Dominant Sequences of Human Major Histocompatibility Complex Conserved Extended Haplotypes from HLA-DQA2 to DAXX

Abstract

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.

Sequences of 95 humanMHChaplotypes reveal extreme coding variation in genes other than highly polymorphicHLA class IandII

“…Other MHC region genes encode complement components, cytokines, transcription factors, structural and developmental proteins, olfactory receptors, and numerous tRNAs (Horton et al 2004). Extensive linkage disequilibrium (LD) characterizes the MHC region, creating long-range haplotypes (Price et al 1999;Larsen et al 2014). This feature complicates the analysis of HLA-associated diseases, because polymorphisms in genes having no known participation in disease causation can be disease-associated (Trowsdale and Knight 2013;O'Donovan 2014).…”

Unique Allelic eQTL Clusters in Human MHC Haplotypes

“…Yet, when compared with the causality of single variants to traits, our current understanding of how haplotype combinations affect phenotypic consequences is inadequate. A key component for understanding this complex relationship is through the analysis of MHC haplotype sequence variations ( de Bakker and Raychaudhuri 2012 ; Larsen et al 2014 ). As such, the ability to demonstrate how MHC haplotype sequence variability can modify gene transcript abundance within the MHC will be an important step toward improving our understanding of the biological effects of specific MHC haplotypes.…”

Intrahaplotypic Variants Differentiate Complex Linkage Disequilibrium within Human MHC Haplotypes

“…Subsequent studies employed target region and next generation re-sequencing approaches to interrogate variations residing within the MHC region 19 20 , but the cell lines investigated were either HLA heterozygous or did not exhibit CEH characteristics in the MHC genomic region. Partial re-sequencing studies were also performed to examine the sequence conservation in the CEHs 21 22 . Unfortunately, less than 20% of the conserved region was sequenced in these studies, and the authors were therefore unable to explore the scope of variation in CEHs definitively.…”