Major reorganization of immunoglobulin V_H segmental elements during vertebrate evolution

Abstract

In mammals, the immunoglobulin heavy-chain variable region (V_H) locus is organized in a linear fashion; individual V_H, diversity (D_H), joining (J_H) and constant (C_H) region segments are linked in separate regions¹. During somatic development, coding segments flanked by characteristic short recombination signal sequences, separated by intervening sequence regions that may exceed 2,000 kilobases (kb), are recombined. Combinatorial joining of different segments as well as imprecision in this process contribute to the diversity of the primary antibody response; subsequent mutation further alters functionally rearranged genes. This basic somatic reorganization mechanism is shared by six major families of genes encoding antigen receptors². Previously, we have shown that multiple germline genes and mammalian-like recombination signal sequences are associated with the V_H gene family of Heterodontus francisci (horned shark), a primitive elasmobranch³. Studies presented here demonstrate that segmental reorganization involving mammalian-like D_H and J_H segments occurs in the lymphoid tissues of this species. In marked contrast to the mammalian system, we find multiple instances of close linkage (∼10 kb) between individual V_H, D_H, J_H and C_H segments. This unique organization may limit combinatorial joining and be a factor in the restricted antibody response of this lower vertebrate^4,5.