PHYSICAL MAP OF THE 3' REGION OF THE HUMAN-IMMUNOGLOBULIN HEAVY-CHAIN LOCUS - CLUSTERING OF AUTOANTIBODY-RELATED VARIABLE SEGMENTS IN ONE HAPLOTYPE

We have constructed the physical map of the 3' region of the human immunoglobulin heavy chain variable region (V(H)) genes. DNA segments extending to 200 kb upstream of the J(H) segment were isolated in two YAC clones. Five V(H) segments were identified in this region in the 5' to 3' order, V(II-5), V(IV-4), V(I-3), V(I-2), and V(VI-1) segments which were all structurally normal and orientated in the same direction as the J(H) segments. From DNA of a different cell line we have isolated a cosmid contig containing the same DNA region which has extraordinary polymorphism. The YAC and cosmid DNAs were called haplotypes A and B, respectively. Haplotype B contained an additional V(H-I) segment (VI-4.1b) between the V(II-5) and V(IV-4) segments. V(I-4.1b) segment is almost identical to a previously published V(H) sequence encoding a rheumatoid factor. Another V(H) segment in the B haplotype (V(I-3b)) corresponding to the V(I-3) segment also showed 99.7% nucleotide sequence homology with an anti-DNA autoantibody V(H) sequence. However, none of the V(H) sequences in haplotype A showed such strong homology with autoantibody V(H) sequences. The results suggest that V(H) haplotypes may have linkage with autoantibody production.