AUTHOR=Kulski Jerzy K. , Suzuki Shingo , Shiina Takashi 

TITLE=SNP-Density Crossover Maps of Polymorphic Transposable Elements and HLA Genes Within MHC Class I Haplotype Blocks and Junction

JOURNAL=Frontiers in Genetics

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2020.594318

DOI=10.3389/fgene.2020.594318

ISSN=1664-8021

ABSTRACT=<p>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, <italic>MICA</italic> and <italic>MICB</italic>, and retroelement indels as haplotypic lineage markers, and single-nucleotide polymorphism (SNP) crossover loci in DNA sequence alignments of different haplotypes across the <italic>Olfactory Receptor</italic> (<italic>OR</italic>) gene region (~1.2 Mb) and the MHC class I region (~1.8 Mb) from the <italic>GPX5</italic> to the <italic>MICB</italic> gene. Our comparative sequence analyses confirmed the identity of 12 haplotypic retroelement markers and revealed that they partitioned the <italic>HLA-A/B/C</italic> 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, <italic>OR12D2, MUC21, MUC22, PSORS1A3, HLA-C, HLA-B</italic>, and <italic>MICA</italic>. In a comparison of more than 250 paired sequence alignments, at least 38 SNP-density crossover sites were mapped across various regions from <italic>GPX5</italic> to <italic>MICB</italic>. In a homology comparison of 16 different haplotypes, seven CEH/AH (<italic>7.1, 8.1, 18.2, 51.x, 57.1, 62.x</italic>, and <italic>62.1</italic>) 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 <italic>LTR16B/ERV3-16A3_I, MLT1, Charlie</italic>, and/or <italic>THE1</italic> sequences and were in close vicinity to structurally polymorphic <italic>Alu</italic> and <italic>SVA</italic> 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 <italic>OR12D2</italic> gene to the centromeric <italic>MICB</italic> 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.</p>