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Analysis of the gene-dense major histocompatibility complex class III region and its comparison to mouse.

ABSTRACT: In mammals, the Major Histocompatibility Complex class I and II gene clusters are separated by an approximately 700-kb stretch of sequence called the MHC class III region, which has been associated with susceptibility to numerous diseases. To facilitate understanding of this medically important and architecturally interesting portion of the genome, we have sequenced and analyzed both the human and mouse class III regions. The cross-species comparison has facilitated the identification of 60 genes in human and 61 in mouse, including a potential RNA gene for which the introns are more conserved across species than the exons. Delineation of global organization, gene structure, alternative splice forms, protein similarities, and potential cis-regulatory elements leads to several conclusions: (1) The human MHC class III region is the most gene-dense region of the human genome: >14% of the sequence is coding, approximately 72% of the region is transcribed, and there is an average of 8.5 genes per 100 kb. (2) Gene sizes, number of exons, and intergenic distances are for the most part similar in both species, implying that interspersed repeats have had little impact in disrupting the tight organization of this densely packed set of genes. (3) The region contains a heterogeneous mixture of genes, only a few of which have a clearly defined and proven function. Although many of the genes are of ancient origin, some appear to exist only in mammals and fish, implying they might be specific to vertebrates. (4) Conserved noncoding sequences are found primarily in or near the 5'-UTR or the first intron of genes, and seldom in the intergenic regions. Many of these conserved blocks are likely to be cis-regulatory elements.

SUBMITTER: Xie T

PROVIDER: S-EPMC403804 | biostudies-literature | 2003 Dec

REPOSITORIES: biostudies-literature

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Analysis of the gene-dense major histocompatibility complex class III region and its comparison to mouse.

Xie Tao T Rowen Lee L Aguado Begoña B Ahearn Mary Ellen ME Madan Anup A Qin Shizhen S Campbell R Duncan RD Hood Leroy L

Genome research 20031201 12

In mammals, the Major Histocompatibility Complex class I and II gene clusters are separated by an approximately 700-kb stretch of sequence called the MHC class III region, which has been associated with susceptibility to numerous diseases. To facilitate understanding of this medically important and architecturally interesting portion of the genome, we have sequenced and analyzed both the human and mouse class III regions. The cross-species comparison has facilitated the identification of 60 gene ...[more]

PMID: 14656967

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Project description:BackgroundThe mouse has more than 30 Major histocompatibility complex (Mhc) class Ib genes, most of which exist in the H2 region of chromosome 17 in distinct gene clusters. Although recent progress in Mhc research has revealed the unique roles of several Mhc class Ib genes in the immune and non-immune systems, the functions of many class Ib genes have still to be elucidated. To better understand the roles of class Ib molecules, we have characterized their gene duplication, organization and expression patterns within the H2 region of the mouse strain C57BL/6.ResultsThe genomic organization of the H2-Q, -T and -M regions was analyzed and 21 transcribed Mhc class Ib genes were identified within these regions. Dot-plot and phylogenetic analyses implied that the genes were generated by monogenic and/or multigenic duplicated events. To investigate the adult tissue, embryonic and placental expressions of these genes, we performed RT-PCR gene expression profiling using gene-specific primers. Both tissue-wide and tissue-specific gene expression patterns were obtained that suggest that the variations in the gene expression may depend on the genomic location of the duplicated genes as well as locus specific mechanisms. The genes located in the H2-T region at the centromeric end of the cluster were expressed more widely than those at the telomeric end, which showed tissue-restricted expression in spite of nucleotide sequence similarities among gene paralogs.ConclusionDuplicated Mhc class Ib genes located in the H2-Q, -T and -M regions are differentially expressed in a variety of developing and adult tissues. Our findings form the basis for further functional validation studies of the Mhc class Ib gene expression profiles in specific tissues, such as the brain. The duplicated gene expression results in combination with the genome analysis suggest the possibility of long-range regulation of H2-T gene expression and/or important, but as yet unidentified nucleotide changes in the promoter or enhancer regions of the genes. Since the Mhc genomic region has diversified among mouse strains, it should be a useful model region for comparative analyses of the relationships between duplicated gene organization, evolution and the regulation of expression patterns.

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.

Project description:Sirenians share with cetaceans and pinnipeds several convergent traits selected for the aquatic lifestyle. Living in water poses new challenges not only for locomotion and feeding but also for combating new pathogens, which may render the immune system one of the best tools aquatic mammals have for dealing with aquatic microbial threats. So far, only cetaceans have had their class II Major Histocompatibility Complex (MHC) organization characterized, despite the importance of MHC genes for adaptive immune responses. This study aims to characterize the organization of the marine mammal class II MHC using publicly available genomes. We located class II sequences in the genomes of one sirenian, four pinnipeds and eight cetaceans using NCBI-BLAST and reannotated the sequences using local BLAST search with exon and intron libraries. Scaffolds containing class II sequences were compared using dotplot analysis and introns were used for phylogenetic analysis. The manatee class II region shares overall synteny with other mammals, however most DR loci were translocated from the canonical location, past the extended class II region. Detailed analysis of the genomes of closely related taxa revealed that this presumed translocation is shared with all other living afrotherians. Other presumptive chromosome rearrangements in Afrotheria are the deletion of DQ loci in Afrosoricida and deletion of DP in E. telfairi. Pinnipeds share the main features of dog MHC: lack of a functional pair of DPA/DPB genes and inverted DRB locus between DQ and DO subregions. All cetaceans share the Cetartiodactyla inversion separating class II genes into two subregions: class IIa, with DR and DQ genes, and class IIb, with non-classic genes and a DRB pseudogene. These results point to three distinct and unheralded class II MHC structures in marine mammals: one canonical organization but lacking DP genes in pinnipeds; one bearing an inversion separating IIa and IIb subregions lacking DP genes found in cetaceans; and one with a translocation separating the most diverse class II gene from the MHC found in afrotherians and presumptive functional DR, DQ, and DP genes. Future functional research will reveal how these aquatic mammals cope with pathogen pressures with these divergent MHC organizations.

Dataset Information

Analysis of the gene-dense major histocompatibility complex class III region and its comparison to mouse.

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Analysis of the gene-dense major histocompatibility complex class III region and its comparison to mouse.

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