Sequence differences between HLA‐B and TNF distinguish different MHC ancestral haplotypes

Abstract

The HLA-B locus is extremely polymorphic. We have sequenced a region, CL, telomeric of HLA-B that also shows a high degree of allelic variation which we have shown previously by RFLP analysis. The polymorphism can be accounted for by sequence variation in duplicated, reiterated sequence elements called geometric elements. Comparison of the CL1 and CL2 sequences from the 57.1, 8.1, 18.2 and 7.1 ancestral haplotypes revealed that the lengths of the elements vary, both between the duplicated loci within a haplotype and between haplotypes, apparently because certain sequences are inserted or deleted. It is possible, using the polymerase chain reaction, to amplify these elements in genomic DNA from ancestral haplotypes for which sequence data of the CL region are not available and to obtain gel patterns which are characteristic of different ancestral haplotypes. The most striking feature of the data is the fact that the majority of the CL patterns are haplospecific; i.e. have a particular pattern that is unique for a particular ancestral haplotype and can be used to type these ancestral haplotypes. At least 12 different allelic patterns have been identified within a panel of 29 cell lines representing 16 ancestral haplotypes. For these 16 ancestral haplotypes, all examples of each haplotype have the same CL pattern. The haplotypic nature of the patterns confirms that ancestral haplotypes are conserved chromosomal segments and that coding and non-coding sequences are identical by descent from a remote ancestor.

MICA, MICB, and MHC Beta Block Matching in Bone Marrow Transplantation: Relevance to Transplantation Outcome

“…One of these blocks, the beta block, spans about 300 kb [4] and contains the immunologically relevant HLA-B, HLA-Cw, MICA, and MICB genes. Retrospective and prospective studies have shown that matching donors and recipients for non-HLA DNA sequences in the MHC (beta and delta block matching) can result in improved patient survival and less severe acute graft versus host disease (GVHD) [7][8][9][10].…”

A linkage disequilibrium map of the MHC region based on the analysis of 14 loci haplotypes in 50 French families

“…5,6 Their likely conservation in human populations has led some authors to define the notion of 'ancestral' haplotypes, preserved for various possible reasons from early human populations. 7,8 However, the choice of an accurate statistical measure of linkage disequilibrium, as well as its biological interpretation, is not straightforward. 9,10 One reason why linkage disequilibrium is often poorly estimated is that it requires an accurate estimation of haplotype frequencies, which is difficult when sample sizes are small.…”

HLA-allelotype associations with nevirapine-induced hypersensitivity reactions and hepatotoxicity

“…In addition, the application of an IPD metaanalysis would allow for the verification of the results presented in this study, while at the same time haplotypes could be investigated. A strong linkage disequilibrium between HLA-B*35, HLA-C*04:01 and HLA-DRB1*01:01 alleles has been shown to be preserved from early White populations [38,39]. Thus further information is needed to define whether the associations reported to date represent independent alleles or haplotype dependent effects between different populations.…”