and X.
Mapping of imprinting effects requires, ideally, genetic markers with four different alleles labeling the four different parental chromosomes. The information content of genetic markers in our pedigree was very variable from chromosome to chromosome. For example, on chromosome 11 (Figure 2B,D) it increased from approximately 0.4 near the centromere to between 0.7 and 0.8, and was more or less restricted to this level, although the marker density was fairly high on the second half of this chromosome. On chromosome 12, the two founder animals were homozygous for alternative alleles at all three markers. With a single marker, the information content for imprinting would be zero in such a situation, because it would not be possible to distinguish between heterozygous Qq and qQ F2 animals. With the relatively closely linked markers on chromosome 12 (distances 11.7 and 8.7 cM), an information content of 0.15 could be reached, with little variation along the chromosome.
The search for parent-of-origin effects was performed independently from the QTL search, in the sense that locations with a significant FIMP ratio for imprinting were reported, no matter if they were at or near a significant QTL or not. The alternative would be to report only those FIMP values that were calculated at the positions of significant QTLs. This may result, however, in an unnecessary loss of experimental power, and is undesirable, especially if the focus is directed toward the identification of imprinting effects, which may then be subject to subsequent confirmation and perhaps fine mapping.
Usually the maximum F values for imprinting and for a linked QTL were close together on a chromosome (e.g., for liver weight on chromosome 14; Table 4). However, the situation was different on chromosome 11 for the traits liver weight and spleen weight with maximum FQTL values at 69 cM and 70 cM, respectively, and genome-wide significant imprinting effects at 1 cM from the centromere. At the latter location, the FQTL statistics for liver weight were already above the 1% genome-wide significance threshold, while the same quantity for spleen weight was clearly below (Figure 2A,C). The QTL for abdominal fat weight (genome-wide error probability 0.0535) at 10 cM confirms the existence of a second region with impact on phenotypes on proximal chromosome 11.
A look at loci with significant imprinting effects (Table 5) shows that the estimated effects of heterozygous genotypes are, on average, more remote from the family mean than the homozygous genotypes with the same allele expressed; for example, the paternal imprinting effect of chromosome 11 at 1 cM on liver weight: the average deviation from the family mean was –0.134 g for qQ animals compared to –0.063 g for qq progeny and 0.106 g for Qq individuals compared to 0.063 g for homozygous QQ genotypes. There is little doubt that this effect is purely statistical rather than an indication of a kind of overdominant gene action. From simulation studies it is known that QTL effects are on average heavily overestimated, if only significant results are considered (e.g., Georges et al. 1995). In analogy, an upward bias for the difference between the two classes of heterozygotes can be expected at the locations with significant parent-of-origin effect.
Extensive mouse genetic studies have shown that proximal chromosome 11 is subject to genomic imprinting (Beechey et al. 2004). Maternal duplication of this region is associated with a small body size and paternal duplication with a large body size. Clearly, this strongly supports both our finding of imprinting effects on proximal chromosome 11 as well as the paternal imprinting pattern with higher organ weights when the grandparental (Q) allele is paternally derived. So far no imprinted genes with an impact on the growth of inner organs in mice near the centromere of chromosome 11 are known. Potential candidate genes are glucokinase (Gk; 0.7 cM), insulin-like growth factor binding protein 1 (Igfbp1; 1.3 cM), and insulin-like growth factor binding protein 3 (Igfbp3; 1.35 cM). The enzyme glucokinase is a hexokinase that is expressed in pancreatic ß cells and hepatocytes, catalyzing phosphorylation of glucose to glucose-6-phosphate, in the way that hepatocytes respond to insulin level by adjusting glucose uptake and production. Presently there are no hints that the glucokinase gene is imprinted. Targeted mutations that block glucokinase production in liver as well as in pancreatic ß cells cause elevated blood glucose and reduced insulin secretion in heterozygotes, and severe hyperglycemia and early death in homozygote mice. Thus a putative imprinting of the glucokinase gene in mice would potentially affect the amount of insulin production. As a consequence, murine growth development in general and associated growth of the inner organs might be influenced.
Igfbp1 and Igfbp3 are members of a family of binding proteins influencing the activity of insulin-like growth factors (IGFs) (Schuller et al. 1993, 1994). The IGF binding proteins are involved in the regulatory network of the IGF system controlling growth and differentiation. Igf2, as a key gene of the IGF regulatory system, has been shown to be imprinted and to affect muscle mass and fat deposition in pigs (Jeon et al. 1999; Nezer et al. 1999). Changes in organ weights have been reported in Igfbp transgenic mice (Hoeflich et al. 1999; Schneider et al. 2000). Therefore a putative imprinting of the binding proteins in mice might influence the growth-promoting activities of the IGFs and insulin on the development of the murine inner organs—liver and spleen—as observed within our study. Igfbp1 has also been suggested as a candidate gene for Russell-Silver syndrome in humans, a phenotype that shows pre- and postnatal growth retardation and other dysmorphologies (classical facial phenotype and asymmetry) that are caused by maternal uniparental disomy of the proximal human chromosome 7p. The chromosomal region is homologous to the imprinted region on mouse chromosome 11 that harbors the growth-related genes Igfbp1, growth factor receptor bound protein 10 (Grb10), and epidermal growth factor receptor (Egf). However, no influence on the development of human inner organs has been reported for Russell-Silver syndrome.
The observed parent-of-origin effect on mouse chromosome 11 could also be due to a coregulated cluster of imprinted genes rather than a single candidate gene. For example, the Callipyge (CLPG) mutation (homologous to mouse chromosome 12, at 54 cM) responsible for an inherited muscular hypertrophy in sheep has been shown to affect the imprinting effect of four imprinted genes (Charlier et al. 2001). The same mode of inheritance has been found in the pig chromosomal region that is homologous to the CLPG locus in sheep (Kim et al. 2004).
To our knowledge, no imprinting effects on pre- or postnatal growth development have been reported for chromosome 14. Though parent-of-origin effects on chromosome 14 were only significant on a suggestive level, the imprinting pattern was consistently maternal for body weight and the weights of liver, kidney, and spleen. The murine region of chromosome 14, which has been found to be suggestive for imprinting, is a homologue to the human chromosomal segment 14q22-q23. In humans, maternal uniparental disomy of chromosome 14 is associated with a specific pattern of malformation. This effect seems to be mediated by the chromosome segment 14q23-14q24.2 (Martin et al. 1999). Human cytogenetic data may therefore been taken as support of our results, keeping in mind that imprinting is often conserved between species.
Suggestive imprinting effects for a single trait were found on each of the chromosomes 3, 5, and X. These effects may therefore be somewhat more likely to be spurious than those on chromosome 14. Although parental gametic effects on fatness traits have been identified in various investigations in humans, for example, obesity-related phenotypes such as the Prader-Willi syndrome (Nicholls et al. 1992) and in several livestock species, imprinting effects on mouse fatness traits have not been reported so far.
It can be summarized that the identified genome-wide significant parent-of-origin effects on liver weight and spleen weight on chromosome 11 agree well with the known imprinting of this genomic region in the mouse. New, but only suggestive evidence for imprinting has been found on mouse chromosome 14. We conclude from our data the location of an imprinted locus on chromosome 14 with an effect on organometry. Suggestively significant imprinting effects on abdominal fat percentage, spleen weight, and liver weight on chromosomes 3, 5, and X need further clarification and confirmation. The results show that imprinting analyses of similar experiments will help to better understand the importance of parent-of-origin effects for traits such as postnatal growth development in the mouse and, by targeted analysis of homologous chromosome regions underlying the imprinted QTLs, in other mammalian species.
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Acknowledgments |
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This study was supported by the Deutsche Forschungsgemeinschaft (Re 1345/2-1 and Br 1285/4-1).
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Footnotes |
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Corresponding Editor: Christine Kozak
Received April 14, 2004
Accepted December 15, 2004
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References |
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Barton SC, Adams CA, Norris ML, and Surani MAH, 1985. Development of gynogenetic and parthenogenetic inner cell mass and trophectoderm tissues in reconstituted blastocysts in the mouse. J Embryol Exp Morphol 90:267–285.[Web of Science][Medline]
Beechey CV, Cattanach BM, Blake A, and Peters J, 2004. MRC Mammalian Genetics Unit, Harwell, Oxfordshire. Genetic and physical imprinting map of the mouse Available at http://www.mgu.har.mrc.ac.uk/research/imprinting/.
Brockmann GA, Haley CS, Renne U, Knott SA, and Schwerin M, 1998. QTLs affecting body weight and fatness from mouse line selected for extreme high growth. Genetics 150:369–381.
Bünger L, Schüler L, Kupatz B, and Renne U, 1983. Selection for growth in laboratory mice. II. Direct selection response. Arch Tierzucht 26:281–293.
Cattanach BM, 1986. Parental origin effects in mice. J Embryol Exp Morphol (Suppl) 97:137–150.
Cattanach BM, and Beechey CV, 1990. Autosomal and X-chromosome imprinting. Dev Suppl:63–72.
Charlier C, Segers K, Karim L, Shay T, Gyapay G, Cockett N, and Georges M, 2001. The callipyge mutation enhances the expression of coregulated imprinted genes in cis without affecting their imprinting status. Nat Genet 27:367–369.[CrossRef][Web of Science][Medline]
Churchill GA, and Doerge RW, 1994. Empirical threshold values for quantitative trait mapping. Genetics 138:963–971.[Abstract]
de Koning DJ, Rattink AP, Harlizius B, van Arendonk JA, Brascamp EW, and Groenen MA, 2000. Genome-wide scan for body composition in pigs reveals important role of imprinting. Proc Natl Acad Sci USA 97:7947–7950.
de Vries AG, Kerr RJ, Tier B, Long T, and Meuwissen THE, 1994. Gametic imprinting effects on rate and composition of pig growth. Theor Appl Genet 88:1037–1042.
Engellandt T, and Tier B, 2002. Genetic variances due to imprinted genes in cattle. J Anim Breed Genet 119:154–165.[CrossRef]
Falconer DS, and Mackay TFC, 1996. Introduction to quantitative genetics, 4th ed London: Longman.
Fournier C, Goto Y, Ballestar E, Delaval K, Hever AM, Esteller M, and Feil R, 2002. Allele-specific histone lysine methylation marks regulatory regions at imprinted mouse genes. EMBO J 21:6560–6570.[CrossRef][Web of Science][Medline]
Georges M, Charlier C, and Cockett N, 2003. The callipyge locus: evidence for the trans interaction of reciprocally imprinted genes. Trends Genet 19:248–252.[CrossRef][Web of Science][Medline]
Georges M, Nielsen D, Mackinnon M, Mishra A, Okimoto R, Pasquino AT, Sargeant LS, Sorensen A, Steele MR, Zhao X et al., 1995. Mapping quantitative trait loci controlling milk production in dairy cattle by exploiting progeny testing. Genetics 139:907–920.[Abstract]
Green P, Falls K, and Crooks S, 1990. Documentation for CRIMAP, version 2.4 St. Louis: Washington University School of Medicine.
Haley CS, and Knott SA, 1992. A simple regression method for mapping quantitative trait loci in line crosses using flanking markers. Heredity 69:315–324.[Web of Science][Medline]
Hitchins MP, and Moore GE, 2002. Genomic imprinting in fetal growth and development Exp Rev Mol Med 9 May; available at http://www.expertreviews.org/0200457Xh.htm.
Hoeflich A, Wu M, Mohan S, Foll J, Wanke R, Froehlich T, Arnold GJ, Kolb HJ, and Wolf E, 1999. Overexpression of insulin-like growth factor-binding protein-2 in transgenic mice reduces postnatal body weight gain. Endocrinology 140:5488–5496.
Jeon JT, Carlborg O, Tornsten A, Giuffra E, Amarger V, Chardon P, Andersson-Eklund L, Andersson K, Hansson I, Lundstrom K et al., 1999. A paternally expressed QTL affecting skeletal and cardiac muscle mass in pigs maps to the IGF2 locus. Nat Genet 21:157–158.[CrossRef][Web of Science][Medline]
Kim KS, Kim JJ, Dekkers JC, and Rothschild MF, 2004. Polar overdominant inheritance of a DLK1 polymorphism is associated with growth and fatness in pigs. Mamm Genome 15:552–559.[Web of Science][Medline]
Knott SA, Elsen JM, and Haley CS, 1996. Methods for multiple-marker mapping of quantitative trait loci in half-sib populations. Theor Appl Genet 93:71–80.[CrossRef][Web of Science]
Knott SA, Marklund L, Haley CS, Andersson K, Davies W, Ellegren H, Fredholm M, Hansson I, Hoyheim B, Lundstrom K et al., 1998. Multiple marker mapping of quantitative trait loci in a cross between outbred wild boar and large white pigs. Genetics 149:1069–1080.
Kotzot D, Schmitt S, Bernasconi F, Robinson WP, Lurie IW, Ilyina H, Mehes K, Hamel BCJ, Otten BJ, Hergersberg M et al., 1995. Uniparental disomy 7 in Silver-Russell syndrome and primordial growth retardation. Hum Mol Genet 4:583–587.
Kruglyak L, Mark JD, Reeve-Daly MP, and Lander E, 1996. Parametric and non parametric linkage analysis: a unified multipoint approach. Am J Hum Genet 58:1347–1363.[Web of Science][Medline]
Lander ES, and Botstein D, 1989. Mapping Mendelian factors underlying quantitative traits using RFLP linkage maps. Genetics 121:185–199.
Martin RA, Sabol DW, and Rogan PK, 1999. Maternal uniparental disomy of chromosome 14 confined to interstitial segment (14q23–14q24.2). J Med Genet 8:633–636.
McGrath J, and Solter D, 1984. Completion of mouse embryogenesis requires both the maternal and paternal genomes. Cell 37:179–183.[CrossRef][Web of Science][Medline]
Morison IM, Paton CJ, and Cleverley SD, 2001. The imprinted gene and parent-of-origin effect database. Nucleic Acids Res 29:275–276.
Nezer C, Moreau L, Brouwers B, Coppieters W, Detilleux J, Hanset R, Karim L, Kvasz A, Leroy P, and Georges M, 1999. An imprinted QTL with major effect on muscle mass and fat deposition maps to the IGF2 locus in pigs. Nat Genet 21:155–156.[CrossRef][Web of Science][Medline]
Nicholls RD, Knoll JHM, Butler MG, Karami S, and Lalande M, 1989. Genetic imprinting suggested by maternal heterodisomy in non-deletion Prader-Willi syndrome. Nature 342:281–285.[CrossRef][Medline]
Nicholls RD, Richnik EM, and Driscoll DJ, 1992. Genomic imprinting in mammalian development: Prader-Willi and Angelman syndromes as disease models. Semin Dev Biol 3:139–152.
Peters J, and Beechey C, 2004. Identification and characterisation of imprinted genes in the mouse. Brief Funct Genomic Proteomic 2:320–333.
Rainier S, Johnson LA, Dobry CJ, Ping AJ, Grundy PE, and Feinberg AP, 1993. Relaxation of imprinted genes in human cancer. Nature 362:747–749.[CrossRef][Medline]
Rattink AP, de Koning DJ, Faivre M, Harlizius B, van Arendonk JA, and Groenen MA, 2000. Fine mapping and imprinting analysis for fatness trait QTLs in pigs. Mamm Genome 11:656–661.[CrossRef][Web of Science][Medline]
Reik W, Brown KW, Schneid H, Le Bouc Y, Bickmore W, and Maher ER, 1995. Imprinting mutations in the Beckwith-Wiedemann syndrome suggested by an altered imprinting pattern in the IGF2-H19 domain. Hum Mol Genet 4:2379–2385.
Reik W, and Walter J, 2001. Genomic imprinting: parental influence on the genome. Nat Rev Genet 2:21–32.[Web of Science][Medline]
Reinsch N, 1999. A multiple-species, multiple-project database for genotypes at codominant loci. J Anim Breed Genet 116:425–435.[CrossRef]
Schneider MR, Lahm H, Wu M, Hoeflich A, and Wolf E, 2000. Transgenic mouse models for studying the functions of insulin-like growth factor binding proteins. FASEB J 14:629–640.
Schuller AG, Zwarthoff EC, and Drop SL, 1993. Gene expression of the six insulin-like growth factor binding proteins in the mouse conceptus during mid- and late gestation. Endocrinology 132:2544–2550.
Schuller AG, Groffen C, van Neck JW, Zwarthoff EC, and Drop SL, 1994. cDNA cloning and mRNA expression of the six mouse insulin-like growth factor binding proteins. Mol Cell Endocrinol 104:57–66.[CrossRef][Web of Science][Medline]
Schüler L, 1985. Mouse strain Fzt:Du and its use as model in animal breeding research. Arch Tierzucht 28:357–363.
Surani MA, Barton SC, and Norris ML, 1984. Development of reconstituted mouse eggs suggested imprinting of the genome during gametogenesis. Nature 308:548–550.[CrossRef][Medline]
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