Hbnr2^SWR
QTL Variant Detail

Summary

• QTL variant: Hbnr2^SWR
• Name: Heligmosomoides bakeri nematode resistance 2; SWR
• MGI ID: MGI:2660606
• QTL: Hbnr2 Location: Chr17:28885971-28886119 bp Genetic Position: Chr17, Syntenic

Variant origin

• Strain of Specimen: SWR

Variant description

• Allele Type: QTL
• Mutation: Undefined
• Mutation details: This allele confers resistance to infection by the nematode Heligmosomoides polygyrus compared to CBA. This allele confers decreased IgE levels and increased granuloma scores compared to CBA. (J:82261)

Expression

In Structures Affected by this Mutation:

1 anatomical structure(s)

Notes

Decreased IgE levels exhibit recessive inheritance while increased granuloma scores exhibits dominant inheritance.

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

J:82261

Linkage analysis was performed on an (SWR x CBA)F2 intercross population to identify loci affecting resistance/susceptibility to infection by the nematode Heligmosomoides polygyrus. Animals were orally infected with 125 larvae of H. polygyrus weekly for a period of 6 weeks. Parental strain SWR is resistant to nematode infection whereas CBA is susceptible. Loci with significant linkage were detected on mouse Chromosomes 1 and 17. Hpnr1 maps to 15 cM on mouse Chromosome 1 with LOD=12.52 for total worm count at D1Mit211. SWR-derived alleles appear to confer dominantly inherited resistance to nematode infection at Hpnr1. Hpnr2 and Hpnr3 map to 15.1 cM and 50.6 cM on mouse Chromosome 17, respectively. Hpnr2 is linked to total worm count with a LOD score of 4.28 at D17Mit29. SWR-derived alleles confer resistance to nematode infection at Hpnr2. Hpnr3 is linked to fecal egg count with a LOD score of 3.95 between D17Mit93 and D17Mit123. SWR-derived alleles confer dominantly inherited susceptibility to nematode infection at Hpnr3.

J:85787

500 (SWR x CBA)F2 animals were screened for 175 polymorphic markers to identify QTLs associated with immune response to gastrointestinal nematode infection. Parental strain SWR is resistant to infection by the nematode Heligmosomoides polygyrus compared to susceptible parental strain CBA. Following infection with Heligmosomoides polygyrus, parental strain CBA exhibits increase ganuloma scores (GS), increased IgG1, decreased IgE, and decreased levels of mucosal mast cell protease 1 (MMCP1).

Previously identified QTLs Hpnr1, Hpnr2, and Hpnr3 were detected in this study. Hpnr1 reached LOD=8.4 at 21 cM on mouse Chromosome 1 between D1Mit211 (15 cM) and D1Mit214 (43 cM). SWR-derived alleles confer decreased fecal egg count and total worm count with dominantinheritance at Hpnr1. Hprn2 reached LOD=5.02 at 17 cM on mouse Chromosome 17 between D17Mit29 (15.1 cM) and D17Mit176 (24 cM). SWR-derived alleles confer increased granuloma scores with dominant inheritance at Hnpr2. Hprn3 reached LOD=2.56 at 57 cM on mouse Chromosome 17 between D17Mit93 (50 cM) and D17Mit123 (57 cM). SWR-derived alleles confer increased fecal egg count and total worm count with dominant inheritance at Hnpr3.

The following novel QTL reaching a statistical significant of P>0.01 were identified:

Hpnr4 mapped to 85 cM on mouse Chromosome 1 with LOD=3.07 between D1Mit102 (73 cM) and D1Mit362 (106.3 cM). SWR-derived alleles confer increased MMCP1 levels with recessive inheritance at Hpnr4.

Hpnr5 mapped to 30 cM on mouse Chromosome 2 withLOD=2.79 between D2Mit296 (18 cM) and D2Mit44 (47 cM). SWR-derived alleles confer decreased fecal egg count and total worm count with dominant inheritance at Hpnr5.

Hpnr6 mapped to 44 cM on mouse Chromosome 12 with LOD=4.13 between D12Mit177 (36 cM) andD12Mit194 (45 cM). SWR-derived alleles confer increased in IgE levels with recessive inheritance at Hpnr6.

Hpnr7 mapped to 32 cM on mouse Chromosome 17 with LOD=6.15 between D17Mit176 (22 cM) and D17Mit180 (40.2 cM). SWR-derived alleles confer decreasedIgG1 levels with dominant inheritance at Hpnr7.

Hpnr8 mapped to 36 cM on mouse Chromosome 19 with LOD=2.77 between D19Mit88 (34 cM) and D19Mit89 (41 cM). SWR-derived alleles confer decreased fecal egg count and total worm count with dominant inheritanceat Hprn8.

J:110034

Advanced intercross lines derived from SWR/Ola and CBA/Ola inbred strains were used to refine nematode resistance QTLs Hpnr1 (Heligmosomoides polygyrus nematode resistance 1) on mouse Chromosomes 1 and Hpnr2 (Heligmosomoides polygyrus nematode resistance2) on mouse Chromosome 17. Five hundred mice at the F6 generation and 600 mice at the F7 generation were infected orally with larval Heligmosomoides polygyrus every 7 days starting at 10 weeks of age for a duration of 6 weeks. Parental strain SWR/Ola is resistant to H. polygyrus infection compared to parental strain CBA/Ola. Polymorphic markers spaced 5 cM - 10 cM on chromosomes 1 and 17 were screened for fine map analysis.

Hpnr1 was localized to 24.1 cM (peak at D1Mit478) on mouse Chromosome 1 with a 95% confidence interval spanning 20 cM - 32 cM. This locus shows strongest linkage to the following traits: fecal egg count weeks 4 and 6 (LOD=11.1 and 9.7, respectively), average fecal egg count (LOD=12.1), and total worm count (LOD=12.9). Hpnr1 is also significantly linked to the following traits with smaller effects: fecal egg count week 2 (LOD=4.5), blood packed cell volume at week 6 of infection (LOD=3.5), immunoglobulin G1 on L4 larvae [IgG1-L4] (LOD=2.9), and immunoglobulin G1 on adult worms [IgG1-Ad] (LOD=3.6). SWR/Ola-derived alleles at Hpnr1 confer decreased fecal egg counts, total worm counts, IgG1-L4 and IgG1-Ad. SWR/Ola alleles also confer increased blood packed cell volume at week 6. Idd5a (38.5 cM) is a previously identified diabetes QTL mapping near Hpnr1. Potential candidate genes in this region include Ctla4 (30.1 cM), Icos (32 cM), Als2cr19, Cflar (30.1 cM), and Nrp2.

Hpnr2 was localized to 18.1 cM (peak at D17Mit176) on mouse Chromosome 17 with a 95% confidence interval spanning 17.9 cM - 18.4 cM. This locus shows strongest linkage to fecal egg count at weeks 4 and 6 (LOD=15.3 and 10.3, respectively), average fecal egg count (LOD=12.7), total worm count (LOD=13.3), granuloma score on intestinal mucosa (LOD=25.4), immunoglobulin G1 on adult worm [IgG1-Ad] (LOD=16.5), and immunoglobulin E on L4 larvae [IgE-L4] (LOD=12). Hpnr2 exhibits smaller linkages to mMCP1 [mucosal mast cell protease 1] (LOD=3.5) and immunoglobulin G1 on L4 larvae [IgG1-L4] (LOD=5.2). SWR/Ola-derived alleles at Hpnr2confer decreased fecal egg count, total worm count, IgG1-Ad, and IgE-L4. SWR/Ola alleles also confer increased granuloma scores, mMCP1, and IgG1-L4. Hpnr2 maps almost exactly to a previously identified trypanosome resistance QTL named Tir1 at 18.2 cM. Asecond locus at 35 cM was potentially detected in a two-QTL model for fecal egg count at week 4.

References

• Original: J:82261 Iraqi FA, et al., Chromosomal regions controlling resistance to gastro-intestinal nematode infections in mice. Mamm Genome. 2003 Mar;14(3):184-91
• All: 3 reference(s)