The Noncoding Regions of HLA-DRB Uncover Interlineage Recombinations as a Mechanism of HLA Diversification

Abstract

The mechanisms generating new alleles at the MHC loci are still unknown in detail, and several proposals have been made to explain the extent of polymorphism. The patchwork pattern of polymorphism in the 2nd exon of HLA-DRB1 recommends this locus as a model for the study of the potential of interallelic gene conversion. In general, the inference of gene conversion-like events based exclusively on exon sequence comparisons may be misleading because the identity of the putative donor allele remains unknown. In this study, we describe five alleles of the HLA-DRB1 gene, which intron regions give evidence for interlineage recombination events either strictly located at the 2nd exon or involving the adjacent introns. Furthermore, we show that the noncoding regions provide important clues to the mechanisms of the generation of new alleles, and our results indicate that interlineage recombinations may be hidden and are perhaps more frequent than currently expected.

The nature of diversity of HLA‐DRB1 exon 3

“…The DRB1 exon 3 sequences supplied through our study yielded supporting evidence that DRB1*0302 served as a founder allele for DRB1*1402, DRB1*1406, and DRB1*1413 in different ethnic populations including South American Indians (4). Such evidence further elucidates the origin of alleles and the mechanisms driving sequence diversification.…”

Interallelic recombination is probably responsible for the occurrence of a new αs1‐casein variant found in the goat species

“…However, as over the 10 kb separating exon 8 from the end of the transcription unit there are no sequence clues indicating a second cross over, it seems most likely that the M allele originated in an interallelic recombination event. Gene conversion events, which usually account for exchanges over short sequence tracts [31], have been mainly described and intensively investigated as mechanisms generating allelic diversity in highly polymorphic genetic systems, such as the loci encoding the class‐II cell surface antigens of the major histocompatibility complex in humans [32,33]. Both mechanisms have also been thought to account for genetic disorders in humans, such as sporadic Alzheimer disease cases [34] and diabetic pathology involving the gene encoding insulin [35].…”

DRB1*1446 allele variations in the group‐specific annealing sites of common amplification primers

“…A new HLA‐DRB1*14 allele was finally confirmed by molecular cloning and sequencing using primers outside exon 2, in non‐coding regions of the HLA‐DRB1*1402 allele. The sense primer (I1SB14) was in intron 1 (6) and the antisense primer in intron 2 was previously designed as I2RB28 (7). The sequence of several clones from three different clonings corroborated that the new HLA‐DRB1*1446 allele was similar to DRB1*1402 at exon 2, but differed in various bases at nucleotide positions 15, 16, 17, 18, 19 and 22 of exon 2 (Fig.…”