Linkage of a major quantitative trait locus toYaa gene-induced lupus-like nephritis in (NZW × C57BL/6)F1 mice

Abstract

In the present study, we mapped the major quantitative trait loci (QTL) differing between the NZW and C57BL/6 inbred strains of mice by making use of (NZW × C57BL/6.Yaa)F1 mice, a model in which the lupus-like autoimmune syndrome observed in male mice is associated with the presence of an as yet unidentified Y chromosome-linked autoimmune acceleration gene, Yaa. Linkage analysis of 126 C57BL/6 × (NZW × C57BL/6.Yaa)F1 backcross males provided evidence for a major QTL on chromosome 7 controlling both the severity of glomerulonephritis and the production of IgG anti-DNA autoantibody and retroviral gp70-anti-gp70 immune complexes. Two additional QTL of C57BL/6 origin on chromosome 17 had no apparent individual effects, but showed strong epistatic interaction with chromosome 7 QTL for disease severity and anti-DNA autoantibody production. Our data also identified on chromosome 13 a QTL of NZW origin with a major effect on the level of gp70, and showing an additive effect with the chromosome 7 QTL on the level of gp70 immune complexes. Our study thus provides a model to dissect the complex genetic interactions that result in manifestations of murine lupus-like disease.

A Novel Susceptibility Locus On Chromosome 2 in the (New Zealand Black × New Zealand White)F1 Hybrid Mouse Model of Systemic Lupus Erythematosus

“…Weak linkage was found to marker locus D7 Mit246 ( 2 ϭ 4.74; p Ͻ 0.03), which mapped between Sle3 and Sle5 loci on chromosome 7 (6). A similar locus was previously identified in Yaa (Y-linked autoimmune acceleration) gene-induced lupus-like nephritis in (NZW ϫ C57BL/6)F 1 mice (22). For anti-histone Ab production, we identified weak linkage to two loci: one colocalized with D1 Mit17 ( 2 ϭ 7.66; p Ͻ 7 ϫ 10 Ϫ3 ), which had the strongest effect on anti-dsDNA autoantibody production, and the other was D4 Mit17 ( 2 ϭ 7.26; p Ͻ 7 ϫ 10 Ϫ3 ) which is located 13 cM centromeric to the Sle2 locus.…”

A Novel Locus Regulates Both Retroviral Glycoprotein 70 and Anti-Glycoprotein 70 Antibody Production in New Zealand Mice When Crossed with BALB/c

“…In the current two crosses, no consistent suggestion for linkage to gp70 and/or gp70IC was seen at the region of chromosome 13 (ϳ40 cM from the centromere), previously described in NZB ϫ C57BL/6 (9), as Bxs6 in BXSB ϫ C57BL/10 (11) and in NZW ϫ C57BL/6.Yaa (12) crosses. This suggests that allelic differences exist between NZ and BALB/c mice at the proximal chromosome 12 locus, but not at the mid-chromosome 13 locus described above.…”

“…A region on chromosome 13, between 30 and 50 cM from the centromere, was linked to gp70 and gp70IC levels in NZB, NZW, and BXSB mice on a C57BL/10 or C57BL/6 background (9,11,12). A region on distal chromosome 4 was linked to serum gp70 levels in NZB mice on a C57BL/6 background (9), and linkage with serum gp70 and/or serum gp70IC levels has also been demonstrated on chromosome 7 in NZW and 129 mice on a C57BL/6 background (12,13). A number of other loci have demonstrated weak linkage to gp70 and gp70IC, including chromosome 17, at the H2 complex, in non-H2-matched cohorts (8,12,14).…”

Dominant NZB contributions to lupus in the (SWR×NZB)F1 model

“…Morel et al, 11 mapped GN susceptibility to the p locus on Chr 7 (peak at 28 cM), where the NZM/NZW allele promotes disease, and the B6 allele is protective. Santiago et al, 15 have also mapped GN susceptibility to a NZW locus on Chr 7 (peak at 25 cM). The NZB dominant locus for GN on Chr 7 that is mapped by the present analysis is positioned between these loci, with a peak at 31 cM.…”

“…[5][6][7][8][9][10][11][12][13] In addition, genetic studies in the BXSB and MRL/lpr strains have also shed light on additional loci predisposing to lupus. [14][15][16][17][18][19][20] Among the different loci identified in these studies, four certainly appear to tower above the rest, as they light up in most of the studies. These include loci on Chr 1 (Sle1/Nba2), 4 (Sle2/Lbw2/Sbw2, and Nba1), 7 (Sle3/Sle5), and 17 (H2).…”