HrI1^A/J
QTL Variant Detail

Summary

• QTL variant: HrI1^A/J
• Name: host response to influenza 1; A/J
• MGI ID: MGI:5750530
• QTL: HrI1 Location: unknown Genetic Position: Chr16, Syntenic

Variant origin

• Strain of Specimen: A/J

Variant description

• Allele Type: QTL
• Inheritance: Not Specified

Notes

(A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ and WSB/EiJ) affected the host response similarly and were associated with decreased influenza resistance (i.e. higher titers, higher weight loss, more pathology). NZO/HILtJ and PWK/PhJ alleles within the PreCC#/Unc population shared similar effects and increased influenza resistance. The authors report a novel CAST/EiJ allele in the Mx1 gene that confers limited protection from viral replication, but does protect from virus-induced weight loss.

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

J:196204

QTL Reference Notes

The Collaborative Cross (CC) is a large (~1,000 line) panel of recombinant inbred (RI) mouse strains being developed through a community effort (Churchill et al. 2004). The CC combines the genomes of eight genetically diverse founder strains - A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HlLtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ - to capture nearly 90% of the known variation present in laboratory mice. CC strains are derived using a unique funnel breeding scheme. Once inbred, the RI CC lines can be used to generate thousands of potential 'outbred' but completely reproducible genomes through the generation of recombinant inbred crosses (RIX). The designation 'PreCC' is used to describe a mapping population of CC mice that is still at incipient stages of inbreeding. CTC (2004), Churchill, G. A., et al.. The Collaborative Cross, a community resource for the genetic analysis of complex traits. Nat Genet. 36, 1133-7.

Linkage analysis was performed on 155 PreCC#/Unc mice using 181,752 SNP markers to identify QTL associated with host response to influenza A virus 4 days post-infection. The following phenotypes were measured:

Clinical Disease

- D4 weight

- D4 clinical score

- Hemorrhage

- Gross Edema

Viral Replication

- Log Titer

- IHC score

Virus-induced inflammation

- Airway inflammation

- Airway neutrophils

- Airway monocytes

- Vascular inflammation

- Vascular neutrophils

- Vascular monocytes

- Alveolar inflammation

Pathology

- Airway damage

- Alveolar damage

- Pulmonary edema

- Fibrin deposition

Transcription

- D4 lung expression

QTL HrI1 maps to 97.5 - 98.2 Mb on Chromosome 16 (Build 37). Peak LOD score and location are not given. HrI1 is taken to signify a locus influencing overall response to influenza A infection, statistically contributing to the following disease-associated phenotypes: D4 weight, D4 clinical score, log titer, IHC score, airway inflammation, and airway damage. The protein coding gene Mx1 was identified as the leading candidate gene. (A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ and WSB/EiJ) affected the host response similarly and were associated with decreased influenza resistance (i.e. higher titers, higher weight loss, more pathology). NZO/HlLtJ and PWK/PhJ alleles within the PreCC#/Unc population shared similar effects and increased influenza resistance. The authors report a novel CAST/EiJ allele in the Mx1 gene that confers limited protection from viral replication, but does protect from virus-induced weight loss.

Despite the large effect of Mx1 on influenza response, there was large phenotypic variation within both the functional and non-functional Mx1 allele classes. This suggested the presence of modifier alleles segregating in the PreCC#/Unc population. To find these modifiers, the authors conducted additional genome scans after accounting for genotype at the most significant HrI1 marker, thereby controlling for Mx1 allele. The resulting QTL, HrI2, maps to 89.13 - 96.76 Mb on Chromosome 7 (Build 37). Peak LOD score and location are not given. HrI2 is significant for D4 weight. The A/J allele showed less weight loss than other animals (increased resistance to infection), and animals with a 129S1/SvImJ allele showed more weight loss than other animals (increased susceptibility to infection).

In order to account for the effect of the Mx1 allele, the authors conducted QTL mapping in a Mx1-/- subpopulation. The analysis identified a QTL, HrI3, significant for pulmonary edema post-viral infection. QTL HrI3 maps to 21.77 - 29.08 Mb on Chromosome 1 (Build 37). Peak LOD score and location are not given. NZO/HlLtJ and WSB/EiJ alleles reduced edema in the PreCC#/Unc population.

References

• Original: J:196204 Ferris MT, et al., Modeling host genetic regulation of influenza pathogenesis in the collaborative cross. PLoS Pathog. 2013 Feb;9(2):e1003196
• All: 1 reference(s)