A FETALLY EXPRESSED IMMUNOGLOBULIN V(H)1 GENE BELONGS TO A COMPLEX SET OF ALLELES

The immunoglobulin V(H) gene 51p1, a member of the large V(H)1 gene fa mily, is preferentially expressed by B cells in the fetus and in chron ic lymphocytic leukemia (CLL) and appears to be the source for many cr yoglobulin rheumatoid factors. Polymorphism of 51p1 may therefore be f unctionally important. We have studied the germline representation of 51p1 and closely related V(H) elements to establish their prevalence a nd allelic relationship. A panel of oligonucleotide probes directed to the complementarily determining regions (CDR1 and CDR2) of 51p1 and a similar gene, hv1263, was used in restriction fragment polymorphism a nalysis of 48 unrelated individuals and six families. 13 V(H) alleles to the 51p1 locus were identified, each distinguished by its restricti on fragment size, hybridization profile, or both. On some haplotypes t he locus was duplicated. Null alleles were not seen. The 13 alleles we re cloned, yielding nine distinct nucleotide sequences that were > 98. 2% identical and included 51p1 and hv1263. These germline variations c ould influence specificity for antigen, because the corresponding prot ein sequences differed by up to five amino acids, including three nonc onservative changes in the CDR. Two of the most prevalent variants con tained 51p1. These findings expand the spectrum of polymorphism seen a mong human V(H) , genes and elucidate the germline origin of V(H)1 seq uences frequently expressed in autoantibodies and CLL. We conclude tha t the 51p1 locus is polymorphic, and that the 51p1 element is the pred ominant member of a complex set of alleles.