Adult B-cell repertoire is biased toward two heavy-chain variable-region genes that rearrange frequently in fetal pre-B cells

Fetal pre-B cells rearrange a very restricted set of immunoglobulin variable genes for the heavy chain (V(H)). To determine whether the adult B-cell repertoire is similarly skewed, we first identified the genes that rearrange in pre-B cells from BALB/c mice and then determined their frequency of rearrangement in adult B cells. In fetal pre-B cell lines, two genes, V(H)81X from the 7183 subfamily and V(H)Ox2 from the Q52 subfamily, comprise 75% of the rearranged alleles of an estimated 1000 genes (P < 0.001). Sequencing analyses revealed that rearrangements involving the two genes were both productive and nonproductive. The biased rearrangement of these two V(H) genes persists in B-cell hybridomas from adult mice at a frequency of 22%, as determined by Southern gel analysis and RNA sequencing. The sequence of one V(H)Ox2 rearrangement from a hybridoma shows that the rearrangement is productive, suggesting that the gene encodes an antibody that could participate in the immune response. The data indicate that the adult B-cell repertoire is not random concerning usage of individual V(H) genes, and it may be shaped by the unknown mechanisms that cause preferential rearrangement of certain genes early in ontogeny.