Linkage analysis was performed on over 350 (129S6/SvEvTac-Prf1tm1Sdz x C57BL/6J-Prf1tm1Sdz)F1 x 129S6/SvEvTac-Prf1tm1Sdz backcross animals to identify loci associated with NK cell-mediated bone marrow (BM) graft rejection. Parental strain 129S6/SvEvTac-Prf1tm1Sdz does not efficiently reject BM grafts compared to C57BL/6J-Prf1tm1Sdz. Phenotypically extreme backcross animals (49 accepting BM grafts and 89 rejecting BM grafts) were genotyped at 78 polymorphic markers at 75% genome coverage.
Bmgr1 (bone marrow graft rejection 1) mapped to 37 cM on mouse Chromosome 8 near D8Mit249 (LOD=3.87). C57BL/6J-derived alleles at Bmgr1 confer BM graft resistance. Potential candidate genes mapping to this region include Mmp2 (44 cM0, Mmp15 (44.5 cM), IL12rb1(33.5 cM), Il15 (38 cM), Plcg2 (62 cM), and Jak3 (33 cM).
Bmgr2 (bone marrow graft rejection 2) mapped to 28 cM on mouse Chromosome 2 near D2Mit237 (LOD=2.48). C57BL/6J-derived alleles at Bmgr2 confer BM graft rejection. Potential candidate genes for Bmgr2 include Il15ra (6.4 cM), Vav2 (15.3 cM), Prkcq (2 cM), and Gata3 (7 cM). A second locus on chromosome 2 named Bmgr3 mapped to 99 cM near D2Mit291 (LOD=2.55). Homozygosity for 129S6/SvEvTac-derived alleles at Bmgr3 confer BM graft rejection. Potential candidate genes near Bmgr3 include Mmp9 (96 cM), Mmp24 (87.5 cM), Nfatc2 (formerly Nfat1, 95.5 cM), and Plcg1 (92 cM).
A suggestive locus named Bmgr4 (bone marrow graft rejection 4) mapped to 44.5 cM on mouse Chromosome 4 near D4Mit145 (LOD=2.01). C57BL/6J-derived alleles at Bmgr4 confer increased BM graft rejection. Potential candidate genes for Bmgr4 include the Ifnga family genes (42.6 cM), Ifnb1 (42.6 cM), and Jak1 (46.3 cM).
Ebmgr1 (epsitatic bone marrow graft rejection 1) mapped to 87.6 cM on mouseChromosome 3 near D3Mit163. This locus interacts with Bmgr4 on chromosome 4. Homozygosity for 129S6/SvEvTac-derived alleles at Ebmgr1 in conjunction with a C57BL/6J-derived allele at Bmgr4 confers BM graft rejection. Potential candidate genes for Ebmgr1 include Gbp1 (67.4 cM), Gbp2 (67.4 cM), and Gbp5 (67.4 cM).