Iba4^C57BL/6J
QTL Variant Detail

Summary

• QTL variant: Iba4^C57BL/6J
• Name: induction of brown adipocytes 4; C57BL/6J
• MGI ID: MGI:2446818
• QTL: Iba4 Location: Chr19:26305715-26305821 bp Genetic Position: Chr19, cM position of peak correlated region/allele: 20.99 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
• Mutation: Undefined
• This allele is associated with enhanced Ucp1 induction compared to A/J. (J:65478)
• Inheritance: Not Specified

Notes

Iba3 and Iba4 show interactive effects. Animals carrying an A/J-derived allele at Iba3 and a C57BL/6J-derived allele at Iba4 exhibit the highest levels of Ucp1 induction.

Candidate Genes

J:99477

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 Iba4 (20 cM) on mouse Chromosome 19 as identified by ExQuest are Aldh1a1 (12 cM), Aldh1a7, Vldlr (20 cM), and Plce1. Vldlr exhibits 15.6-fold increased expression in the liver of Tally Ho compared to C57BL/6 animals. For QTL Afw8 (26 cM), potential candidate genes Pi4k2a, Cpn1, and Elovl3 (47 cM) were identified. For QTLs Nobq2 (47 cM) and Bglq13 (51 cM), potential candidate genes Ins1 (49 cM), Gpam (52 cM), and Acsl5 were identified. For QTLs Tanidd1 (50 cM) and T2dm2 (53 cM), potential candidate genes Gfra1, Pnlip (29 cM), Pnliprp1 (29 cM), and Pnliprp2 were identified. Pnliprp2 exhibits 21.8-fold decreased expression in the pancreas of Tally Ho animals in response to a 4% fat diet.

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

J:65478

Selective genotyping (using 80 microsatellite markers at an average spacing of 20 cM) was performed population of (C57BL/6J x A/J)F1 x A/J backcross animals to identify loci associated with induction of uncoupling protein 1 (Ucp1) in white fat tissue. The animals were exposed to cold for 1 week to induce Ucp1. Enhanced induction of Ucp1 is correlated to the ability to lose weight in obesity-prone inbred mouse strains. Inbred strain C57BL/6J exhibits lower Ucp1 induction compared to A/J. Four loci, Iba1 (induction of brown adipocytes), Iba2, Iba3, and Iba4 were identified on mouse Chromosome 2 at 47 cM, mouse Chromosome 3 at 49.7 cM, mouse Chromosome 8 at 31 cM, and mouse Chromosome 19 at 20 cM, respectively. Iba1 yields a peak LOD = 8.59 at D2Mit66 with a QTL range from 40.4 cM - 50.3 cM, Iba2 yields a peak LOD = 4.98 at D3Mit10 with a QTL range from 41 cM - 58.8 cM, and Iba3 yields a peak LOD = 12.54 at D8Mit128 with a QTL range from 30 cM - 33 cM. A/J-derived alleles are associated with enhanced Ucp1 induction at Iba1, Iba2, and Iba3. Possible candidate genes in the region of Iba1 include Gad1, Chrna1 (Acra), and HoxD. Possible candidate genes in the region of Iba2 include Gja5, Nras, Tshb, Kcna2, Gja8, Kcna3, Kcna4, and Kcna8. Possible candidate genesin the region of Iba3 include Jak3, Npy1r, and Pde4c. Iba4 yields a peak LOD = 3.63 at D19Mit86 with a QTL range from 22 cM - 24 cM. C57BL/6J alleles are associated with enhanced Ucp1 induction at Iba4. Possible candidate genes in the region of Iba4 are Vldlr, Rln, and Jak2. There evidence of interaction between Iba3 and Iba4. Animals carrying the A/J allele at Iba3 and the C57BL/6J allele at Iba4 exhibit the highest levels of Ucp1 induction.

J:101371

Linkage analysis was performed on a population of (C57BL/6J x A/J)F1 x A/J backcross animals to identify loci associated with regulation of Ucp1, Ppara, Ppargca1, and Dio2 (deiodinase type II) expression during cold-induced brown adipocyte induction. Animals were fed either a low fat (LF) or high fat (HF) diet and exposed to cold (5 degrees Celsius) for 7 days. Parental strain A/J displays significantly increased brown fat expression of Ucp1, Ppargc1a, Dio2, and Ppara mRNA after 7 days of cold exposure compared to C57BL/6J.

A previously identified QTL named Iba1 (induction of brown adipocytes 1) was detected in this study. Iba1 maps to 47.8 cM on mouse Chromosome 2 near D2Mit66. This locus is linked to cold-induced Dio2 expression on LF and HF diets andcold-induced Ppara expression on a HF diet. A novel locus named Iba6 (induction of brown adipocytes 6) mapped to 10 cM on mouse Chromosome 2 near D2Mit80. Iba6 is linked to cold-induced Dio2 expression on LF and HF diets.

Previously identified Iba2 (induction of brown adipocytes 2) was detected in this study at 48.2 cM on mouse Chromosome 3 near D3Mit101. This locus is linked to cold-induced Dio2 expression and cold-induced Ppara expression on a LF diet.

A novel locus linked to cold-induced Dio2 expression on a LF diet mapped to 49.5 cM on mouse Chromosome 4 near D4Mit175. This QTL is named Iba7 (induction of brown adipocytes 7).

Previously identified Iba5 (induction of brown adipocytes 5) was detected in this study at 24 cM on mouse Chromosome 5 nearD5Mit182. This locus is linked to cold-induced Dio2 expression and cold-induced Ppara expression on a LF diet.

Previously identified Iba3 (induction of brown adipocytes 3) was detected in this study at 37 cM on mouse Chromosome 5 near Ucp1. This locus is linked to cold-induced Dio2 expression on a LF diet and cold-induced Ppara expression on a HF diet.

A novel locus linked to cold-induced Dio2 expression and cold-induced Ppara expression on a LF diet mapped to 49 cM on mouse Chromosome 15 near D15Mit107. This QTL is named Iba8 (induction of brown adipocytes 8). Ppara is located at 48.8 cM and may be responsible for this locus.

Previously identified Iba4 (induction of brown adipocytes 4) was detected in this study at 20 cM on mouse Chromosome 19 near D19Mit86. This locus is linked to cold-induced Dio2 expression and cold-induced Ppara expression on a HF diet.

J:83834

400 (C57BL/6J x A/J)F1 x A/J backcross animals were screened for loci at an average spacing of 20 cM to identify QTLs regulating the induction of Ucp1 and Ppargc1 in retroperitoneal white adipose tissue. Parental strain A/J exhibits strong Ucp1 inductionafter 7 days of cold exposure whereas parental strain C57BL/6J exhibits low Ucp1 induction.

Previously identified QTLs Iba1 (chr2), Iba2 (chr3), Iba3 (chr8), and Iba4 (chr19) were detected in this study, and a new QTL on mouse Chromosome 5, Iba5, was identified. All QTLs showed significant linkage to Ucp1 induction but only Iba2 showed strong linkage to both Ucp1 (LOD=6.6) and Ppargc1 (LOD=5.7) induction at D3Mit101 (49.7 cM).

Iba5 maps to 21 cM on mouse Chromosome 5 with peak linkage at D5Mit182 (P=6.3 x 10-7). Iba5 maps near Ppargc1. Ppargc1 was sequenced but no polymorphisms were uncovered between C57BL/6J and A/J. The 10 kb of sequence flanking Ppargc1 also did not contain any polymorphisms.

Suggestive linkages to Ucp1 induction (P=.02) were detected at 40 cM (D4Mit116) on mouse Chromosomes 4 and at 19 cM (D10Mit214) on mouse Chromosome 10. These loci were more significantly linked to Ppargc1 induction (P=5.5 x 10-4 at D4Mit116) and (P=2.0 x 10-4 at D10Mit214).

References

• Original: J:65478 Koza RA, et al., Synergistic gene interactions control the induction of the mitochondrial uncoupling protein (Ucp1) gene in white fat tissue. J Biol Chem. 2000 Nov 3;275(44):34486-92
• All: 1 reference(s)