The Journal of Heredity 2001:92(4)
© 2001 The American Genetic Association 92:355-357
Brief Communication |
Characterization of a Major X-Linked Quantitative Trait Locus Influencing Body Weight of Mice
From the Institute of Cell, Animal, and Population Biology, University of Edinburgh, West Mains Road, Edinburgh EH9 3JT, Scotland, UK.
Address correspondence to Peter D. Keightley at the address above or e-mail: p.keightley@ed.ac.uk
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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Growth rate in mice is an archetypal quantitative trait that has long been studied genetically, physiologically, and metabolically, but its genetic basis is still poorly understood due to its complex inheritance and the influence of environment. We measured differences in 17 growth-related traits between a pair of partially congenic lines that differ for a segment of the X chromosome containing a quantitative trait locus (QTL) that we identified in a genomewide QTL scan. The QTL has a large effect on mean body weight of approximately 20% at all ages, and affects early growth rate to a greater extent than late growth rate. Feed is converted to body mass more efficiently in the high chromosome segment-bearing line than the low line. The weights of various internal organs are affected to a somewhat greater extent by the QTL than body weight. The proportional change in body length is smaller than body weight, but this may be an effect of scale. Body weight at late ages appears to allow the most efficient detection of allelic differences at the QTL, although assignment of genotypic state based on phenotype is never unambiguous.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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The recent availability of genetic analysis resources, such as dense genetic maps of neutral markers, has encouraged the study of the genetics of complex traits in many species. In mice, several quantitative trait loci (QTL) mapping studies have identified loci that are scattered over the genome (Barsh et al. 2000; Pomp 1997), and attention in several cases is now focused on fine mapping of individual QTL. In our laboratory, we have lines of mice ("P6" lines) divergently selected on body weight for more than 50 generations (Bünger and Hill 1999). Reciprocal crossing experiments between high and low lines provided evidence that an X-linked factor accounts for approximately 20% of the selection response (Hastings and Veerkamp 1993). A further analysis by marker-based QTL mapping indicated that a single QTL located between the microsatellite markers DXMit50 and DXMit25 explains almost the entire X-linked effect (Rance et al. 1997b). By backcrossing and selection of marker genotypes, the region containing the high-line QTL "allele" was introgressed into an inbred low selection line background (Rance et al. 1997a). Efforts to refine the position of the QTL by high-resolution mapping indicate that the QTL maps to a short interval of the X chromosome between the microsatellite markers DXMit226 and DXMit68, and that the QTL does not recombine into more than one factor (Liu et al. 2000). However, our knowledge of its phenotypic effects is rather scanty, and is limited to body weight and fatness (Rance et al. 1997b). Here we measure the effects of the QTL on a range of growth-related traits in order to obtain information on the mode of action of the QTL that may be important for identification of the causal genetic factor.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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To study the effects of the QTL we used a partially congenic high line (H) containing alleles at DXMit50 and DXMit25. This line originates from a backcross family containing segment 4 in Table 4 of Rance et al. (1997a) that was derived by backcrossing the high selection line (P6 high) for five generations onto a partially inbred line (L) at generation 12 of full-sib mating, derived from the P6 low line, while selecting for high-line DXMit50 and DXMit25 alleles. One further generation of backcrossing to L was then carried out, and males and females intercrossed to produce homozygotes for the QTL-bearing segment. Apart from the segment containing DXMit50 and DXMit25, the H line is expected to contain about 1.5% of the P6 high genome. To investigate if specific growth traits are affected to a greater or less extent by the QTL, we compared phenotypes of homozygotes from the congenic line and line L. Twelve matings were set up in each background, and each was maintained for up to three parities. Offspring were weaned at 21 days, then randomly housed in single-sex cages with up to 10 animals each. Animals were fed ad libitum with a standard expanded diet (Rat and Mouse no. 3, Special Diet Services, Witham, Essex, UK), containing digestible crude oil, 3.9%; crude protein, 20.9%; starch, 27.3%; sugars, 11.2%; digestible energy, 12.1 MJ/kg; access to unlimited water for drinking; and maintained with controlled lighting (12 h light) at a temperature of 21°C ± 1°C. Mating cages were checked daily around the expected birth day, and litter size and body weight of individual pups recorded. Body weight was also recorded every other day from birth to weaning, then weekly from 3 to 6 weeks, and at 10 weeks. Body length from the tip of the nose to the anus, and total body length from the tip of nose to the end of tail were recorded at 3, 6, and 10 weeks by measuring fully anesthetized mice stretched supine on a ruler. Tail length is total body length minus body length. At 5 weeks of age, individuals selected randomly from each family were caged in single-sex pairs, and food intake recorded weekly from 6 to 10 weeks. All of the animals were killed and dissected at 10 weeks of age. The weights of the heart, kidney, liver, spleen, and empty carcass (all of organs removed from body cavity) were recorded.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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The body weights of the H mice were significantly higher than those of the L mice (P < .05) from birth to 10 weeks of age in both sexes (Table 1). The percentage increases in body weight associated with the high-line segment are 17.2, 16.9, 8.4, and 19.5 in females, and 27.4, 24.0, 15.5, and 18.4 in males at birth, 3, 6, and 10 weeks of age, respectively (Figure 1). The effect of the QTL at different ages is therefore similar to what we saw previously (Rance et al. 1997a,b). Dragani et al. (1995) mapped an X-linked body weight QTL, Bw3, in a cross between ASB and HSB mice, which is very close to the Dob7 locus, a QTL affecting adiposity and body weight (York et al. 1997). However, both of these QTLs map far away from the QTL in this study. Another QTL, Bw1, which maps close to DXMit48 on the X chromosome (Dragani et al. 1995), is at a similar location to the present QTL; whether they are alleles at the same loci remains to be investigated.
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Mirroring the differences in body weight, the growth rates of H mice are significantly higher than those of L mice from birth to 3 weeks (Table 1). After 3 weeks of age the growth rate increases in both lines and sexes, and the difference between H males and L males remains significant (P < .05), but the difference between H and L females is nonsignificant. After 6 weeks of age the growth rate declines. It is still higher in H mice than L mice, but the differences are nonsignificant (Figure 1). There are significant sex x line interactions for body weight at 3 weeks (P < .05) and 6 weeks (P < .01), and tail length at 3 weeks (P < .05), reflecting somewhat higher proportional differences in males between the high and low lines (Figure 1). Overall, our results indicate that the X-linked QTL mainly affects early growth from birth to 3 weeks. Several studies have also shown evidence for largely separate genetic and physiological systems for early (1–3 weeks) and later (6–10 weeks) murine growth (Cheverud et al. 1996; Falconer et al. 1978; Vaughn et al. 1999).
Tail and body lengths are significantly higher in the H line at all ages (Table 1), although the percentage increases are substantially lower than for body weight or growth rate (Figure 1). A smaller effect on body length than body weight implies that the QTL is also effects body "width" and "height"; the higher effect on body weight presumably reflects the simultaneous effect in all three dimensions. Lembertas et al. (1996) reported an X-linked locus, Bdln 1, affecting body length in mice, which was mapped to the interval between DXMit73 and the farnesyl pyrophosphate locus (Fpsl 9). This locus is very close to the present QTL. It is therefore possible that these are alleles at the same loci, though the two loci are unlikely to originate from a common ancestor, since the X-linked QTL in the Lembertas et al. (1996) study was derived from an interspecific backcross [(C57BL/6J x Mus spretus)F1 x C57BL/6J], while the X-linked QTL in this study was discovered from a outbred base [(JU x CBA)F1 x CFLP].
The QTL also has significant effects on all of the organ weights at 10 weeks, except for spleen weight in females (Table 1). The percentage increase is generally higher in females than in males (Figure 1). Empty carcass weight mainly reflects features of skeletal muscles and bones because the QTL effects on growth are not accompanied by changes in fatness (Rance et al. 1997b). Taken together, the data suggest that the QTL has somewhat greater effects on organ weights that body weight (or organ weights as a fraction of body weight), although the organ weight measures are subject to greater noise. Total food intake and daily food intake in H mice are significantly higher than those in L mice in both sexes (P < .05). In terms of feeding efficiency, food intake per gram gain implies higher energy consumption per gram gain in L mice than in H mice, but the differences are nonsignificant (P > .05) (Table 1, Figure 1).
In summary, H mice have higher body weight, organ weight, and food intake, and longer body size and tail length than L mice. Although the QTL can be detected through its effects on several traits, the data suggest that body weight at 10 weeks is close to the optimal single trait for testing the QTL effect: it is easy to measure and subject to low environmental variance. All of the traits affected by the QTL are controlled by highly complex processes. The most promising approach to further the understanding of the QTL would seem to be identification of the underlying locus.
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Acknowledgments |
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We thank Fiona Oliver for help in measuring some traits, and Andy Peters for advising us on the data analysis. This work was funded by a grant from the UK Medical Research Council.
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Footnotes |
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Corresponding Editor: Leif Andersson
Received August 12, 2000
Accepted January 15, 2001
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References |
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