Allelic exclusion simplifies the problem of immune recognition. It ensures that each B cell makes antibodies that recognize only one target because, once the DNA of a single immunoglobulin allele has rearranged to form a functional gene, the other allele is prevented from rearranging. Now Esther Roldán, Jane Skok (University College London, UK), and colleagues find that allele exclusion may rely on putting different parts of the unrearranged gene too far from each other to allow rearrangement.
Rearrangement is only possible in such huge loci because of DNA contraction and (as shown here) looping that juxtaposes distant DNA sites. Skok and colleagues now show that successful rearrangement is immediately followed by decontraction of the unrearranged allele. Proximal variable (V) regions are still within reach of the rearrangement apparatus, but the products of these rearrangements are disfavored later because they pair poorly with immunoglobulin light chains and usually fail to induce positive selection of cells.
There is a backup mechanism for allele exclusion. Coincident with decontraction, the unrearranged allele is also recruited to repressive centromeric domains. But Skok says she thinks decontraction “is the most important factor. Decontraction seems to be irreversible and immediate, whereas recruitment is reversible.”