PREFERENTIAL REARRANGEMENT IN NORMAL RABBITS OF THE 3' VHA ALLOTYPE GENE THAT IS DELETED IN ALICIA MUTANTS - SOMATIC HYPERMUTATION CONVERSION MAY PLAY A MAJOR ROLE IN GENERATING THE HETEROGENEITY OF RABBIT HEAVY-CHAIN VARIABLE REGION SEQUENCES

The rabbit is unique in having well-defined allotypes in the variable region of the heavy chain. Products of the V(H)a locus, (with alleles a1, a2, and a3), account for the majority of the serum immunoglobulins. A small percentage of the serum immunoglobulins are a-negative. In 1986, Kelus and Weiss described a mutation that depressed the expression of the Ig V(H) a2 genes in an a1/a2 rabbit. From this animal the Alicia rabbit strain was developed and the mutation was termed ali. We previously showed, using Southern analysis and the transverse alternating field electrophoresis technique, that the difference between the ali rabbit and normal is a relative small deletion including some of the most 3' V(H) genes. The most J(H) proximal 3' V(H)1 genes in DNA from normal rabbits of a1, a2 and a3 haplotypes encode a1, a2 and a3 molecules respectively, and it has been suggested that these genes are responsible for allelic inheritance of V(H)a allotypes. The present study suggests that the 3' end of the V(H) locus probably plays a key role in regulation of V(H) gene expression in rabbits because V(H) gene(s) in this region are the target(s) of preferential VDJ rearrangements. This raises the possibility that mechanisms such as somatic gene conversion and hypermutation are at work to generate the antibody repertoire in this species. Our data support the view that the 3' V(H)1 gene may be the preferred target for rearrangement in normal rabbits, and for the normal chromosome in heterozygous ali animals. However, homozygous ali rabbits with a deletion that removed the a2-encoding V(H)1 on both chromosomes do survive, rearrange other V(H) genes and produce normal levels of immunoglobulins as well as a significant percentage of B cells which bear the a2 allotype. This challenges the view that one V(H) gene, V(H)1, is solely responsible for the inheritance pattern of V(H)a allotypes.