The human Major Histocompatibility Complex as a paradigm in genomics research

Abstract

Since its discovery more than 50 years ago, the human Major Histocompatibility Complex (MHC) on chromosome 6p21.3 has been at the forefront of human genetic research. Here, we review from a historical perspective the major advances in our understanding of the nature and consequences of genetic variation which have involved the MHC, as well as highlighting likely future directions. As a consequence of its particular genomic structure, its remarkable polymorphism and its early implication in numerous diseases, the MHC has been considered as a model region for genomics, being the first substantial region to be sequenced and establishing fundamental concepts of linkage disequilibrium, haplotypic structure and meiotic recombination. Recently, the MHC became the first genomic region to be entirely re-sequenced for common haplotypes, while studies mapping gene expression phenotypes across the genome have strongly implicated variation in the MHC. This review shows how the MHC continues to provide new insights and remains in the vanguard of contemporary research in human genomics.

Profiles of Epigenetic Histone Post-translational Modifications at Type 1 Diabetes Susceptible Genes

“…MHC is a gene dense locus in the human genome that displays the highest density of single nucleotide polymorphism (SNP) variations (36). Its short form spans 3.6 Mb and contains ϳ140 genes between flanking genetic marks MOG and COL11A2 on chromosome 6p21.3 ( Fig.…”

Expression QTL analysis of top loci from GWAS meta-analysis highlights additional schizophrenia candidate genes

“…It regulates the immune response and has been associated to a large number of immune phenotypes and diseases. 37 The association of SNPs in these MHC genes can result from mere physical closeness to the schizophrenia variant within the MHC region. However, that would not explain the difference in gene expression of MHC genes presented here, as expression transcripts are not in LD.…”

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

“…12 From a genetics standpoint, it has been difficult to clearly determine the disease-causing variant(s) for most MHC class II associated diseases owing to extended linkage disequilibrium and the great sequence diversity shown by genes in this region. [13][14][15] However, it is becoming clear that structural variation alone cannot fully account for disease associations in the MHC class II region and there is increasing interest in defining genetic variants that may modulate gene expression. [16][17][18] Support for this comes from recent genome-wide analyses of gene expression as a quantitative trait, which have highlighted the affect of cis-acting genetic variation on expression of class II genes such as HLA-DQA1, HLA-DRB1, HLA-DPA1 and HLA-DQB1.…”