An unusual type of V–J joining diversifies the primary repertoire of mouse λ1 light chains

Abstract

It is well established that B lymphocytes can achieve an almost unlimited antibody repertoire by using combinations of at least three different basic mechanisms¹. First, the mammalian genome has multiple, distinct germline variable (V), joining (J) and diversity (D) gene segments which can presumably combine randomly to give V–D–J joins in the heavy (H)-chain loci and V–J joins in the light (L)-chain loci during the formation of functional antibody genes. Second, the actual joining points between any two combining gene segments can vary considerably, increasing the germline diversity. Further variability is generated in the heavy-chain locus by de novo addition of extra nucleotides between the combining gene segments. Finally, somatic mutations independent from joining events can accumulate in V regions during the lifetime of B lymphocytes. Here we report that when V and J regions join in the formation of functional λ1 light-chain genes, ‘lethal’ out-of-frame joins can be compensated for by the deletion of nucleotides several bases upstream of the actual joining points; this generates small stretches of nucleotides in a new frame between the deletion and the V–J joining point, thus creating additional diversity in the third hypervariable regions of the mouse λ1 light chains.