Dominant sequences of human major histocompatibility complex conserved extended haplotypes from HLA-DQA2 to DAXX

We resequenced and phased 27 kb of DNA within 580 kb of the MHC class II region in 158 population chromosomes, most of which were conserved extended haplotypes (CEHs) of European descent or contained their centromeric fragments. We determined the single nucleotide polymorphism and deletion-insertion...

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Bibliographic Details
Published in:PLoS genetics 2014-10, Vol.10 (10), p.e1004637-e1004637
Main Authors: Larsen, Charles E, Alford, Dennis R, Trautwein, Michael R, Jalloh, Yanoh K, Tarnacki, Jennifer L, Kunnenkeri, Sushruta K, Fici, Dolores A, Yunis, Edmond J, Awdeh, Zuheir L, Alper, Chester A
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - genetics
Base Sequence
Biology and Life Sciences
Chromosomes
Chromosomes, Human, Pair 6
Co-Repressor Proteins
Conserved Sequence
Deoxyribonucleic acid
DNA
DNA sequencing
European Continental Ancestry Group - genetics
Genes, Dominant
Genetic aspects
Genetic research
Genomics
Haplotypes
HLA-DP beta-Chains - genetics
HLA-DQ Antigens - genetics
HLA-DQ beta-Chains - genetics
Humans
Linkage Disequilibrium
Major histocompatibility complex
Major Histocompatibility Complex - genetics
Medical research
Medicine and Health Sciences
Molecular Chaperones
Mutation
Nuclear Proteins - genetics
Nucleotide sequencing
Polymorphism, Single Nucleotide
Population
Recombination, Genetic
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Summary:We resequenced and phased 27 kb of DNA within 580 kb of the MHC class II region in 158 population chromosomes, most of which were conserved extended haplotypes (CEHs) of European descent or contained their centromeric fragments. We determined the single nucleotide polymorphism and deletion-insertion polymorphism alleles of the dominant sequences from HLA-DQA2 to DAXX for these CEHs. Nine of 13 CEHs remained sufficiently intact to possess a dominant sequence extending at least to DAXX, 230 kb centromeric to HLA-DPB1. We identified the regions centromeric to HLA-DQB1 within which single instances of eight "common" European MHC haplotypes previously sequenced by the MHC Haplotype Project (MHP) were representative of those dominant CEH sequences. Only two MHP haplotypes had a dominant CEH sequence throughout the centromeric and extended class II region and one MHP haplotype did not represent a known European CEH anywhere in the region. We identified the centromeric recombination transition points of other MHP sequences from CEH representation to non-representation. Several CEH pairs or groups shared sequence identity in small blocks but had significantly different (although still conserved for each separate CEH) sequences in surrounding regions. These patterns partly explain strong calculated linkage disequilibrium over only short (tens to hundreds of kilobases) distances in the context of a finite number of observed megabase-length CEHs comprising half a population's haplotypes. Our results provide a clearer picture of European CEH class II allelic structure and population haplotype architecture, improved regional CEH markers, and raise questions concerning regional recombination hotspots.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1004637