Igf1sl2^C57BL/6J
QTL Variant Detail

Summary

• QTL variant: Igf1sl2^C57BL/6J
• Name: IGF-1 serum levels 2; C57BL/6J
• MGI ID: MGI:3046883
• QTL: Igf1sl2 Location: Chr10:87694127-99936278 bp Genetic Position: Chr10, cM position of peak correlated region/allele: 47.06 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

Expression

In Structures Affected by this Mutation:

1 anatomical structure(s)

Notes

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

J:66640

Phenotypically extreme female animals from a (C57BL/6J x C3H/HeJ)F2 intercross were genotyped at 114 polymorphic loci at a resolution of 14 cM to identify QTLs associated with serum IGF-1 levels and bone mineral density (BMD). Parental strain C3H/HeJ exhibits increased serum IGF-1 and increased BMD compared to C57BL/6J. Since osteoblasts from C3H/HeJ animals secrete more IGF-1 compared to osteoblasts from C57BL/6J animals a correlation between IGF-1 levels and BMD was investigated. 682 F2 female animals were used in the final analysis.

Significant linkage mapped to 51 cM on mouse Chromosome 6 near D6Mit150 (LOD=9). This locus in named Igf1sl1 (IGF-1 serum level 1). C3H/HeJ-derived alleles confer decreased serum IGF-1 at this locus. A correlation betweenserum IGF-1 levels and BMD was observed for Igf1sl1.

Igf1sl2 mapped to 51 cM on mouse Chromosome 10 near D10Mit95 (LOD=4.5). C3H/HeJ-derived alleles confer increased serum IGF-1 at this locus. Correlation between serum IGF-1 levels and BMD was not observed for Igf1sl2. The Igf1 (48 cM) gene maps very close to this locus, just 3 cM proximal to Igf1sl2.

Igf1sl3 mapped to 32 cM on mouse Chromosome 15 near D15Mit209 (LOD=4.4). C3H/HeJ-derived alleles confer increased serum IGF-1 at this locus. Correlationbetween serum IGF-1 levels and BMD was not observed for Igf1sl1.

A fourth QTL, Igf1sl4, was identified via pairwise interaction analysis. Ifg1sl4 maps to 1.1 cM on mouse Chromosome 11 near D11Mit71 and is epistatic to Igf1sl1 on mouse Chromosome 6. Homozygosity for C3H/HeJ-derived alleles at Igf1sl4 negates the IGF-1 lowering effect of Igf1sl1. When Igf1sl4 is homozygous or heterozygous for C57BL/6J-derived alleles the effect of Igfsl1 can be observed. Correlation between serum IGF-1 levels and BMD wasobserved for Igf1sl4. Potential candidate genes mapping near Igf1sl4 are Igfbp1 (1.3 cM) and Igfbp3 (1.35 cM).

To test the theory that C3H/HeJ-derived alleles at Igfsl1 and C57BL/6J-derived alleles at Igfsl4 impact serum IGF-1 and BMD, a congenic line (B6.C3H-6) carrying C3H/HeJ-derived DNA on chromosome 6 on the genetic background of C57BL/76J was studied. Congenic animals exhibit a 16% decrease in serum IGF-1 and a 4% decrease in femoral BMD compared to C57BL/6J.

J:111677

Previously identified QTL Igf1sl2 (51 cM) on mouse Chromosome 10 was narrowed to a 18.3 Mb interval containing 148 genes using congenic line analysis. C3H/HeJ-derived alleles at Igf1s2 spanning a 57 Mb interval were introgressed onto a C57BL/6J genetic background for 10 generations. The congenic line, named B6.C3H-Igf1sl2, displays increased serum and skeletal IGF-1, increased trabecular bone volume fraction, more trabeculae, and increased osteoclast number at 16 weeks of age, thus confirming the presence of Igf1sl2.

Seven nested congenic sublines were derived from B6.C3H-Igf1sl2. Phenotype analysis localized Igf1sl2 to an interval between Igf1 (48 cM) and Kitlg (57 cM). Soc2 (52 cM) and Elk3 (51 cM) are potential candidate genes mapping to this interval. Previously identified QTLs Vtbt (51 cM), Bgeq8 (57 cM), Si5lq4 (69.9 cM), and Igfbp3q2 (46 cM) are located near Igf1sl2.

References

• Original: J:66640 Rosen CJ, et al., Mapping quantitative trait loci for serum insulin-like growth factor-1 levels in mice. Bone. 2000 Oct;27(4):521-8
• All: 2 reference(s)