Allelic diversity is generated by intraexon sequence exchange at the DRB1 locus of primates.

Abstract

The loci encoding the class II cell surface antigens HLA-DR, -DQ, and -DP exhibit a remarkable degree of aflelic polymorphism. Most of the class I allelic diversity is localized to the second exon, which encodes a fl-pleated sheet followed by an a-helical domain. Here, phylogenetic analysis of 39 human DR8I alleles and 21 DRBI alleles obtained by polymerase chain reaction (PCR) amplification from a set of closely related primates reveals that sequences encoding the fl-pleated sheet and those encoding the a-helix of the second domain have different evolutionary histories. The polymorphisms in the fpleated sheet have been conserved between species and appear to reflect the ancestral relationships among haplotypes, whereas polymorphic segments encoding the a-helical domain appear to have been inserted by interallelic sequence exchange into the framework of different ancestral DRBI sequences. Allelic polymorphism at the DRBl locus may thus have been generated in part by combining different variants of the two structural domains.Loci in the major histocompatibility complex (MHC) class II region encode cell surface antigens that consist of highly polymorphic a and fl glycoprotein chains (1-5). The T-cell receptor recognizes antigen peptide fragments bound to the class II molecule on the surface of antigen-presenting cells (6,7). Most of the polymorphism in the class II molecule is located in the NH2-terminal domain, which forms the putative sites for binding foreign antigen peptides and is encoded by the second exon of the a-and f-chain loci (8).Recently, alleles at primate MHC loci have been shown to predate the divergence of hominoids, and in some cases even that of Old World monkeys, indicating that the polymorphism has been conserved by selection over long evolutionary periods (9)(10)(11)(12). The patchwork ofallelic sequence diversity at some ofthe human class II loci has been taken to indicate that allelic diversity is generated by recombination or segmental transfer. For instance, the similarity between DRB1 and DRB5 sequences on the DR2 haplotype was postulated to be due to a reciprocal exchange (13), and, similarly, sequences from the second exon of DRB3 on a DRw6 haplotype were suggested to have been donated by gene conversion to the DRBI locus (14). However, the presence of shared polymorphism between alleles could, in principle, be due to either common ancestry, convergent evolution, or sequence exchanges between members of different allelic lineages. § MATERIALS AND METHODSThe second exon ofHLA-DRBI was enzymatically amplified by 30 cycles ofPCR (15, 16) using the oligonucleotide primers GH46 and GH50 (17) and 1 ug of genomic DNA from 13 chimpanzees (Pan troglodytes), 4 pygmy chimpanzees (Pan paniscus), 6 gorillas (Gorilla gorilla), 2 rhesus monkeys (Macaca mulatta), and 2 baboons (Papio leucophaeus). Amplified DNA fragments were ligated into phage M13 mp18 and sequenced by the chain-termination method (18). The amino acid sequence of each allele was inferred from the nucleotide sequence of at le...

Pathway-based analysis of genetic susceptibility to cervical cancer in situ: HLA-DPB1 affects risk in Swedish women

“…This pattern has been proposed to reflect extensive gene conversion involving the region of exon 2 encoding the part of the a-helix. 35 Consistent with this explanation, we detected strong LD between SNP haplotypes in the DPB1 region and motifs in the second exon encoding part of the b-pleated sheet of the b-chain.…”

“…34) and DRB1 (ref. 35) , that there is strong LD between the region of exon 2 encoding part of the b-pleated sheet (codons 8-60) and downstream intron sequences, whereas the region of exon 2 encoding the first part of the a-helix (codons 61-78) shows less LD to other parts of the second exon or intron sequences. This pattern has been proposed to reflect extensive gene conversion involving the region of exon 2 encoding the part of the a-helix.…”

Understanding the phylogeographic patterns of European hedgehogs, Erinaceus concolor and E. europaeus using the MHC

“…However, a higher d S value in the b-floor region than for the a-helix region suggests different evolutionary histories. Similar patterns have been noted in DRB sequences (Gyllensten et al, 1991;Schwaiger et al, 1993) and a conserved recombination motif, present also in the hedgehog DQB sequences, has been identified (Wu et al, 1986).…”

Distinguishing recombination and intragenic gene conversion by linkage disequilibrium patterns

“…Usually, nucleotide sequence patterns of a number of different haplotypes in a population are used to characterize candidate regions for conversion events which may have taken place in the past. Phylogenetic (Gyllensten et al, 1991), graphical or statistical (Sawyer, 1989 ;Kuhner et al, 1991 ;Betran et al, 1997 ;Weiller, 1998) methods are employed. However, it is generally very difficult to reconstruct ancestral haplotypes.…”

“…Several statistical approaches to the detection of conversion have been suggested in the past. These generally involve either the examination of the distribution of nucleotide substitutions along the DNA sequence (Sawyer, 1989 ;Stephens, 1985), or the comparison of phylogenetic trees inferred from different segments within a DNA region (Gyllensten et al, 1991). Takahata (1994) found that, while in some cases significant clustering of nucleotide site configurations across sequences could be detected, such clustering does not imply that conversion has taken place.…”