Recombination signature of germline immunoglobulin variable genes

Abstract

Summary In human and mouse, the germline contains a tandem array of highly homologous variable (V) gene elements which encode part of the antigen-binding region of the antibody protein. During evolution this array apparently arose by gene duplication followed by diversi®cation of duplicated genes via point mutation and recombination. Analysis of germline V gene sequences using a novel algorithm shows that major recombination sites coincide with the borders of the leader intron and the cap site, consistent with the hypothesis that over evolutionary time cDNA derived by reverse transcription of pre-mRNA in B lymphocytes has recombined with germline DNA.

Soma‐to‐germline feedback is implied by the extreme polymorphism at IGHV relative to MHC

“…triplet‐based in‐frame insertion and deletion differences, and heavy chains show evidence of fused in‐frame VD genes suggestive of a somatic origin in these vertebrate species. Again on translation these differences cause amino acid replacements . Generally flanking and V coding regions show different phylogenies suggesting they are evolving independently . The major sites of genetic recombination between non‐allelic homologous V genes coincide with predicted sites of soma‐to‐germline retrotransposition , as indicated by “x” in Fig. .…”

The signature of somatic hypermutation appears to be written into the germline IgV segment repertoire

“…The PhylPro computer program (59) has been devised which implements the algorithm. We have used the phylogenetic profile method (the Weiller algorithm) to detect genetic recombination in germhne V element DNA sequences (37).…”

“…Fig. 5(see Weiller et al(37) for further analysis and discussion). There-300 400 Phylogenetic profile plot of 49 hnman germline V^ subgronp I genes as produced by the PhylPro program.…”

“…There-300 400 Phylogenetic profile plot of 49 hnman germline V^ subgronp I genes as produced by the PhylPro program. Full details of the analytical procedure can be found in Weiller et al(37). An original alignment of subgroup 1 genes was assembled.…”

“…Removal of invariable columns and columns containing more than 20 alignment gaps condensed the original alignment from 752 to 460 positions. The phylogenetic profile was constructed using the linear correlation of p-distances in 50 bp-wide windows(37,58). The positions 25 to 445 are shown on the horizontal axis.The corresponding gene structure is given on the top.…”