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Polymorphism in a second ABC transporter gene located within the class II region of the human major histocompatibility complex.

ABSTRACT: Recent studies have identified genes within the major histocompatibility complex (MHC) that may play a role in presentation of antigenic peptides to T cells. We have previously described RING4, a gene within the human MHC class II region that has sequence homology with members of the ABC ("ATP-binding cassette") transporter superfamily. We now report the nucleotide sequence of RING11, a second ABC transporter gene located approximately 7 kilobases telomeric to RING4, RING11 is gamma-interferon inducible, a property shared with other genes involved in antigen presentation. Comparison between the amino acid sequences of RING11 and RING4 reveals strong homology. We propose that they form a heterodimer that transports peptides from the cytoplasm into the endoplasmic reticulum. We have identified two RING11 alleles, which differ in the length of their derived protein sequence by 17 amino acids. The more common of these alleles is present in a Caucasoid population at a frequency of 79%.

SUBMITTER: Powis SH

PROVIDER: S-EPMC48471 | biostudies-other | 1992 Feb

REPOSITORIES: biostudies-other

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Polymorphism in a second ABC transporter gene located within the class II region of the human major histocompatibility complex.

Powis S H SH Mockridge I I Kelly A A Kerr L A LA Glynne R R Gileadi U U Beck S S Trowsdale J J

Proceedings of the National Academy of Sciences of the United States of America 19920201 4

Recent studies have identified genes within the major histocompatibility complex (MHC) that may play a role in presentation of antigenic peptides to T cells. We have previously described RING4, a gene within the human MHC class II region that has sequence homology with members of the ABC ("ATP-binding cassette") transporter superfamily. We now report the nucleotide sequence of RING11, a second ABC transporter gene located approximately 7 kilobases telomeric to RING4, RING11 is gamma-interferon i ...[more]

PMID: 1741401

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Project description:BackgroundThe Major Histocompatibility Complex (MHC) is a genomic region containing genes with crucial roles in immune responses. MHC class I and class II genes encode antigen-presenting molecules expressed on the cell surface. To counteract the high variability of pathogens, the MHC evolved into a region of considerable heterogeneity in its organization, number and extent of polymorphism. Studies of MHCs in different model species contribute to our understanding of mechanisms of immunity, diseases and their evolution. Camels are economically important domestic animals and interesting biomodels. Three species of Old World camels have been recognized: the dromedary (Camelus dromedarius), Bactrian camel (Camelus bactrianus) and the wild camel (Camelus ferus). Despite their importance, little is known about the MHC genomic region, its organization and diversity in camels. The objectives of this study were to identify, map and characterize the MHC region of Old World camelids, with special attention to genetic variation at selected class MHC II loci.ResultsPhysical mapping located the MHC region to the chromosome 20 in Camelus dromedarius. Cytogenetic and comparative analyses of whole genome sequences showed that the order of the three major sub-regions is "Centromere - Class II - Class III - Class I". DRA, DRB, DQA and DQB exon 2 sequences encoding the antigen binding site of the corresponding class II antigen presenting molecules showed high degree of sequence similarity and extensive allele sharing across the three species. Unexpectedly low extent of polymorphism with low numbers of alleles and haplotypes was observed in all species, despite different geographic origins of the camels analyzed. The DRA locus was found to be polymorphic, with three alleles shared by all three species. DRA and DQA sequences retrieved from ancient DNA samples of Camelus dromedarius suggested that additional polymorphism might exist.ConclusionsThis study provided evidence that camels possess an MHC comparable to other mammalian species in terms of its genomic localization, organization and sequence similarity. We described ancient variation at the DRA locus, monomorphic in most species. The extent of molecular diversity of MHC class II genes seems to be substantially lower in Old World camels than in other mammalian species.

Project description:The major histocompatibility complex (MHC) on chromosome 6p21 is one of the most single-nucleotide polymorphism (SNP)-dense regions of the human genome and a prime model for the study and understanding of conserved sequence polymorphisms and structural diversity of ancestral haplotypes/conserved extended haplotypes. This study aimed 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 the National Center for Biotechnology Information to identify and characterize the polymorphic human leukocyte antigen (HLA)-class II genes, the MTCO3P1 pseudogene alleles, the indels of transposable elements 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 2 indels composed of a mosaic of different transposable elements) 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 the 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.

Dataset Information

Polymorphism in a second ABC transporter gene located within the class II region of the human major histocompatibility complex.

Publications

Polymorphism in a second ABC transporter gene located within the class II region of the human major histocompatibility complex.

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