Experiment
Linkage analysis was performed on 86 female animals from a NZB x (SWR x NZB)F1 backcross population to identify dominant SWR-derived QTLs associated with lupus phenotypes. (SWR x NZB)F1 hybrid animals are susceptible to lupus nephritis. 122 autosomal microsatellite markers at an average spacing of 10 cM were used for the genome scan.
Suggestive linkage to IgG anti-nuclear antibody (ANA) production mapped to 86 cM on mouse Chromosome 1 near D1Mit15 (LOD=2.89-2.91). This locus is designated Swrl1 (SWR lupus locus 1). NZB-derived alleles at Swrl1 confer increased ANA production with a dominant mode of inheritance. This locus overlaps with previously identified lupus QTLs Nba2 (95 cM) and Sle1 (88 cM). Potential candidate genes for Swrl1 are Cr2 (106.6 cM), Cfh (74 cM), and Fasl (85 cM).
Suggestive linkage to early mortality mapped to 55 cM on mouse Chromosome 4 near D4Mit147 (LOD=1.48). The NZB-derived allele confers early mortality with a recessive mode of inheritance. This locus overlaps with previously identified lupus QTLs Lbw2, Sbw2, and Sle2.
Suggestive linkage to glomerulonephritis susceptibility mapped to 75 cM on mouse Chromosome 4 near D4Mit190 (LOD=2.23). This locus is thought to be the previously identified autoimmunity QTL Nba1. NZB-derived alleles at this locus confer susceptibility to glomerulonephritis with a recessive mode of inheritance. Potential candidate genes for Nba1 are Tnfrsf4 (79 cM), Tnfrsf9 (75 cM), and Tnfrsf1b (75 cM). Nba1 appears to interact with Swrl2. Animals homozygous for NZB-derived alleles at Nba1 and heterozygous at Swrl2 exhibit significantly increased glomerulonephritis susceptibility.
07.15.2015 Curator Note: Nba1 was originally mapped in J:18261 in 1994 using an NZB/BlNJ x NZW/LacJ)F1 x NZW/BlNJ backcross which differs from the cross used here. We consider this a separate mapping experiment and have assigned this QTL as Nba8 to preserve the significance of the interaction.
Suggestive linkage to glomerulonephritis susceptibility mapped to 36 cM mouse Chromosome 14 near D14Mit37 (LOD=2.48). This locus is named Swrl2 (SWR lupus locus 2). SWR-derived alleles at Swrl2 confer glomerulonephritis susceptibility with a dominant mode of inheritance. Potential candidate genes for Swrl2 are Cdc25c (15 cM), Apc (15 cM), Mcc (21 cM), Bin1(14 cM), Camk4 (12 cM), and Egr1 (16 cM).
The H2 locus on mouse Chromosome 17 showed the strongest linkage to several phenotypes. H2 is linked to early mortality (LOD=4.59-5.38), glomerulonephritis susceptibility (LOD=2.37), and IgG anti-nuclear antibody(ANA) formation (LOD=5.48). SWR-derived alleles confer increased susceptibility/severity of the above lupus traits with a dominant mode of inheritance. Potential candidate genes for the H2 locus are H2 (23 cM),Tnf (19 cM), Lta (19 cM), C2(18.8 cM), C4(18.8 cM), Tnfsf7 (20 cM),Notch4 (18.7 cM), and Daxx (17 cM). The H2 locus shows strong interaction with Swrl3. Animals heterozygous at both H2 and Swrl3 exhibit significantly increased penetrance of the IgG ANA phenotype.
Suggestive linkage to IgG anti-nuclear antibody (ANA) production mapped to 14 cM on mouse Chromosome 18 near D18Mit17 (LOD=2.07-2.13). This locus is designated Swrl3 (SWR lupus locus 3). SWR-derived alleles confer increased ANA production with a dominant mode of inheritance.Potential candidate genes for Swrl3are Fgf17 (38 cM), Dok2 (39 cM), and Nkx3-1 (30 cM).
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