Experiment
Susceptibility to systemic lupus erythematosus was mapped using 156 C1qatm1Mjw homozygous female animals from a (129P2/Ola-C1qatm1Mjw x C57BL/6-C1qatm1Mjw)F2 intercross. Genome scan was performed using genetic markers at a resolution of 10 cM. Parental strains 129P2/Ola-C1qatm1Mjw and C57BL/6-C1qatm1Mjw do not develop autoimmune disorder, however F1 hybrids are susceptible to lupus-like disease. Experimental animals were monitored for 1 year and assessed for anti-nuclear antibodies (ANA), anti-chromatin antibodies (Abs), anti-double stranded (anti-ds) DNA antibodies, anti-single (anti-ss) stranded DNA antibodies, and glomerulonephritis. Identified QTLs were confirmed by reanalysis of a larger cohort of 297 females which include (129X1/Sv x C57BL/6)F2 animals.
Significant linkage to ANA (LOD=4), anti-dsDNA Abs (LOD=5.3), and anti-ssDNA Abs (LOD=5.5) mapped to 95 cM on mouse Chromosome 1 with peak marker D1Mit206. Linkage to anti-chromatin Abs was suggestive (LOD=2.2). Analysis of the expanded cohort confirmed this locus and increased statistical significant for all measures- ANA (LOD=6.3), anti-dsDNA Abs (LOD=7.6), anti-ssDNA Abs (LOD=8.3), anti-chromatin Abs (LOD=4.7). This locus colocalizes with Sle16 (systematic lupus erythematosus susceptibility 16) and most likely represents the same QTL. 129-derived alleles at Sle16 confer increased autoimmune traits with dominant inheritance. Previously identified autoimmune QTLs mapping near Sle16 include Sle1 (103 cM), Nba2 (95 cM), Yaa4 (formerly Bxs3; 100 cM), and Lbw7 (90 cM). Potential candidate genes include Slamf1 (93 cM), Slamf6 (89.5 cM), Cd48 (93.3 cM), Cd84, Cd244, Ly9, and the Cd2 family (87 cM - 106 cM).
04.02.2015 Curators Note: Sle16 was originally mapped in J:93297 in 2004 using an (129S6/SvEvTac x C57BL/6)F2 intercross, which differs from the 129 substrain used here, we consider the current study a different mapping experiment and have named the QTL colocalizing here with Sle16, as Sle21.
Suggestive linkage to ANA mapped to 55 cM on mouse Chromosome 3 with peak marker D3Mit103 (LOD=2.3). Analysis of the expanded cohort increased linkage to LOD=8 at 50 cM between D3Mit103 and D3Mit106. This locus colocalizes with Sle18 (systematic lupus erythematosus susceptibility 18) and most likelyrepresents the same QTL.
04.02.2015 Curators Note: Sle18 was also originally mapped in J:93297 in 2004 using an (129S6/SvEvTac x C57BL/6)F2 intercross, which differs from the 129 substrain used here, we consider the current study a different mapping experiment and have named the QTL colocalizing here with Sle18, as Sle22.
C57BL/6-derived alleles at Sle22 confer increased ANA with recessive inheritance. Previously identified QTLs Sles3 (35 cM) and Sle11 (formerly Bsx5; 39.7 cM) map proximally to Sle22.
QTL interaction was observed between Sle21 (chr1) and Sle22 (chr3). F2 animals with at least one 129-derived allele at Sle21 and homozygous for C57BL/6-derived alleles at Sle22 display significantly greater ANA compared to other F2 genotypes.
Linkage toglomerulonephritis mapped to an interval on mouse Chromosome 7 between D7Mit246 (15 cM) and D7Mit30 (37 cM) with LOD=2.2. Analysis of only phenotypically extreme F2 animals gave linkage at 26.3 cM near D7Mit230. The expanded cohort confirmed linkage to glomerulonephritis (LOD=3.8). This locus is designated Sle19 (systematic lupus erythematosus susceptibility 19). C57BL/6-derived alleles at Sle19 confer increased glomerulonephritis. Previously identified autoimmune QTL mapping near Sle19 include Sle3 (15 cM), Lbw5 (23 cM), and Nba3 (31 cM)).
Suggestive linkage to glomerulonephritis was detected on mouse Chromosome 13 in the expanded cohort with LOD=2.4 near D13Mit64 (30 cM). C57BL/6J-derived alleles at this locus confer increased glomerulonephritis.
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