HrI4^C57BL/6J
QTL Variant Detail

Summary

• QTL variant: HrI4^C57BL/6J
• Name: host response to influenza 4; C57BL/6J
• MGI ID: MGI:5811837
• QTL: HrI4 Location: unknown Genetic Position: Chr2, Syntenic

Variant origin

• Strain of Specimen: C57BL/6J

Variant description

• Allele Type: QTL

Notes

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

J:184057

In the current study host genetic control of the mouse adapted influenza strain A/HK/1/68-MA20 (H3N2) was examined using the AcB/BcA reciprocal series of recombinant congenic strains (RCS). The panel of 29 closely RCS were created from influenza susceptible A/J and influenza resistant C57BL/6J mice. The mouse model reproduced the hallmark high viral load and over expression of cytokines associated with susceptibility to severe influenza in humans. Candidate genes were identified for two sex specific QTL identified on Chromosomes 2 and 17.

For each RCS at least 6 male and 6 female mice were challenged with a dose of 10⁴ PFU/22g of influenza HK/68 and monitored for 14 days. Survival was a continuous variable identifying the day of sacrifice during the experimental period. The continuous variable 'survival' was transformed into the binary variable 'susceptibility' that indicated whether the animal was sacrificed during the experimental period.

Mice were genotyped using 110,567 polymorphic markers from the Mouse Diversity Genotyping array, 1,449 polymorphic markers from the MD linkage panel and 625 mircosatellite markers. A set of 1215 markers that spanned mouse genome Build 37 were selected that covered the relevant break points in the AcB/BcA panel of mice.

A significant effect of strain background (AcB vs BcA, p<0.0001), as well as a significant effect of strain (p<0.0001) and a significant sex x strain interaction was observed for the BcA70 (p<0.05) and the BcA72 (p<0.05) mouse strains. The continuous distribution of both survival time and susceptibility across the panel of 29 strains suggested complex genetic control of susceptibility to the influenza virus in A/J and C57BL/J6 mice.

Using the simplified binary measure of survival during the 14 day infection period genome wide linkage analysis was performed and 2 cQTL (clinical QTL) associated with increased susceptibility to influenza HK/68 infection were identified:

HrI4, host response to influenza 4, mapped in strain BcA72 was identified on Chromosome 2, mapping between 24-38 Mb, p<0.01 and reached genome wide significance only the female population.

HrI5, host response to influenza 5, mapped in strain BcA70 reached genome wide significance only in the male population and was identified on Chromosome 17, mapping between 37-48 Mb, p<0.01.

To confirm the novel locus on Chr 17 the susceptible BcA70 mice were backcrossed with resistant B6 mice generating an F2 population. The informative A/J genomic segments of BcA70 covered the linked region of Chromosome 17. 177 F2 mice were infected as above and monitored for the 14 day period to obtain measures of time to sacrifice or survival. Looking at the survival of mice per genotype at each marker linkage of susceptibility was confirmed with Chromosome 17 (peaking at marker rs13482997 at 43 Mb, p=0.009) when male F2 mice were analyzed, as noted by the lower survival of the AA genotype at marker positions. The finding suggests that the chromosome 17 male specificity was determined by cis factors. A cQTL was also detected on Chromosome 4, peaking at marker rs27661282 at 116 Mb, p=0.027 in this cross, in the combined analysis of male and female mice. [Fig 5. A.B.]

To identify primary candidate genes within the chromosome 2 and chromosome 17 cQTL linkage analysis was performed using microarray expression data from uninfected lung tissue of 54 mice from the AcB/BcA panel.

Hc was the most significant of five eQTL ( Dpp7, Phpt1, Notch1, St6galnac4 an Hc, Fig 6A) located within the female specific cQTL on chromosome 2. A/J mice are known to have a mutation that causes a stop codon in Hc, resulting in A/J mice showing drastic reductions in the expression of transcripts for this gene compared to B6.

Tnfrsf21 and Pla2g7 were colocalized within the male specific cQTL on Chromosome 17. In both cis-eQTL identified on Chromosome 17, the A/J allele had higher expression compared with the B6 allele.

References

• Original: J:184057 Boivin GA, et al., Mapping of clinical and expression quantitative trait loci in a sex-dependent effect of host susceptibility to mouse-adapted influenza H3N2/HK/1/68. J Immunol. 2012 Apr 15;188(8):3949-60
• All: 1 reference(s)