Genetic fixity in the human major histocompatibility complex and block size diversity in the class I region including HLA-E

Viviana Romero,Lama El-Dahdah,Zaheed Husain,Edward A Fox,Jonathan S Duke-Cohan,Olga P Clavijo,Joaquin Zuñiga,Charles E Larsen,Ingrid Almeciga,Edmond J Yunis,Dennis R Alford,Dolores A Fici,Chester A Alper,Tatiana Romero,Zuheir L Awdeh

doi:10.1186/1471-2156-8-14

Abstract

BackgroundThe definition of human MHC class I haplotypes through association of HLA-A, HLA-Cw and HLA-B has been used to analyze ethnicity, population migrations and disease association.ResultsHere, we present HLA-E allele haplotype association and population linkage disequilibrium (LD) analysis within the ~1.3 Mb bounded by HLA-B/Cw and HLA-A to increase the resolution of identified class I haplotypes. Through local breakdown of LD, we inferred ancestral recombination points both upstream and downstream of HLA-E contributing to alternative block structures within previously identified haplotypes. Through single nucleotide polymorphism (SNP) analysis of the MHC region, we also confirmed the essential genetic fixity, previously inferred by MHC allele analysis, of three conserved extended haplotypes (CEHs), and we demonstrated that commercially-available SNP analysis can be used in the MHC to help define CEHs and CEH fragments.ConclusionWe conclude that to generate high-resolution maps for relating MHC haplotypes to disease susceptibility, both SNP and MHC allele analysis must be conducted as complementary techniques.

Highlights

The definition of human major histocompatibility complex (MHC) class I haplotypes through association of HLA-A, HLA-Cw and HLA-B has been used to analyze ethnicity, population migrations and disease association
It is well recognized that conserved extended haplotype (CEH) may be represented as a higher order of association, through successive generations, of four or more defined MHC blocks, showing a stronger linkage disequilibrium (LD) to that expected by random recombination
To improve human MHC haplotype resolution, we initially set about determining HLA-E allele polymorphism in the HLA-A/HLA-Cw interval

Summary

Introduction

The definition of human MHC class I haplotypes through association of HLA-A, HLA-Cw and HLA-B has been used to analyze ethnicity, population migrations and disease association. The rich polymorphism in this region is a critical determinant for success in tissue transplantation, and in recent years has found a further use in characterizing both ethnic and geographical population relationships. Haplotype analysis is based on the conservation of short blocks of conserved DNA sequence containing specific allele combinations of two or more adjacent or nearby genetic loci. Within the MHC region, a limited number of specific haplotypes are known to be shared by unrelated individuals of well-defined human populations. These relatively long stretches of conserved DNA sequence in the MHC have been termed conserved extended haplotypes (CEHs) [1] or ancestral haplotypes [2,3]. It is well recognized that CEHs may be represented as a higher order of association, through successive generations, of four or more defined MHC blocks, showing a stronger linkage disequilibrium (LD) to that expected by random recombination

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Discussion

Conclusion