Mapping and Phenotype information for this QTL,
its variants and associated markers
Analysis of F2 progeny from a cross between female C57BL/6J (aa; BB; CC) and male KK-A (Aa; BB; Cc) mice were used to locate quantitative trait loci associated with obesity/body weight. KK mice are known as a polygenic model for non-insulin-dependent diabetes mellitus with moderate obesity. Significant linkage in a/a (LOD 4.5) and A/a (LOD 3.7) progeny was found with marker D4Mit1 on mouse Chromosome 4. This locus is called Bwq1 by the authors.
95 informative loci were genotyped in a population of 147 (C57BL/6J x KK-A)F2 animals to confirm and characterize 2 previously identified body weight QTLs named Bwq1 and Bwq2. Parental strain KK-A exhibits increased body weight compared to C57BL/6J, and F2 animals carrying the A allele appear to be heavier compared to F2 animals carrying the a allele. Bwq1 maps to proximal mouse Chromosome 4 and reached a peak LOD score of 5.5 for body weight at 50 days of age at D4Mit111 (21.9 cM). The 95% confidence interval of Bwq1 spans approximately 6.3 cM - 32 cM. The nearest flanking markers are D4Mit1 and D4Mit166. Bwq1 also shows significant linkage to body weight at 40 and 60 days and significant linkage to weight gain at 30-40 days. The KK-derived allele appears to confer increased body weight and weight gain at Bwq1. Other previously identified body weight QTLs mapping near Bwq1 are Bglq4 (6.5 cM) and Wta1 (7 cM). Bwq2 maps to proximal mouse Chromosome 6 and reached a peak LOD score of 8.8 for body weight at 70 days of age at D6Mit361 (35.2 cM). The 95% confidence interval of Bwq2 spans approximately 29 cM - 47 cM. The nearest flanking markers are D6Mit123 and D6Mit256. Bwq2 also shows significant linkage to body weight at 40, 50, 60, 80, 90, and100 days, and significant linkage to weight gain at 30-40 days. The KK-derived allele confers increased body weight and weight gain at Bwq2 and appears to interact specifically with the A allele. Two candidate genes for Bwq2 that are expressed in adipose tissue are Pparg (52.7 cM) and Hrh1 (49 cM). Sequence analysis of Pparg and Hrh1 did not reveal any polymorphisms between C57BL/6J and KK-A. Other previously identified body weight QTLs mapping near Bwq2 are Bw18 (35 cM), Obq14 (43.5 cM),Adip2 (46.3 cM), and Bgeq4 (46.3 cM).A suggestive body weight locus mapped to mouse Chromosome 16. This locus is linked to body weight at 40 days (LOD=3.7) and 50 days (LOD=3.3).
Authors used novel data mining tool ExQuest to identify novel candidate genes for existing diabesity QTLs. Next, candidate gene expression in the liver, adipose, and pancreas of diabesity-prone Tally Ho mice and diabesity-resistant C57BL/6J mice was assessed by quantitative PCR analysis. Several potential candidate genes, some with no previous association to diabesity QTLs, were identified. Since QTL intervals may be large and could contain hundreds or thousands of potential candidate genes, this method allows researchers to focus on those with strong potential as well as identify novel candidate genes. Potential candidate genes for Tafat (80 cM) on mouse Chromosome 4 as identified by ExQuest are Ela2, Ela3b, and Dvl1 (82 cM). Chr 10 locus Ela2 exhibits 55-fold decreased expression in the pancreas of Tally Ho animals compared to C57BL/6J. For QTL Bwq1 (6.3 cM), potential candidate gene Decr1 was identified. For QTLs Triglq1 (6.5 cM) and Bglq4 (6.5 cM), potential candidate genes Ttpa, Bhmt(Chr 13), Baat(22.7 cM), and Aldob (22.3 cM) were identified. For QTLs Nidd1 (48 cM) and Dob1 (50 cM), potential candidate genes Lepr (46.7 cM), Dio1 (48.7 cM), Scp2 (52 cM), Faah (56.5 cM), and Usp1 were identified.
Ninety-seven informative loci were genotyped in a population of 147 (C57BL/6J x KK-A)F2 animals of A/a genotype to identify QTLs for glucosuria. A population of a/a F2 animals was also examined. Males from parental strain KK-A exhibit significant susceptibility to glucosuria (80% incidence at 40 days of age) compared to C57BL/6J. Experimental animals were tested for glucosuria at 40-, 50-, and 60-days of age. Significant linkage to glucosuria at 40 days mapped to mid-chromosome 6 (29 cM) near D6Mit123 (LOD=6) in the A F2 population. This locus explains 32% of the phenotypic variance and is named Guq1 (glucosuria QTL 1). KK-derived alleles at Guq1 confer increased glucosuria severity. This locus also shows suggestive linkage to glucosuria at50 days (LOD=2) and glucosuria at 60 days (LOD=2). Guq1 also displays linkage to glucose tolerance in a/a F2 animals. Since the fasting glucose QTL Fglu (16 cM) maps to this region, Guq1 and Fglu may represent the same locus. Potential candidate genes for Guq1 include Pparg (52.7 cM), Hrh1(49 cM), Npy (26 cM), Crhr2 (28 cM), and Gfpt1 (35.5 cM). Previously identified QTLs overlapping with Guq1 include Obq13 (26.8 cM), Nidd3n (35.5 cM), Dbm1, Adip2 (46.3 cM), Obwq3 (42 cM), Tabw2, and Obq14 (43.5 cM).A second locus for glucosuria at 40 days in A F2 mice named Guq2 (glucosuria QTL 2) mapped to 21.5 cM on mouse Chromosome 16 near D16Mit57 (LOD=3.3). This locus explains 20% of the phenotypic variance. C57BL/6J-derived alleles at Guq2 confer increased glucosuria severity. Suggestive linkage to glucosuria at 40 days mapped to mouse Chromosome 4 between D4Mit166 (44.5 cM, LOD=2.3) and D4Mit234 (71 cM, LOD=3.8). Significantlinkage to body weight mapped to mouse Chromosome 16 near D16Mit131 (4.3 cM) and D16Mit136 (28 cM) in the A/a F2 population. This locus is named Bwq10 (body weight QTL 10). The LOD scores for body weight at 40-, 50-, and 60-days of age are 3.6, 3.5, and2.1, respectively. C57BL/6J-derived alleles at Bwq10 confer increased body weight. Bwq10 (95% CI interval = 23 cM - 48 cM) and Guq2 (95% confidence interval = 19 cM - 37 cM) overlap and may represent the same locus. Bwq1 (4.3 cM on chr4) and Bwq2 (35cMon chr6) were also detected in this study. These loci show significant linkage to body weight at all time points in A/a F2 animals. For Bwq1, LOD scores body weight at 40-, 50-, and 60-days of age are 6.1, 5.9, and 5.9, respectively. For Bwq2, LOD scores for body weight at 40-, 50-, and 60-days of age are 5.4, 5.5, and 7.6, respectively.