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Gene map of the extended human MHC

Key Points

  • The gene map for the extended major histocompatibility complex (xMHC) comprises 421 loci (excluding RNA genes) in a sequence length of 7.6 Mb — extending the previous gene map of the classical MHC, which was 3.6 Mb long and contained 224 loci.

  • All 421 xMHC loci have been assigned definitive and approved gene symbols.

  • About 50% of the xMHC gene loci are present in clusters or superclusters that are not restricted only to immune genes. The two largest clusters, comprising histone and tRNA genes are the largest of their type in the genome.

  • Transcription hotspot analysis indicates that it is just as likely that the classical MHC is hitch-hiking with gene clusters of the xMHC as the reverse.

  • About 22% of the expressed xMHC genes show a higher than average number of non-synonymous coding polymorphisms.

  • About 28% of the xMHC genes can be associated with immune system function.

  • About 10% of the xMHC genes are currently known to be disease-causing or disease-associated.

  • About 20% of the xMHC genes have putative paralogues elsewhere in the genome, indicating considerable potential for functional redundancy.

  • The gene map of the xMHC provides an invaluable resource for the study of the most important genetic region of the human genome in relation to infectious, inflammatory and autoimmune diseases.

Abstract

The major histocompatibility complex (MHC) is the most important region in the vertebrate genome with respect to infection and autoimmunity, and is crucial in adaptive and innate immunity. Decades of biomedical research have revealed many MHC genes that are duplicated, polymorphic and associated with more diseases than any other region of the human genome. The recent completion of several large-scale studies offers the opportunity to assimilate the latest data into an integrated gene map of the extended human MHC. Here, we present this map and review its content in relation to paralogy, polymorphism, immune function and disease.

The gene map of the xMHC is also available as a poster, which accompanies this issue and is available at http://www.nature.com/nrg/posters/mhcmap/index.html.

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Figure 1: Gene map of the extended major histocompatibility complex (xMHC).
Figure 2: Distribution of major histocompatibility complex (MHC) paralogues in the human genome.

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Acknowledgements

We wish to thank S. Rogers and J. Kaufman for sharing prepublication data. The work of the HUGO Gene Nomenclature Committee is supported by the US National Institutes of Health, the UK Medical Research Council and the Wellcome Trust.

Author information

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Corresponding author

Correspondence to Stephan Beck.

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Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Entrez

HFE

MICA

MICB

B2M

TRIM

TNF

LTA

LTB

OMIM

Ankylosing spondylitis

FURTHER INFORMATION

Anthony Nolan Research Institute

Beck's laboratory

ENSEMBL

HUGO Gene Nomenclature Committee (HGNC)

Human Annotation Workshop (HAWK)

Human Genome Mapping Project resource centre

IMGT/HLA Sequence Database

International Histocompatiblity Working Group

International ImMunoGeneTics Information System

MHC Haplotype Project

MHCPEP database of MHC-binding peptides

NCBI MHC database

NCBI Single Nucleotide Polymorphism database

Poster of the xMHC map

Trowsdale's laboratory

UCSC Genome Browser

VEGA

Ziegler's laboratory

Glossary

T CELLS

These are lymphocytes that have an important role in the primary immune response, so named because their final stages of development occur in the thymus. CD8+ killer or cytotoxic T cells destroy infected cells, whereas CD4+ or helper T-cells regulate the function of other lymphocytes.

CLASS III COMPLEMENT PROTEINS

Proteins that are involved in a cascade of proteolytic cleavage of glycoproteins, ultimately leading to the induction of inflammatory responses and damage to pathogens.

CYTOKINE GENES

These encode a wide array of proteins that mediate signalling between cells either at close range or at a distance.

HAPLOTYPE

The combination of alleles at several loci on a single chromosome of a given individual. For example, for a marker with alleles M and m that is linked to another locus with alleles Q and q, possible haplotypes are MQ, Mq, mQ and mq.

LINKAGE DISEQUILIBRIUM

The non-random association of alleles at adjacent loci.

CONSERVED SYNTENY

The occurrence of genomic collinearity between homologous genes in different organisms.

PGF CELL LINE

A consanguineous B-lymphoblastoid cell line, derived from a European caucasoid male, with a homozygous HLA haplotype.

IMMUNO-PROTEASOME

Large protease complexes that degrade proteins into peptides for association with MHC class I molecules. The immuno-proteasome contains some subunits that are induced by γ interferon, two of which are encoded in the MHC.

NATURAL KILLER CELL

Large granular non-T, non-B-type lymphocytes. Natural killer cells are important for the early response to viruses. They produce cytokines, kill certain tumour cells and have appropriate receptors for antibody-dependent cell-mediated cytotoxicity.

LEUKOCYTE RECEPTOR COMPLEX

A cluster of genes on chromosome 19q13.4. The products of some of the IgSF genes in the LRC are expressed on natural killer cells and serve as receptors for MHC class I molecules.

NATURAL KILLER COMPLEX

A cluster of genes on chromosome 12. The products of some of the lectin-related genes in the NKC are expressed on natural killer cells and serve as receptors for MHC class I ligands.

SPERM-RECEPTOR SELECTION HYPOTHESIS

This theory proposes that olfactory receptors that are expressed on spermatozoa and polymorphic antigens (for example, MHC class I molecules) might be functionally connected, ensuring that spermatozoa have a higher chance to fertilize a genetically different oocyte than spermatozoa that share alleles with the female, in particular on the MHC.

PURIFYING SELECTION

Alternatively known as negative selection. A process in which more non-synonymous (amino-acid changing) than synonymous substitutions have been eliminated. It is observed, for example, when a substitution is deleterious and therefore has been eliminated from a population.

POSITIVE SELECTION

A process in which more non-synonymous (amino-acid changing) than synonymous substitutions have been preserved. It is observed when non-synonymous substitutions in a gene are selectively advantageous, for example, increasing the fitness of the species.

POLYGENY

The presence of several different but related genes with similar function. Polygeny of MHC class I genes ensures that each individual produces different MHC molecules.

MULTIFACTORIAL DISEASE

A disease that is influenced by multiple genetic, epigenetic or environmental factors.

ADVANCED GLYCATION

Non-enzymatic glycoxidation process involving sugars and basic amino acids of various proteins. The end products (AGEs) are chemically diverse, stable and implicated in various diseases in which deposits are formed, including amyloidosis, atherosclerosis and rheumatoid arthritis.

microRNAs

A class of small (approximately 22-bp) non-coding RNAs that have an important role in gene regulation.

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Horton, R., Wilming, L., Rand, V. et al. Gene map of the extended human MHC. Nat Rev Genet 5, 889–899 (2004). https://doi.org/10.1038/nrg1489

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