Civq6^A/J
QTL Variant Detail

Summary

• QTL variant: Civq6^A/J
• Name: cerebral infarct volume QTL 6; A/J
• MGI ID: MGI:6324353
• QTL: Civq6 Location: Chr7:126707335-126707335 bp Genetic Position: Chr7, Syntenic

Variant origin

• Strain of Specimen: A/J

Variant description

• Allele Type: QTL
• Inheritance: Not Specified

Notes

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

J:276815

In a mouse model of focal cerebral ischemia, infarct volume is highly variable and strain dependent, but the natural genetic determinants responsible for this difference remain unknown. To identify genetic determinants regulating ischemic neuronal damage and to dissect the role of individual genes and physiological mechanisms in infarction in mice, the authors performed QTL analysis of surgically-induced cerebral infarct volume.

After permanent occlusion of the distal middle cerebral artery (MCA), infarct volume was determined for 16 inbred strains of mice. The authors observed that infarct volumes 24 hours after MCA occlusion were significantly different between inbred strains C57BL/6J and BALB/cByJ. Across strains, the authors observed a wide range of infarct volume, with as much as 30-fold difference between the strain pair at the phenotypic extremes (C57BLKS/J versus SWR/J). Trait heritability was estimated to be 0.88.

To exploit these differences for identification of natural genetic determinants of infarct volume, the authors performed a reciprocal F1 intercross between strains C57BL/6J and BALB/cByJ. A total of 105 F2 mice were genotyped for 239 SNP markers that were informative in this cross. The average spacing between fully informative SNP markers was 6.8 +/- 1.6 cM, affording complete coverage of the mouse genome. Reported genetic map positions were retrieved from the SNP database (build 37.1) of NCBI.

Genome-wide linkage analysis was performed for infarct volume as a quantitative trait. Genome-wide scans were plotted using the J/QTL mapping program, version 1.2.1.

Three QTL were identified:

Significant QTL Civq1 (cerebral infarct volume QTL 1) maps to Chr 7 with a peak LOD score of 11.9 at rs13479513 and an additive mode of inheritance. The C57BL/6J allele confers protection against focal cerebral ischemia at Civq1. Civq1 is the strongest QTL in the study and accounts for 56% of the observed variance in infarct volume.

Suggestive QTL Civq2 (cerebral infarct volume QTL 2) maps to Chr 1 with a peak LOD score of 2.7 at rs13475783 and a dominant mode of inheritance. The C57BL/6J allele confers protection against focal cerebral ischemia at Civq2. Civq2 accounts for 7% of the observed variance in infarct volume.

Suggestive QTL Civq3 (cerebral infarct volume QTL 3) maps to Chr 8 with a peak LOD score of 3.2 at rs8253516 and an additive mode of inheritance. The BALB/cByJ allele confers protection against focal cerebral ischemia at Civq3. Civq3 accounts for 12% of the observed variance in infarct volume.

The authors conducted a second intercross between inbred strains C57BL/6J and SWR/J, which also differ 6-fold in infarct volume (P < 0.001).

Infarct volumes were measured in both sexes for a total of 78 F2 intercross progeny. F2 mice were genotyped for 215 SNP markers that were informative between the C57BL/6J and SWR/J strains.

One significant QTL was identified:

Civq5 (cerebral infarct volume QTL 5) maps to Chr 7 with a peak LOD score of 9.7 at rs13479513, matching the interval of Civq1. Civq5 explains 57% of the total variance of infarct volume, and the C57BL/6J allele confers protection against focal cerebral ischemia at Civq5.

The authors merged the genotype and phenotype data from the 2 intercrosses and performed genome-wide linkage analysis on the combined data. The combined animals from both intercrosses yielded an overall LOD score of 21.7 at rs13479513 on Chr 7. This analysis resulted in a 1.5-LOD interval of 9.9 Mb encompassing 225 potential candidate genes named Civq6 (cerebral infarct volume QTL 6).

Allelic variation at Civq6 is most likely attributable to a gene that maps within an ancestral haplotype block that is shared between BALB/cByJ, A/J, and SWR/J, but that is different from C57BL/6J. The authors examined all haplotypes throughout the 1.5-LOD interval of Civq6, defining a haplotype block to be 3 or more adjacent consecutive shared SNP alleles. Sixteen haplotype blocks, encompassing a combined total of 900 kb, exhibited the appropriate pattern of haplotype variation or relatedness. These 16 haplotype blocks contained only 12 possible candidate genes for Civq6.

References

• Original: J:276815 Keum S, et al., A locus mapping to mouse chromosome 7 determines infarct volume in a mouse model of ischemic stroke. Circ Cardiovasc Genet. 2009 Dec;2(6):591-8
• All: 1 reference(s)