Experiment
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 Hpnr2 confer 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.
Analysis Tools