Cq4^KK-A(y)
QTL Variant Detail

Summary

• QTL variant: Cq4^KK-A(y)
• Name: cholesterol QTL 4; KK-A^y
• MGI ID: MGI:3029257
• QTL: Cq4 Location: Chr9:32411751-32411890 bp Genetic Position: Chr9, cM position of peak correlated region/allele: 17.8 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: KK-A^y

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers increased plasma cholesterol compared to C57BL/6J. (J:87328)
• Inheritance: Other (see notes)

Expression

In Structures Affected by this Mutation:

1 anatomical structure(s)

Notes

Cq4 exhibits additive inheritance.

Candidate Genes

J:99474

Linkage analysis was performed on 3 separate F2 crosses in 3 previous studies: J: 54322, J:87328 and J:94251 to map QTLs associated with plasma cholesterol levels. Cq1, Cq2, and Cq6 mapped to mouse Chromosome 1, Cq3 mapped to mouse Chromosome 3, and Cq4 and Cq5 mapped to mouse Chromosome 9.

Cq2 and Cq6 map to the same location on distal mouse Chromosome 1 at approximately 100 cM. Cq2 was identified in a (C57BL/6J x KK-A^y)F2 intercross and Cq6 was identified in a (C57BL/6J x RR)F2 intercross. Apoa2 wasinvestigated as a possible candidate gene. The Apoa2^b allele is found in KK and RR strains and is associated with increased cholesterol levels while inbred strain C57BL/6J carries the Apoa2^a allele. It is thought that the Apoa2^b allele may be responsible for the QTL effects of Cq2 and Cq6.

Inbred strains A/J and SM/J carry the Apoa2^c allele. It was previously unknown whether the Apoa2^a and Apoa2^c alleles had the same or different influences on plasma cholesterol level. An F2 intercross between congenic strains C57BL/6J-Apoa2^a and C57BL/6J-Apoa2^c revealed no physiological differences between the Apoa2^a and Apoa2^c alleles. Therefore, the Apoa2^b allele confers increased plasma cholesterol compared to the Apoa2^a and Apoa2^c alleles.

Cq4 and Cq5 map to the same location on mouse Chromosome 9 at approximately 27 cM and Apoa1 and Apoa4 were investigated as possible candidate genes. Cq4 was identified in a (C57BL/6J x KK-A^y)F2 intercross and Cq5 was identified in a (KK x RR)F2 intercross. Sequence analysis of Apoa1 revealed that polymorphic differences between the involved strains did not correlate to cholesterol phenotype. Analysis of Apoa4 revealed a silent polymorphism (C771T) that exhibits complete correlation to cholesterol phenotype. Inbred strain KK carries the T allele whereas inbred strain C57BL/6J and RR carry the C allele. Another polymorphism in Apoa4 was detected involving a 12 nucleotide insertion encoding Glu-Gln-Ala/Val-Gln. Inbred strain KK carries 3 repeats, inbred strain C57BL/6J carries 4 repeats, and inbred strain RR carries 5 repeats. However, it could not be determined if this particular polymorphism explains the QTL effect of Cq4 and Cq5 on cholesterol levels.

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

J:87328

Authors reanalyzed a (C57BL/6J x KK-A^y)F2 cross to confirm QTLs associated with plasma cholesterol and triglyceride levels. A new (KK x RR)F2 cross was also analyzed at 82 microsatellite markers at an average resolution of 19.5 cM for the same traits. Parental strain KK-A^y exhibits increased plasma cholesterol and triglycerides compared to parental strains C57BL/6J and RR. The RR strain exhibits a slight tendency towards obesity.

In the (C57BL/6J x KK-A^y)F2 cross the following QTLs were confirmed:Cq1, Cq2, and Cq3. A new QTL associated with plasma cholesterol level, Cq4, was identified at 9 cM on mouse Chromosome 9 with LOD=4.4 at D9Mit90. KK-derived alleles confer increased cholesterol at Cq4 with an additive mode of inheritance. Candidate genesmapping near Cq4 include Ldlr, Apoa1, Apoa4, Apoa5, Apoc3, and Cyp11a1. Cq4 maps near an obesity QTL named Obq5.

A novel QTL associated with triglyceride levels was also identified in the reanalysis of the (C57BL/6J x KK-A^y)F2 cross. Tgq1 mapped to 33 cM on mouse Chromosome 9 with LOD=5 at D9Mit163. Candidate genes for Tgq1 include Apoc3, Apoa5, and Lipc.

In the (KK x RR)F2 cross novel QTLs Cq5 and Tgq2 were identified. Cq5 maps to 28 cM on mouse Chromosome 9 with LOD=5.6 at D9Mit229. The KK-derivedallele at Cq5 confers increased plasma cholesterol consistent with an additive or recessive mode of inheritance. Cq5 maps to the same general vicinity as Cq4 and has candidate genes in common.

Tgq2 maps to 30 cM on mouse Chromosome 8 with LOD=4.7 at D8Mit205. KK-derived alleles confer increased triglyceride levels at Tgq2 with an additive or recessive mode of inheritance. Candidate genes mapping near Tgq2 include Cpe, Lpl, and Ucp1. Lpl appears to be an attractive candidate gene since transgenic mice overexpressing Lpl exhibit decreased triglyceride levels while Lpl knockout animals exhibit elevated triglycerides. Tgq2 maps near previously identified QTLs Giq1 (glucose intolerance) and Tg-1 (triglyceride 1, Shike et al, 2001).

References

• Original: J:87328 Suto J, et al., Quantitative trait locus analysis of plasma cholesterol and triglyceride levels in KK x RR F2 mice. Biochem Genet. 2003 Oct;41(9-10):325-41
• All: 1 reference(s)