J:97472

Linkage analysis was performed on 123 recombinant congenic animals at the N8 generation to identify QTLs associated with airway hyperresponsiveness (AHR). A recombinant congenic line was created by repeated backcrossing of (C57BL/6J x A/J)F1 animals to C57BL/6J for 7 generations and selecting for the AHR phenotype at each generation. Donor strain A/J exhibits increased naive AHR compared to background strain C57BL/6J. At generation N8 the recombinant congenic line displayed 80% of the donor A/J AHR phenotype. This line retained A/J-derived donor DNA on chromosomes 2 from D2Mit259 - D2Mit148, chromosome 6 from D6Mit86 - D6Mit9, and chromosome 10 from D10Mit95 - D10Mit103.

When analyzed separately the loci on chromosomes 2 (Bhr1) and 6 (Bhr8) show only asuggestive linkage to AHR. The combined effect of these 2 loci when inherited together show a highly significant linkage to AHR with LOD=5.5, and explains 18.7% of the total variance. It is believed that A/J-derived alleles confer dominantly inherited susceptibility to AHR.

The region of the human genome that has conserved syntenty with the retained A/J regions of chromosome 2 and 6 is large. Human studies have associated SNPs in the ADAM33 gene with asthma. It is notable that metalloprotease Adam33 is located in the retained region on chromosome 2.

Recent data in the mouse suggest that differences in Adam33 activity are not likely to account for the strain-specific AHR phenotypes, as a multistrain comparison of 198 potential SNPs in Adam33 genomic sequences (including extensive upstream and downstream regions) found that none differed bewteen the A/J and C57BL/6J strains. (http://mousesnp.roche.com/).

Also, dipeptidyl peptidase, DPP10 was found to be associated with asthma in humans and was also reported to be in a region of conserved synteny with mouse loci on chromosome 2 linked to elevated AHR. However, the mouse ortholog of DPP10 (GenBank: AK046842) maps to mouse chromosome 1 and is consequently not a candiate for causing elevated AHR in A/J mice.

J:29231

Airway hyperresponsiveness in mice is inherited as a polygenic trait in C57BL/6J and A/J mice. The asthma-like phenotype in A/J mice is expressed differently then the phenotype expressed in C57BL/6J mice, therefore allowing for the quantitative mapping (QTL) of this trait in (C57BL/6J x A/J)F1 x C57BL/6J backcross mice. A genome wide scan using Mit markers indicated that one such locus, Bhr1, mapped to mouse Chromosome 2 between D2Mit397 and D2Mit266 with a LOD score of 3.0.

Bhr3 interacts with Bhr1 andBhr2. Homozygosity for C57BL/6J-derived alleles at either Bhr1 or Bhr3 confers simlilar decrease in airway hyperresponsiveness as homozygosity at both Bhr1 and Bhr3.

Heterozygosity at either Bhr2 or Bhr3 confers similar increase in airway hyperresponsiveness as heterozygosity at both Bhr2 and Bhr3.

J:97472

Linkage analysis was performed on 123 recombinant congenic animals at the N8 generation to identify QTLs associated with airway hyperresponsiveness (AHR). A recombinant congenic line was created by repeated backcrossing of (C57BL/6J x A/J)F1 animals to C57BL/6J for 7 generations and selecting for the AHR phenotype at each generation. Donor strain A/J exhibits increased naive AHR compared to background strain C57BL/6J. At generation N8 the recombinant congenic line displayed 80% of the donor A/J AHR phenotype. This line retained A/J-derived donor DNA on chromosomes 2 from D2Mit259 - D2Mit148, chromosome 6 from D6Mit86 - D6Mit9, and chromosome 10 from D10Mit95 - D10Mit103.

When analyzed separately the loci on chromosomes 2 and 6 show only a suggestive linkage to AHR. The combined effect of these 2 loci when inherited together show a highly significant linkage to AHR with LOD=5.5, and explains 18.7% of the total variance. It is believed that A/J-derived alleles confer dominantly inherited susceptibility to AHR.

The chromosome 10 locus did not show evidence of linkage to AHR.

The chromosome 2 locus was identified in a previous AHR study as Bhr1 (bronchial hyperresponsiveness 1) peaking at 74 cM. In the current study Bhr1 maps to a 25 cM interval betweenD2Mit259 (80 cM) and D2Mit148 (105 cM).

The chromosome 6 locus was identified in a previous AHR study as Bhr5 (bronchial hyperresponsiveness 5) peaking at 50.5 cM. In the current study Bhr5 maps to a 36.5 cM interval between D6Mit86 (0.5 cM) and D6Mit9(36.5 cM).

2.10.2015 Curator Note: Because Bhr5 was originally mapped in J:33778 using a (C3H/HeJ x A/J)F1 x A/J backcross which differs from the cross used here we have named this QTL, mapping to Chr 6 to a 36.5 cM interval between D6Mit86 (0.5 cM) andD6Mit9 (36.5 cM), Bhr8.