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

TITLE=Haplotype Shuffling and Dimorphic Transposable Elements in the Human Extended Major Histocompatibility Complex Class II Region

JOURNAL=Frontiers in Genetics

VOLUME=Volume 12 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2021.665899

DOI=10.3389/fgene.2021.665899

ISSN=1664-8021

ABSTRACT=The major histocompatibility complex (MHC) on chromosome 6p21 is one of the most SNP-dense regions of the human genome and a prime model for understanding  conserved sequence polymorphisms and structural diversity of ancestral haplotypes/conserved extended haplotypes. The aim of this study was to follow up on a previous analysis of the MHC class I region by using the same set of 95 MHC haplotype sequences downloaded from a publicly available BioProject database at NCBI to identify and characterize the polymorphic Human Leukocyte Antigen (HLA)-class II genes, the MTCO3P1 pseudogene alleles, the indels of transposable elements (TEs) as haplotypic lineage markers, and SNP-density crossover (XO) loci at haplotype junctions in DNA sequence alignments of different haplotypes across the extended class II region (~1 Mb) from the telomeric PRRT1 gene in class III to the COL11A2 gene at the centromeric end of class II. We identified 42 haplotypic indels (20 Alu, 7 SVA, 13 LTR or MERs and two indels composed of a mosaic of different TEs) that were linked to particular HLA-class II alleles. Comparative sequence analyses of 136 haplotype pairs revealed 98 unique XO sites between SNP-poor and SNP-rich genomic segments with considerable haplotype shuffling located in proximity of putative recombination hotspots. The majority of XO sites occurred across various regions including in the vicinity of MTCO3P1 between HLA-DQB1 and HLA-DQB3, between HLA-DQB2 and HLA-DOB, between DOB and TAP2, and between HLA-DOA and HLA-DPA1 where most XOs were within a HERVK22 sequence. We also determined the genomic positions of the PRDM9-recombination suppression sequence motif ATCCATG/CATGGAT and the PRDM9 recombination activation partial binding motif CCTCCCCT/AGGGGAG in the class II region of the human reference genome (NC_ 000006) relative to published meiotic recombination positions. Both the recombination and anti-recombination PRDM9 binding motifs were widely distributed throughout the class II genomic regions with 50% or more found within repeat elements, the anti-recombination motifs were found mostly in L1 fragmented repeats. This study shows substantial haplotype shuffling between different polymorphic blocks and confirms the presence of numerous putative ancestral recombination sites across the class II region between various HLA class II genes. [352 words].