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Review
, 94 (5), 649-59

Gene Discovery and the Genetic Basis of Calcium Consumption

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Review

Gene Discovery and the Genetic Basis of Calcium Consumption

Michael G Tordoff. Physiol Behav.

Abstract

This review makes the case that gene discovery is a worthwhile approach to the study of ingestive behavior in general and to calcium appetite in particular. A description of the methods used to discover genes is provided for non-geneticists. Areas covered include the characterization of an appropriate phenotype, the choice of suitable mouse strains, the generation of a hybrid cross, interval mapping, congenic strain production, and candidate gene analysis. The approach is illustrated with an example involving mice of the C57BL/6J and PWK/PhJ strains, which differ in avidity for calcium solutions. The variation between the strains can be attributed to at least seven quantitative trait loci (QTLs). One of these QTLs is most likely accounted for by Tas1r3, which is a gene involved in the detection of sweet and umami tastes. The discovery of a novel function for a gene with no previously known role in calcium consumption illustrates the power of gene discovery methods to uncover novel mechanisms.

Figures

Fig. 1
Fig. 1
Mean ± SE preferences for 75 mM CaCl2 solution of 40 inbred strains of mice (n=0 males and 10 females per group). Note that three strains (JFl/Ms, BTBRT+ tf/J and PWK/PhJ) have preferences that were (a) above indifference (dotted line) and (b) notably higher than the other 37 strains.
Fig. 2
Fig. 2
Preferences of male C57BL/6J and PWK/PhJ mice for various taste solutions. CaLa = calcium lactate, QHCl = quinine hydrochloride, NaLa = sodium lactate, IMP = inosine monophosphate.
Fig. 3
Fig. 3
Representation of the mating scheme used to generate mice for a genome scan. C57BL/6J (B6) and PWK/PhJ (PWK) mice were mated to produce F1 mice and these were mated brother-to-sister to produce 484 F2 mice. Coat color is used to represent any phenotype (in fact, the B6 are black and PWK agouti). On the right is shown pairs of chromosomes from individual mice that are shaded based on parental origin. Note that all mice in the parental and F1 generations are isogenic but F2 mice are essentially random combinations of the B6 and PWK genomes. This is reflected in the phenotype which is expressed to varying degrees depending on whether the F2 mouse has inherited alleles that promote or detract from the phenotype. Interval mapping is used to associate the phenotype with particular locations in the genome.
Fig. 4
Fig. 4
Three-dimensional solution of correlation coefficient matrix based on taste preferences of 484 B6 × PWK F2 mice. Values in each dimension are arbitrary units. The distance between taste solutions gives an idea of common mechanisms. CaCl2, CaLa, and MgCl2 fall close together which is consistent with a common underlying mechanism for calcium-magnesium taste. This cluster is distinct from the mechanisms underlying preferences for saltiness (NaCl), sourness (citric acid), bitterness (QHCl), and sweetness (saccharin). Preferences for NH4Cl and KCl fall between these extremes [redrawn from [95]]A
Fig. 5
Fig. 5
Interval maps based on preferences for CaCl2, CaLa, MgCl2 and saccharin. Horizontal dotted and filled lines shows significance at p<0.05 and p<0.01, respectively. Note that all four traits are linked to distal chromosome 4. (data extracted from Ref. 95)
Fig. 6
Fig. 6
Preference for various concentrations of saccharin, CaCl2, calcium lactate (CaLa), and MgCl2 by 129.B6-Sac congenic mice and their littermate controls. The two types of mice are almost identical except for a 194-kb fragment containing Tas1r3. The congenics have a B6 allele at this locus whereas the controls are homozygous 129. Note that congenic mice more strongly avoid CaCl2, CaLa, and MgCl2 than do controls, which implies that the introgressed genetic fragment is involved in calcium consumption.
Fig. 7
Fig. 7
Mean ±SE preferences of Tas1r3 knockout mice (KO; n = 8) and their littermate controls (WT; n = 8, and Het; n = 15) for four solutions. Note that the KOs prefer some concentrations of CaCl2, CaLa, and MgCl2 more than water. Note also that the KOs dislike high concentrations of saccharin, presumably because its bitter taste component predominates.

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