Uneven distribution of repetitive trinucleotide motifs in human immunoglobulin heavy variable genes.

Abstract

Insertions and deletions of entire codons have recently been discovered as a mechanism by which B cells, in addition to conventional base substitution, evolve the antibodies produced by their immunoglobulin genes. These events frequently seem to involve repetitive sequence motifs in the antibody-encoding genes, and it has been suggested that they occur through polymerase slippage. In order to better understand the process of codon deletion, we have analyzed the human immunoglobulin heavy variable (IGHV) germline gene repertoire for the presence of trinucleotide repeats. Such repeats would ensure that the reading frame is maintained in the case of a deletional event, as slippage over multiples of three bases would be favored. We demonstrate here that IGHV genes specifically carry repetitive trinucleotide motifs in the complementarity-determining regions (CDR) 1 and 2, thus making these parts of the genes that encode highly flexible structures particularly prone to functional deletions. We propose that the human IGHV repertoire carries inherent motifs that allow an antibody response to develop efficiently by targeting codon deletion events to the parts of the molecule that are likely to be able to harbor such modifications.