Kcal2^CAST/EiJ
QTL Variant Detail

Summary

• QTL variant: Kcal2^CAST/EiJ
• Name: kilocalorie 2; CAST/EiJ
• MGI ID: MGI:2449301
• QTL: Kcal2 Location: Chr17:26401012-52911704 bp Genetic Position: Chr17, Syntenic

Variant origin

• Strain of Specimen: CAST/EiJ

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers increased calorie intake over a 10 day period compared to C57BL/6J. (J:81234)

Notes

Candidate Genes

J:117468

Previously identified QTLs Mnic1 (macronutrient intake, carbohydrate 1) and Kcal2 (kilocalorie 2) at 20 cM on mouse Chromosome 17 were confirmed by analysis of speed congenic lines. B6.CAST- (D17Mit19-D17Mit91) carries a 38 cM region of CAST/EiJ-derived DNA from D17Mit19 (3 cM; 4.7 Mb) to D17Mit91 (37.8 cM; 63.5 Mb) on a C57BL/6J genetic background. The congenic interval contains Mnic1 and Kcal2. Donor strain CAST/EiJ displays significantly higher total daily caloric intake compared to background strain C57BL/6J. Likewise, congenic line B6.CAST-(D17Mit19-D17Mit91) displays 17% higher total calorie intake compared to C57BL/6J and prefers a carbohydrate diet (27% increase) over a fat diet.

Glp1r at 18 cM is a positional candidate gene for Kcal2. Glp1r exhibits decreased expression in the hypothalamus and antral stomach, and increased expression in the pancreas, of CAST/EiJ mice compared to C57BL/6J mice. In B6.CAST- (D17Mit19-D17Mit91) mice, Glp1r expression is increased in the pancreas and decreased in the stomach compared to C57BL/6J mice. Sequence analysis of Glp1r revealed 3 polymorphisms between CAST/EiJ and C57BL/6J, one of which results in an amino acid substitution in exon 13 (C416Y). Glo1 at 16 cM is a positional candidate gene for Mnic1. Glo1 exhibits increased expression in liver and hypothalamus of congenic mice compared to C57BL/6J. Sequence analysis of Glo1 detected one silent polymorphism between CAST/EiJ and C57BL/6J. Other potential candidate genes mapping to the congenic interval include Clps (13.1 cM), Ppard (13.5 cM), and Apom.

Mapping and Phenotype information for this QTL, its variants and associated markers

J:81234

502 animals from an F2 cross between C57BL/6J and CAST/EiJ were typed for 98 polymorphic markers at an average spacing of 20 cM to identify QTLs associated with diet preference and calorie intake. Parental strain C57BL/6J exhibits a greater fat/protein (F/P) diet preference and F/P kilocalorie intake compared to CAST/EiJ, and parental strain CAST/EiJ exhibits a greater carbohydrate/fat (C/P) intake preference compared to C57BL/6J. F1 hybrid animals exhibit intermediate F/P preference but greater total calorie intake compared to both parental strains.

Three fat intake QTLs mapped to mouse Chromosomes 8 (Mnif1), 18 (Mnif2), and X (Mnif3). The Mnif1 QTL range spans 12 cM - 35 cM on mouse Chromosome 18 with peak linkage to F/P kcal intake (LOD=8) between D8Mit24 (18 cM) and D8Mit5 (25 cM). Mnif1 contributes 7% of the total variance for fat intake with C57BL/6J-derived alleles conferring increased F/P kcal intake and F/P preference at this locus. Mnif2 maps to a broad region from10 cM- 40 cM on mouse Chromosome 18. Mnif2 gives peak linkage (LOD=6) to F/P kcal intake near D18Mit10 (26 cM) and contributes 4.8% of the total variance. CAST/EiJ-derived alleles confer increased F/P kcal intake and F/P preference at this locus. Mnif3 maps toa broad interval spanning 15cM - 60cM on mouse Chromosome X with a maximum LOD=4 for F/P kcal intake at approximately 18 cM. The authors hypothesize that Mnif3 may contain 2 or more separate loci. C57BL/6J-derived alleles confer increased F/P kcal intakeand F/P preference at Mnif3. This locus also shows strong linkage to baseline body weight (LOD=12.1) from 12 cM - 26 cM. Mnif3 contributes to 4.6% of the phenotypic variance.

Three carbohydrate intake QTLs mapped to mouse Chromosomes 17 (Mnic1), 6 (Mnifc), and X (Mnic3). CAST/Ei-derived alleles confer increased carbohydrate intake at all 3 Mnic loci. The Mnic1 QTL interval spans 7 cM - 23 cM on mouse Chromosome 17 with a peak LOD=6.7 for C/P kcal intake between D17Mit100 (11.75 cM) and D17Mit16 (17.4 cM).Mnic1 contributes 5.4%of the phenotypic variance. A possible candidate gene for Mnic1 is Clps, but sequence analysis of RT-PCR products revealed 2 silent polymorphismsand no other sequence changes. Mnic2 gives maximum linkage to C/P kcal intake on mouse Chromosome 6 with LOD=3.5 between D6Mit29 (36.5 cM) and D6Mit11 (49.4 cM) and contributes 3.7% of the phenotypic variance. Mnic3 spans a broad QTL range on mouse Chromosome X from approximately 15 cM - 60 cM with a maximum LOD=4 in linkage with C/P kcalintake at approximately 40cM. Mnic3 only appears when body weight is used as a covariate and contributes 3.7% of the phenotypic variance.

Two QTLs linked to total calorie intake mapped to mouse Chromosomes 18 (Kcal1), 17 (Kcal2), and 2 (Kcal3). CAST/Ei-derived alleles confer increased total kcal intake over 10 days at Kcal1 and Kcal2. Kcal1 spans 10 cM - 26 cM on mouse Chromosome 18 with peak linkage (LOD=7.7) at approximately 20 cM. Kcal1 contributes 4.6% of the phenotypic variance and maps near Mnif2 butappears to act as a separate QTL. Kcal2 spans8 cM - 37 cM on mouse Chromosome 17 between D17Mit100 and D17Mit6 with peak linkage (LOD=4.9) at approximately 20 cM. Kcal2 contributes 4.4% of the phenotypic variance and maps near Mnic1 but appears to act as a separate QTL. When Kcal2 is absent, a third QTL, Kcal3 can be detectedon mouse Chromosome 2 from 74 cM - 92 cM with peak linkage to baseline body weight (LOD=7.8) at 82cM. Kcal3 contributes 3.5% of the phenotypic variance. C57BL/6J-derived alleles confer increased total kcal intake over 10 days at this locus.

References

• Original: J:81234 Smith Richards BK, et al., QTL analysis of self-selected macronutrient diet intake: fat, carbohydrate, and total kilocalories. Physiol Genomics. 2002 Dec 3;11(3):205-17
• All: 2 reference(s)