Abstract
The genomic region (~4 Mb) of the human major histocompatibility complex (MHC) on chromosome 6p21 is a prime model for the study and understanding of conserved polymorphic sequences (CPSs) and structural diversity of ancestral haplotypes (AHs)/conserved extended haplotypes (CEHs). The aim of this study was to use a set of 95 MHC genomic sequences downloaded from a publicly available BioProject database at NCBI to identify and characterise polymorphic human leukocyte antigen (HLA) class I genes and pseudogenes, MICA and MICB, and retroelement indels as haplotypic lineage markers, and single-nucleotide polymorphism (SNP) crossover loci in DNA sequence alignments of different haplotypes across the Olfactory Receptor (OR) gene region (~1.2 Mb) and the MHC class I region (~1.8 Mb) from the GPX5 to the MICB gene. Our comparative sequence analyses confirmed the identity of 12 haplotypic retroelement markers and revealed that they partitioned the HLA-A/B/C haplotypes into distinct evolutionary lineages. Crossovers between SNP-poor and SNP-rich regions defined the sequence range of haplotype blocks, and many of these crossover junctions occurred within particular transposable elements, lncRNA, OR12D2, MUC21, MUC22, PSORS1A3, HLA-C, HLA-B, and MICA. In a comparison of more than 250 paired sequence alignments, at least 38 SNP-density crossover sites were mapped across various regions from GPX5 to MICB. In a homology comparison of 16 different haplotypes, seven CEH/AH (7.1, 8.1, 18.2, 51.x, 57.1, 62.x, and 62.1) had no detectable SNP-density crossover junctions and were SNP poor across the entire ~2.8 Mb of sequence alignments. Of the analyses between different recombinant haplotypes, more than half of them had SNP crossovers within 10 kb of LTR16B/ERV3-16A3_I, MLT1, Charlie, and/or THE1 sequences and were in close vicinity to structurally polymorphic Alu and SVA insertion sites. These studies demonstrate that (1) SNP-density crossovers are associated with putative ancestral recombination sites that are widely spread across the MHC class I genomic region from at least the telomeric OR12D2 gene to the centromeric MICB gene and (2) the genomic sequences of MHC homozygous cell lines are useful for analysing haplotype blocks, ancestral haplotypic landscapes and markers, CPSs, and SNP-density crossover junctions.
Highlights
The human major histocompatibility complex (MHC), referred to as human leukocyte antigen (HLA), is investigated continuously because of its importance in the regulation of the innate and adaptive immune system, autoimmunity, and transplantation (Dawkins et al, 1999; Vandiedonck and Knight, 2009; Lokki and Paakkanen, 2019)
A single-nucleotide polymorphism (SNP) XO was detected within the SVA-MIC insertion between the MICA and MICB loci (Figure 4) of the A∗02/C∗03:04/B∗40 haplotype pair ID13 and ID86 (Table 3), suggesting that this insertion locus is near a recombination site that exchanged the MICB∗002:01 allele with MICB∗014
Our study confirms that the genomic sequences of MHC homozygous cell lines are useful for analysing MHC haplotypic landscapes and characterising unique conserved polymorphic sequences (CPSs), haplotypic markers, and XO zones without a need to use linkage disequilibrium (LD) or other probabilistic statistical imputations
Summary
The human major histocompatibility complex (MHC), referred to as human leukocyte antigen (HLA), is investigated continuously because of its importance in the regulation of the innate and adaptive immune system, autoimmunity, and transplantation (Dawkins et al, 1999; Vandiedonck and Knight, 2009; Lokki and Paakkanen, 2019). The MHC class I and class II gene clusters contain numerous sequence duplications, insertions and deletions and considerable sequence diversity or polymorphisms (Trowsdale and Knight, 2013) that have accumulated into distinct multilocus haplotypes with relatively high population frequencies (>1%) (Awdeh et al, 1983; Degli-Esposti et al, 1992; Dawkins et al, 1999; Yunis et al, 2003; Goodin et al, 2018) These date from at least the beginning of human expansion and dispersal out of Africa, 50,000–100,000 years ago (Henn et al, 2012; López et al, 2015). The common Northern European HLA haplotype HLA-A1-B8C7-DRB3-DQ2 (8.1AH) is estimated to have diverged from a single common ancestor about 23,500 years ago (Smith et al, 2006)
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