Mobq1^C57BL/6J
QTL Variant Detail

Summary

• QTL variant: Mobq1^C57BL/6J
• Name: multigenic obesity QTL 1; C57BL/6J
• MGI ID: MGI:2156885
• QTL: Mobq1 Location: Chr7:122250663-122250811 bp Genetic Position: Chr7, cM position of peak correlated region/allele: 66.7 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: C57BL/6J

Variant description

• Allele Type: QTL
• Inheritance: Not Specified

Expression

In Structures Affected by this Mutation:

3 anatomical structure(s)

Notes

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

J:14189

Using MAPMAKER/QTL, mice from a backcross involving (C57BL/6J x M. spretus)F1 x C57BL/6J were analyzed to identify quantitative trait loci that effect obesity. A locus for multigenetic obesity (Mob1) mapped on distal mouse Chromosome 7 and exhibited a peak LOD score of 3.8 with D7Ucla1.

J:24238

Mob1 and Mob2, two previously identified QTLs affecting obesity on mouse Chromosome 7 and mouse Chromosome 6, respectively, were confirmed in a (C57BL/6J x M. spretus)F1 x C57BL/6J backcross population. Interestingly, parental strains C57BL/6J and M. spretus are both lean.

In the present study Mob1 gave a LOD score of 4.6 at D7Mit8 in association with percent body water, and is significantly linked to hepatic lipase activity (LOD = 5.1). Mob1 also showed linkage to total plasma cholesterol (LOD = 4.4), body mass index (LOD = 2.9), body weight (LOD = 2.9), and HDL cholesterol level (LOD = 3.1). Animals heterozygous at Mob1 exhibit 25% increase in body fat compared to animals homozygous for C57BL/6J-derived alleles at Mob1. Congenic strains B10.129(5M)/nSN andB10.C(41N)/Sn carry 129/J-derived and BALB/cJ-derived alleles at Mob1, respectively, on a C57BL/10SnJ background. Animals from both congenic lines exhibit decreased fat pad weight, body weight, and plasma cholesterol compared to C57BL/10SnJ. B10.129(5M)/nSN also exhibits decrease in hepatic lipase activity. Possible candidate genes in the region of Mob1 are Snrpn, Tub, Ath3, Igf1r, Ins2 and Sult1a1.

Mob2 gave a peak LOD score of 4.8 at D6Mit1 in association with femoral fat pad weight. Mob2 also showed linkage to total plasma cholesterol (LOD = 3.4) and percent body water (LOD=3.2). Animals heterozygous at Mob2 exhibit a 2-fold increase in femoral fat pad weight compared to animals homozygous for C57BL/6J-derived alleles at Mob2. A possible candidate gene for Mob2 is Lep (ob).

Two novel QTLs, Mob3 and Mob4, mapped to mouse Chromosome 12 and mouse Chromosome 15, respectively. Mob3 is associated with percent body fat with a LOD score of 4.8 at D12Mit27 on mouse Chromosome 12. Heterozygosity atMob3 results in 44% increase in body fat compared to animals homozygous for C57BL/6J-derived alleles at Mob3. A possible candidate gene for Mob3 is Tshr. Mob4 is associated with mesenteric fat pad weight with a LOD score of 3.4 at D15Mit13 on mouse Chromosome 15. Animals heterozygous at Mob4 exhibit 32% decrease in mesenteric fat pad weight compared to animals homozygous for C57BL/6J-derived alleles at Mob4. A possible candidate gene for Mob4 is Ghr. Mob1, Mob2, Mob3, and Mob4 do not appear to interact.

J:88297

Three different BSB crosses were used to map obesity QTLs and assess the role of Lipc as an obesity gene.

Cross 1: (C57BL/6J-Lipc^-/- x SPRET/Ei)F1 x C57BL/6J-Lipc^-/-

Cross 2: (C57BL/6J-Lipc^-/- x SPRET/Ei)F1 x C57BL/6J

Cross 3: (C57BL/6J x SPRET/Ei)F1 x C57BL/6J-Lipc^-/-

(Note: The C57BL/6J-Lipc^-/- strain carries 129P2/OlaHsd-derive DNA around the region of Lipc.)

In Cross 1, significant linkage to total cholesterol was detected on mouse Chromosome 9 between Lipc (39 cM) and D9Mit8 (42 cM). InCross 2, significant linkage to hepatic lipase activity, total cholesterol, and percent body fat was detected on mouse Chromosome 9 between Lipc (39 cM) and D9Mit8 (42 cM). In Cross 3, significant linkage was detected on mouse Chromosome 9 between D9Mit104 (35 cM) and D9Mit8 (42 cM). Animals with the Lipc^C57BL/6J/- genotype are considerably lean whereas animals with the Lipc^SPRET/Ei/- genotype are the fattest. Animals with the Lipc^SPRET/Ei/- genotype also exhibit a 25% increase in fasting triglycerides compared to Lipc^C57BL/6J/- animals.

Sequence analysis of Lipc revealed 7 polymorphisms between C57BL/6J and SPRET/Ei, 4 of which result in amino acid substitutions. SPRET/Ei also exhibits a 1.8-fold increase in Lipc mRNA expression compared to C57BL/6J.

Previously identified QTL Mob1 (62 cM on mouse Chromosome 7 near D7Mit8) was detected with significant linkage to percent body fat in Cross 2 and Cross 3. The SPRET/Ei-derived allele confers increased body fat percentage compared to animals homozygous for C57BL/6J-derived alleles. The SPRET/Ei allele at Mob1 also confers increased body length, hepatic lipase activity, food intake, total cholesterol levels, and reduced rectal temperature.

Together, Lipc and Mob1 account for 17% and 27% of the variance in percent body fat in Cross 2 and Cross 3, respectively.

References

• Original: J:14189 Warden CH, et al., Coincidence of genetic loci for plasma cholesterol levels and obesity in a multifactorial mouse model. J Clin Invest. 1993 Aug;92(2):773-9
• All: 3 reference(s)