Experiment
Linkage analysis was performed on 615 (M16i x FVB/NJ-TgN(MMTV-PyVT)634Mul)F2 animals to identify QTLs associated with obesity, diet, and mammary tumor susceptibility. At 4 weeks of age F2 animals were randomly assigned to a high-fat (45% fat) diet or normal (10% fat) diet. Body weight was measured at 3, 6, 9 weeks of age and at sacrifice. Onset of mammary tumor development was phenotyped for F2 animals hemizygous for the transgene starting at 4 weeks of age. A panel of 124 SNPs at a resolution of 10 cM -15 cM was used for the genome scan.
Significant linkage to lean body mass at 7-weeks of age (LOD=14.02), liver weight at sacrifice (LOD=7.55), 3-week weight (LOD=4.23), 6-week weight (LOD=9.23), 9-week weight (LOD=12.38), sacrifice weight (LOD=13.55), and lean body mass at sacrifice (LOD=4.99) mapped to approximately 57 cM on mouse Chromosome 2. Linkage to lean body mass at sacrifice and 9-week body weight appears to be affected by diet, while 7-week lean body mass appears significant only on the controldiet. The QTL interval spans approximately 45 cM and 70 cM. This locus is named Plbcq1 (pleiotropic body composition QTL 1). M16i-derived alleles at Pbcq1 confer increased body composition values.
A second locus on chromosome 2 named Plbcq2 (pleiotropicbody composition QTL 2) shows linkage to fat pad percentage (LOD=2.61), fat pad weight at sacrifice (LOD=5.01), body fat percentage at sacrifice (LOD=4.97), and percent fat at 7-weeks of age (LOD=6.88). Linkage to fat weight at sacrifice appears significant in females only. This QTL is located at approximately 73 cM and the QTL interval spans approximately 60 cM - 80 cM. M16i-derived alleles at Plbcq2 confer increased raw sacrifice fat pad weight and percent fat at 7-weeks, and confers decreased percentbody fat, sacrifice fat weight, and percent fat at sacrifice.
Plbcq3 (pleiotropic body composition QTL 3) mapped to 44 cM on mouse Chromosome 6. This locus is linked to 6-week body weight (LOD=6.72), 9-week body weight (LOD=5.88), lean body mass at 7 weeks(LOD=5), and weight at sacrifice (LOD=4.01). Linkage to lean body mass and body weight at 9-weeks and sacrifice appears to be differentially affected by diet, while 6-week body weight appears to be affected by sex. The QTL interval spans approximately30cM - 65 cM. M16i-derived alleles at Plbcq3 confer increased body composition values.
Linkage to 3-week body weight mapped to 50 cM on mouse Chromosome 8 (LOD=4.24) This locus is named Plbcq4 (pleiotropic body composition QTL 4). M16i-derived alleles at Plbcq4 confer increased body weight at 3 weeks of age. The QTL interval spans 21 cM - 59 cM.
Plbcq5 (pleiotropic body composition QTL 5) mapped to 21 cM on mouse Chromosome 9. This QTL is linked to percent fat at 7-weeks of age (LOD=8.02), fat weight atsacrifice (LOD=5.44), and percent fat at sacrifice (LOD=4.5). Percent fat at sacrifice appears to be a female-specific trait, and percent fat at 7-weeks and sacrifice appears to be significant only on the control diet. M16i-derived alleles at Plbcq5 conferdecreased sacrifice fat weight and percent fat, and increased 7-week percent fat. The QTL interval spans approximately 10 cM - 50 cM.
A second locus on mouse Chromosome 9 named Plbcq6 (pleiotropic body composition QTL 6) mapped to 47 cM. This locus is linked to 6-week body weight (LOD=5.1), 9-week body weight (LOD=6.81), body weight at sacrifice (LOD=6.08), and liver percent weight (LOD=7.34). Linkage to body weight at 9-weeks and at sacrifice appears to be differentially affected by sex and significant only on the control diet. The Plbcq6 interval spans approximately 21 cM - 54 cM. M16i-derived alleles at Plbcq6 confer decreased liver percent weight and increased body weight at sacrifice and at 6- and 9-weeks of age.
Significant linkage to lean body mass at sacrifice (LMS=4.34), body weight at 6- and 9-weeks (LOD=6.37 and 6.4, respectively), body weight at sacrifice (LOD=5.4), liver weight (LOD=5.76) and lean body mass at 7-weeks (LOD=5.06) mapped to 30 cM on mouse Chromosome 10. This locus is named Plbcq7 (pleiotropic body composition QTL 7). M16i-derived alleles at Plbcq7 confer increased body composition trait values. Linkage to lean mass at 7-weeks appears to be affected only by the control diet. Linkage to 9-week body weight appears to be differentially affected by the high-fat or control-diet. The Plbcq7 QTL interval spans approximately 15 cM - 55 cM.
Plbcq8 (pleiotropic body composition QTL 8) maps to 35 cM on mouse Chromosome 11 and is linked to lean body mass at 7-weeks (LOD=5.87) and sacrifice (LOD=3.77), body weight at 6-weeks (LOD=8.41), 9-weeks (LOD=6.25) and sacrifice (LOD=6.1), and percent fat at 7-weeks (LOD=4.37). M16i-derived alleles at Plbcq8 confer increased body composition trait values. Linkage to percent fat and 9-week bodyweight appears to only be affected by the control diet. The QTL interval spans approximately 23 cM - 53 cM.
Significant linkage to 6-week body weight mapped to 0 cM on mouse Chromosome 13 (LOD=3.74). This locus is named Plbcq9 (pleiotropic body composition QTL 9). M16i-derived alleles at Plbcq9 confer increased body weight at 6-weeks of age. The QTL interval spans 0 cM - 61 cM. This QTL appears to have a significant effect only on a high fat diet.
Author did not identify any QTLs associated with the mammary tumor-enhancing transgene TgN(MMTV-PyVT)634Mul and or interaction of the transgene with body composition or dietary factors.
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