Asynchronous replication and allelic exclusion in the immune system

The development of mature B cells involves a series of molecular decisions which culminate in the expression of a single light-chain and heavy-chain a ntigen receptor on the cell surface(1,2). There are two alleles for each re ceptor locus, so the ultimate choice of one receptor type must involve a pr ocess of allelic exclusion. One way to do this is with a feedback mechanism that downregulates rearrangement after the generation of a productive rece ptor molecule(3), but recent work suggests that monoallelic epigenetic chan ges may also take place even before rearrangement(4). To better understand the basis for distinguishing between alleles, we have analysed DNA replicat ion timing. Here we show that all of the B-cell-receptor loci (mu, kappa an d lambda) and the TCR beta locus replicate asynchronously. This pattern, wh ich is established randomly in each cell early in development and maintaine d by cloning, represents an epigenetic mark for allelic exclusion, because it is almost always the early-replicating allele which is initially selecte d to undergo rearrangement in B cells. These results indicate that allelic exclusion in the immune system may be very similar to the process of X chro mosome inactivation.