Ath11^FVB/NCr
QTL Variant Detail

Summary

• QTL variant: Ath11^FVB/NCr
• Name: atherosclerosis 11; FVB/NCr
• MGI ID: MGI:2386544
• QTL: Ath11 Location: Chr10:6151945-58693521 bp Genetic Position: Chr10, Syntenic

Variant origin

• Strain of Specimen: FVB/NCr

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers increased aortic lesion size compared to C57BL/6J. (J:76127)
• Inheritance: Other (see notes)

Expression

In Structures Affected by this Mutation:

1 anatomical structure(s)

Notes

Ath11 fits either a dominant or additive mode of inheritance.

Candidate Genes

J:86703

Tnfaip3 was identified and investigated as a candidate gene for the QTL Ath11 on mouse Chromosome 10. No differences in Tnfaip3 expression level was found between parental strains FVB/N and C57BL/6J. However, sequence analysis revealed a Glu627Ala amino acid substitution between C57BL/6J and FVB/N, respectively. This functional polymorphism is thought to result in increased Nfkb inhibition in FVB/N compared to C57BL/6J.

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

J:76127

Two independent strain intercosses that carry atherosclerosis phenotype-sensitizing Apoe deficiency were performed to reveal artherosclerosis susceptibility loci that are distinct from loci linked to lipoprotein levels.

Animals from a C57BL/6J-derived background are susceptible to atherosclerosis and yield several-fold higher aortic lesion scores compared to animals from an FVB/NCr-derived background.

In the first cross, referred to as cross 1, B6.129P2-Apoe^tm1Unc x FVB.129P2-Apoe^tm1Bres F1 mice were crossed and the F1 offspring were intercrossed to create 197 (B6.129P2-Apoe^tm1Unc x FVB.129P2-Apoe^tm1Bres) F2 mice for the QTL analysis. Interval mapping was done with 194 markers at a distance of no more than 10cM.

In the second, confirmatory cross, B6.129P2-Apoe^tm1Unc x FVB.129P2-Apoe^tm1Bres F1 mice were crossed and the F1 offspring were intercrossed to create 186 (B6.129P2-Apoe^tm1Unc x FVB.129P2-Apoe^tm1Bres)F2 mice for QTL analysis. This cross was referred to as cross 2; these mice were genotyped using 127 markers at no more than 10cM intervals.

A highly significant locus on chromosome 10 was identified in both crosses with a LOD score of 7.8 at D10Mit213 in cross 1 and 11.9 at D10Mit214 in cross 2. The locus accounted for 19% of log lesion variance in cross 1 and 25% in cross 2. Interval mapping of chromosome 10 in cross 1 revealed a peak that included both D10Mit13 and D10Mit14. The locus was labeled Ath11.

Highly significant LOD scores were obtained using either a dominant or additive model.

Unexpectedly, in cross one, homozygosity for FVB/NCr-derived alleles conferred increased lesion size when compared to mice heterozygous or homozygous for the C57BL/J allele.

The strongest candidate gene for Ath11 is Ifngr, which is located at 15cM on mouse chromosome 10. Ath11 maps to an interval (0-19cM) that is evolutionarily conserved with human chromosome 6q22-24.

References

• Original: J:76127 Dansky HM, et al., A phenotype-sensitizing apoe-deficient genetic background reveals novel atherosclerosis predisposition Loci in the mouse. Genetics. 2002 Apr;160(4):1599-608
• All: 3 reference(s)