Citations

Three cDNA with D region gene features have been identified from the H-2v haplotype. Provisionally, the sequences have been designated as D/Lv1, D/Lv2, and D/Lv3. The coding segments for the antigen binding domain (ABD) of all three D/Lv genes were engineered into a class I genomic expression vector and expressed in L cells. FACS analysis of the three D/Lv-Ld gene transfectants revealed that the D/Lv1 molecules were recognized by both monoclonal antibodies (mAbs) 141 and 142, and the D/Lv2 molecules were recognized by mAb 143. In addition to the D/Lv1 molecules, the mAb 141 also recognized the D/Lv3 molecules. Both the D/Lv1-Ld and D/Lv2-Ld transfectants were killed efficiently by H-2Dv region-specific alloreactive CTL. The D/Lv3 gene is the first identified D region gene other than D and L that is transcribed abundantly in spleen and the D/Lv3 RNA is present as two alternatively spliced forms. Structural analysis of the D/Lv3 hybrid molecules showed that it was susceptible to proteolysis and thermolabile at 37 degrees C, suggesting D/Lv3 is a transcribed pseudogene. A parsimony tree analysis of three D/Lv sequences with a set of class I gene sequences revealed that the H-2v sequences clustered with D region genes. The presence of a third gene with D/L-like features in H-2v, yet structurally different from the known D/L alleles, raises the possibility that the current D/L genes evolved from a family of D/L-like genes, some of which are no longer represented among many of the mouse major histocompatibility complex haplotypes. The observation that D region alleles cluster into subgroups suggests that the alleles are not all related to each other by linear descent through a single locus. We propose that current alleles are derived from more than one ancestral locus in a manner similar to the origin of the gamma 2 a immunoglobulin constant region alleles.

The apolipoprotein E ( APOE ) gene is the only genetic risk factor that has so far been linked to risk for late-onset Alzheimer's disease (LOAD). However, 50 percent of Alzheimer's disease cases do not carry an APOE4 allele, suggesting that other risk factors must exist. We performed a two-stage genome-wide screen in sibling pairs with LOAD to detect other susceptibility loci. Here we report evidence for an Alzheimer's disease locus on chromosome 10. Our stage one multipoint lod score (logarithm of the odds ratio for linkage/no linkage) of 2.48 (266 sibling pairs) increased to 3.83 in stage 2 (429 sibling pairs) close to D10S1225 (79 centimorgans). This locus modifies risk for Alzheimer's disease independent of APOE genotype.