A Molecular Genetic Approach to Understanding the Evolution of Immunoglobulin Gene Structure and Diversity

Immune function in higher vertebrates is mediated primarilyby multimeric glycoproteins found in the serum and on the surfacesof lymphoid cells. These molecules possess common structuralfeatures suggesting that they belong to a supergene family whichmay have originated from a common ancestral gene. Some multigenicmembers of the supergene family undergo unique forms of chromosomalrearrangement during somatic development. We have identifiedimmunoglobulin heavy chainvariable region (V_H) homologs in speciesrepresenting critical points in the vertebrate radiation, examinedtheir nucleotide sequences and found high degrees of organizationalhomology as well as localized regions of extended nucleotide(and amino acid) sequence identity with mammalian V_H genes.The unexpected high degree of nucleotide sequence identity suggeststhat within this multigene family, selection may be operatingat both the DNA and polypeptide levels.Using several differentapproaches, the V_H gene families in lower vertebrates have beenshown to be remarkably complex, discounting the possibilitythat a reduced number of germline genes accounts for the apparentlyrestricted natureof lower vertebrate immune responses. The lowervertebrate germline V_H genes possess prototypic recombinationsignal sequences, implicated in the somatic reorganization ofmammalian immunoglobulin variable region genes, and segmentalreorganizationresembling that seen in mammals has been observed in an elasmobranch.The detection of a recombination element flanked by short, directrepeats within the intervening sequence of one reptilian V_Hgene suggests that these sequences may be mobile, perhaps functioningoutside of the immunoglobulin loci in other developmental processes.The complex nature of the variable region gene families andtheir capacity to undergo structural change during somatic developmentsuggest that unique genetic mechanisms may govern their evolutionarystabilization and diversification.