Plbcq6^M16i
QTL Variant Detail

Summary

• QTL variant: Plbcq6^M16i
• Name: pleiotropic body composition QTL 6; M16i
• MGI ID: MGI:3784288
• QTL: Plbcq6 Location: unknown Genetic Position: Chr9, Syntenic

Variant origin

• Strain of Specimen: M16i

Variant description

• Allele Type: QTL
• Mutation: Undefined
• Mutation details: This allele confers increased body weight (at 6, 9 weeks and sacrifice) compared to FVB/NJ. This allele confers decreased liver percent weight compared to FVB/NJ. This allele also confers increased axillary tumor weight and mammary tumor count (high-fat diet group) in males compared to FVB/NJ. (J:132804, J:136011)

Expression

In Structures Affected by this Mutation:

3 anatomical structure(s)

Notes

Body weight at 9-weeks and sacrifice appears to be differentially affected by sex and significant only on the control (10% fat) diet.

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

J:132804

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.

J:136011

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 and metastasis. At 4 weeks of age male and female F2 animals were randomly assigned to ahigh-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 via palpation three times a week. Pulmonary metastasis was also phenotyped. Animals on the high-fat diet displayed earlier mammary tumor onset and higher metastatic index compared to animals on the low-fat diet. Several novel mammary tumor metastasis loci were detected. Only one locus on chromosome 9 was also identified in a previous analysis using the same animals for diet and body composition interactions.

Significant linkage to mammary tumor onset (LOD=4.62), tumor metastasis in females (LOD=3.78), and tumor count inmales on high-fat diet (LOD=3.53) mapped to a broad region on mouse Chromosome 1. This locus is named Pldmq1 (pleiotropic diet and mammary tumor QTL 1). Linkage to tumor onset in males and the pooled population and metatstasis in females mapped to approximately 10 cM while tumor count and tumor onset in females mapped to 68 cM. The Pldmq1 locus spans 4 cM to 93 cM. For phenotypes pertaining to tumor onset in the pooled population and metastasis in females a difference was observed between high- and low-fat diets. Pldmq1 explains 10.4% of the tumor onset variance. FVB/NJ-derived alleles at Pldmq1 confer increased pulmonary tumor metastases and mammary tumor onset in females and increased mammary tumor count in males. This allele also confers decreased timeof tumor onset in males and the pooled population.

Linkage to inguinal tumor weight in females mapped to 39.5 cM on mouse Chromosome 5 with LOD=3.86. This locus is named Dmq1 (diet and mammary tumor QTL 1). The QTL confidence interval spans 24.5 cM to85.5 cM. FBV/NJ-derived alleles at Dmq1 confer increased inguinal tumor weight in females.

Linkage to mammary tumor onset in females mapped to 42 cM on mouse Chromosome 7 with LOD=3.82. The confidence interval spans 17 cM to 46 cM and the locus is namedDmq2 (diet and mammary tumor QTL 2). FVB/NJ-derived alleles confer decreased time to mammary tumor onset in females.

A pleiotropic locus exhibiting linkage to average metastasis number (LOD=3.29), average metastasis density (LOD=2.89) and number of metastases (LOD=3.74) infemales mapped to approximately 31 cM on mouse Chromosome 8. This locus also displays linkage to mammary tumor onset (LOD=31.7) in the pooled population and is named Pldmq2 (pleiotropic diet and mammary tumor QTL 2). The Pldmq2 QTL confidence interval spans 2 cM to 74 cM. M16i-derived alleles at Pldmq2 confer increased number of pulmonary metastases in females while FVB/NJ-derived alleles confer increased average metastasis number and density.

Plbcq6 (pleiotropic body composition QTL6) maps to 47 cM on mouse Chromosome 9 and was identified in a previous analysis for body composition using the same cross (MGI reference number J:132804). In the current analysis Plbcq6 displays significant linkage to mammary tumor onset in females on ahigh-fat diet (LOD=3), mammary tumor onset in the pooled population (LOD=4.86), axillary tumor weight in males (LOD=2.36) and tumor count in males on a high-fat diet (LOD=3.53). Peak linkage in this study occurs at 56 cM and the QTL interval spans 4 cM to 69 cM. Plbcq6 explains 10.9% of the tumor onset variance. M16i-derived alleles at Plbcq6 confer increased axillary tumor weight and tumor count in males. FVB/NJ-derived alleles at Plbcq6 confer increased tumor time of onset in females and the pooled population. Plbcq6 colocalizes with mammary tumor QTL Apmt2 (55 cM).

Linkage to number of pulmonary metastases in females mapped to 14 cM on mouse Chromosome 11 (LOD=3.17). This locus is named Dmq3 (diet and mammary tumor QTL 3). The phenotypic effects of Dmq3 show differences between the high- and low-fat diets. The Dmq3 QTL interval spans 5 cM to 73 cM. M16i-derived alleles at Dmq3 confer increased number of pulmonary metastases in females.

An interval on mouse Chromosome 13 between 3 cM and 61 cM exhibits linkage to average metastatic density (LOD=3.09), average metastatic number (LOD=3.49) and mammary tumor onset (LOD=2.94) in females. Peak linkage occurs at approximately 13 cM and this locus is named Pldmq3 (pleiotropic diet and mammary tumor QTL 3).The phenotypes for average metastatic density and number are observed in only the high-fat diet group. FVB/NJ-derived alleles at Pldmq3 confer increased average metastatic number and density in females and decreased tumor time of onset in females.

Pldmq4 (pleiotropic diet and mammary tumor QTL 4) maps to an interval on mouse Chromosome 14 between 7 cM and 57 cM. This locus is associated with axillary tumor weight in males on the low-fat diet (LOD=3.2), onset of mammary tumors in females on the low-fat diet (LOD=3.07) and tumor count (LOD=LOD=2.8) in females. A difference was observed for mammary tumor count phenotype in females between the high- and low-fat diets. Peak linkage occurs around 40 cM. FVB/NJ-derived alleles at Pldmq4 confer increased axillary tumor weight in males and tumor time of onset infemales. This allele also confers decreased mammary tumor count in females.

Linkage to axillary tumor weight in females (LOD=2.63) and mammary tumor onset in males on a low-fat diet (LOD=2.87) mapped to approximately 42 cM on mouse Chromosome 17. This locus is named Pldmq5 (pleiotropic diet and mammary tumor QTL 5). The Pldmq5 confidence interval spans 8 cM to 54 cM. FVB/NJ-derived alleles at Pldmq5 confer increased axillary tumor weight in females and decreased tumor time of onset in males.

Dmq4 (dietand mammary tumor QTL 4) maps to 15.5 cM on mouse Chromosome 19 and shows linkage to number of pulmonary metastases in females on a high-fat diet (LOD=4.21). The confidence interval for this locus spans 7.5 cM to40.5 cM. FVB/NJ-derived alleles at Dmq4 confer increased pulmonary metastases in females. Previously identified metastasis suppressor QTL Mtes1 (4 cM) colocalizes with Dmq4.

References

• Original: J:132804 Gordon RR, et al., Genotype x diet interactions in mice predisposed to mammary cancer. I. Body weight and fat. Mamm Genome. 2008 Mar;19(3):163-78
• All: 2 reference(s)