Human leukocyte antigen super-locus: nexus of genomic supergenes, SNPs, indels, transcripts, and haplotypes

Abstract

The human Major Histocompatibility Complex (MHC) or Human Leukocyte Antigen (HLA) super-locus is a highly polymorphic genomic region that encodes more than 140 coding genes including the transplantation and immune regulatory molecules. It receives special attention for genetic investigation because of its important role in the regulation of innate and adaptive immune responses and its strong association with numerous infectious and/or autoimmune diseases. In recent years, MHC genotyping and haplotyping using Sanger sequencing and next-generation sequencing (NGS) methods have produced many hundreds of genomic sequences of the HLA super-locus for comparative studies of the genetic architecture and diversity between the same and different haplotypes. In this special issue on ‘The Current Landscape of HLA Genomics and Genetics’, we provide a short review of some of the recent analytical developments used to investigate the SNP polymorphisms, structural variants (indels), transcription and haplotypes of the HLA super-locus. This review highlights the importance of using reference cell-lines, population studies, and NGS methods to improve and update our understanding of the mechanisms, architectural structures and combinations of human MHC genomic alleles (SNPs and indels) that better define and characterise haplotypes and their association with various phenotypes and diseases.

Regulation of expression quantitative trait loci by SVA retrotransposons within the major histocompatibility complex

“…6,7 The MHC genomic region contains numerous coding and noncoding gene sequence duplications, insertions, and deletions and considerable sequence diversity or polymorphisms 8,9 that have accumulated by ancestral descent and recombined into thousands of distinct multilocus haplotypes at variable worldwide population frequencies. 5,10,11 The two most frequent (>1%) European HLA ancestral haplotypes 8.1AH (HLA-A*01:C*07:B*08:DRB1*03:DQB1*02) and 7.1AH (HLA-A*03:C*07:B*07:DRB1*15:DQB1*06) 12,13 were estimated to have diverged from their common ancestors at least 23,500 years ago. 14 Polymorphic MHC multilocus haplotypes have been associated with Parkinson's disease (PD) [15][16][17] and autoimmune diseases such as ankylosing spondylitis, type 1 diabetes mellitus, multiple sclerosis, and rheumatoid arthritis.…”

“…1–4 The genomic region that encodes these HLA molecules is known as the major histocompatibility complex (MHC) on the short arm of chromosome 6 at 6p21.3 and it encompasses approximately 160 coding genes within ~ 3–4 MB including three distinct structural regions: class I with the classical and nonclassical HLA class I genes and ∼39 non-HLA genes; class II with the classical and nonclassical HLA class II genes and some proteasome-processing and peptide antigen transportation non-HLA genes; and class III that harbors more than 60 non-HLA genes including those involved in stress response, complement cascade, immune regulation, inflammation, leukocyte maturation, and regulation of T cell development and differentiation. 3–5 Of the many HLA-like genes, 18 HLA class I genes (six protein-coding genes and 12 pseudogenes) and seven MHC class I chain-related (MIC) genes (two protein-coding genes and five pseudogenes) are in the HLA class I region, and 18 HLA class II genes (13 protein-coding genes and five pseudogenes) are in the HLA class II region. The classical HLA class I genes, HLA-A, -B , and -C , and the classical HLA class II genes, HLA-DR, -DQ and -DP , are characterized by their extraordinary large number of polymorphisms, whereas the non-classical HLA class I genes, HLA-E, -F , and -G , are differentiated by their tissue-specific expression and limited polymorphism.…”

Medical Applications of Molecular Biotechnologies in the Context of the Hashimoto’s Thyroiditis

“…At 6p21.3 of eMHC are localized human leukocyte antigen (HLA) genes that are highly polymorphic. HLA expressions are strongly related to infection, immunity, and inflammation [66].…”

Autoimmunity and Carcinogenesis: Their Relationship under the Umbrella of Autophagy

“…Diverse alleles of HLA class I and II molecules have been linked to the development of autoimmune disorders (e.g., T1D, celiac disease, MS, RA, etc.) [ 120 , 121 ]. However, the mechanism by which HLA polymorphisms lead to autoimmunity is currently unclear.…”