Figure 1.

Diversification mechanism of variable lymphocyte receptors in jawless vertebrates. The germ-line VLR gene is incomplete and includes a non-coding intervening sequence flanked by hundreds of partial LRR gene cassettes. So, there are no direct coding sequences for the LRRNT, LRR1, LRRVs, LRRVe, and LLRCT modules in the germ-line configuration of the VLR genes. The assembling of functional VLR occurs during lymphocytes maturation in the thymoid by random and sequential copying of sequences from the flanking LRR cassettes into the non-coding intervening sequence in the direction from the 5’ LRRNT or from the 3’ LRRCT end. Diversification of the VLR repertoire mediates by CDA action and occurs because of the gene conversion-like process with nonreciprocal insertion of LRR cassettes into the germ-line VLR gene, and the “copy choice” mechanism, which includes an original template switch to a donor sequence of another LRR module during replication. This process is presumed to be directed by the short homologous stretches of sequence between the original and donor LRR sequences. The general array of LRR cassettes can be classified into five main structural groups, shown at the bottom of the figure. The mature VLR gene consists of several coding sequences: SP, LRRNT, LRR1, two to eight modules LRRV, LRRVe, CP, LRRCT, and the stalk region with an HP end, which anchors the VLR protein in the lymphocyte membrane. VLR, variable lymphocyte receptor; SP, signal peptide; LRR, leucine-rich repeat; LRRNT, N-terminal LRR-capping module; LRR1, first LRR; LRRV, variable LRR; LRRVe, end variable LRR; CP, connecting peptide; LRRCT, C-terminal LRR-capping module; HP, hydrophobic peptide; UTR, untranslated region; CDA, Cytidine deaminase. The illustration is not drawn to scale.