Polymorphisms in MHC occur mainly by:
• Gene conversion
RECOMBINATION AND MUTATION
There are many genetic mechanisms which generate new alleles. New alleles arise by point mutations or by gene conversion. Here in gene conversion one gene is replaced in part by sequences from a different gene. Mutations can be replacement and silent substitution. Replacement substitution is where one can change an amino acid and silent substitution is where the codon is changed but the amino acid the same. There are peptide binding pockets in the peptide binding grooves where the peptides bind and this occurs through the MHC class I and II. Polymorphisms alter the amino acids and these changes the specificities of the pocket. A person fails to respond to an antigen if there is a change in the sequence which is made. The failure to respond is called immune response gene defects. Mice when infected by a virus generate cytotoxic T cells and this kills the cells. Cytotoxic T cells are virus specific and these are induced in MHCa cells but not in MHCb/c. Hence we can say that cytotoxic T cells kill virus only if they are expressing self MHC. MHC genotype restricts antigen specificity of T cells and this is called MHC restriction. MHC restriction is due to binding specificity of an individual TCR. It is for the complex of peptide along with MHC. Recombination of genes in MHC plays a vital role in generation of alleles at many HLA loci. Degree of polymorphism of class I and II genes are thought to be maintained on the account of heterozygous individuals at HLA loci present a greater variety of antigen peptides than homozygotes resulting in productive immune response of pathogens. The variability in HLA-B and DRB1 genes is because of interallelic recombination. There are studies associated with the molecular genetics of MHC especially those concerning recombination and linkage disequilibrium. Linkage disequilibrium measures historical events that reflect selective pressures; on the other hand recombinant chromosomes measure real time events. Linkage disequilibrium is the non random association of two alleles. Recombination which is an important mechanism is done by typing sufficient number of families based on length of DNA and this is associated to a population. To get the recombination fraction that is the number of recombinant chromosomes in any region of genome it is important to pre select families which do not have recombinant chromosome in any region. The recombination across MHC is lower than ever expected. In HLA-A, B and DR 2.5% recombination occurs around the region between HLA-A and DRB-1 with 6-11% recombination between DRB1 and GLO.
Recombination does not always occur across the genome but there are a number of hot spots in the MHC which are also seen. Recombinant events in HLA-B and-C and DQA1 and DRB1 are not very well defined. There is absence of recombination between DQ and DR in the CEPF families. Recombinant chromosomes have seen to be occurring more in MHC class I molecules in comparison to class II/III MHC only because this region has a longer history that the other two. Class I is typed with greater frequency than class II for HLA typing. Almost the complete sequence of MHC was made available during the recombination of class II region hence it is more advanced and molecular typing for DR, DQ and DP gene occurred in class I. The DQ to DP and DP to HLA-DNA regions are the regions where very little recombination occurs in class II. Understanding of recombination gives a detail insight about the evolution of MHC. The polymorphisms seen in intragenic and intergenic regions of the complex help in rapid identification of crossover events.
Understanding of gene conversion mechanism made an impact on MHC evolution. Gene conversion also helps to understand the diseases in humans. In eukaryocytes gene conversion constitutes the main form of homologous recombination that is initiated by double stranded breaks (DSBs.)Transfer of genetic material from intact homologous sequence to the regions which have DSB is where gene conversion occurs. Gene conversion can be inter allelic or non-allelic. Non allelic gene conversion shows close proximity based on directionality. Frequency of gene conversion in MHC varies from one allele to another. Mutations of MHC have a whole stretch of mutated nucleotides. Template gene can be either another allele of the same MHC locus or belong to a different MHC locus. Affinity mutation of humans happens when a stretch of nucleotides are mutated to another gene. This type of mutation is highly occurring and this phenomenon is called gene conversion. Transfer of gene without the donor being changed is also called gene conversion. Gene conversion has contributed to diversity. Gene conversion of the MHC is not a very common phenomenon it occurs only in germline. Gene conversion in MHC is a mitotic event. The main important thing essential for gene conversion is the existence of genes which have high degree of similarity in some parts of the sequence. Certain germline polymorphisms exist for TCR. Relation between a segment of the human germline of TCR and MHC class II was seen recently. Two variants of VAB1 allele and six common segments of HLA-DRB1 alleles were arranged and analysed. The TCR and MHCII polymorphisms influence IgE via helper T cells. TCR binds to the antigen and is presented by MHC class II which further stimulates helper T cells.
ANTIBODY/TCR GENE POLYMORPHISM
The changes in V gene segment have a great impact on the TCR. The variable portion of the BCR develops by somatic recombination and mutation similar to the processes that generate variable TCRs. It was suggested that somatic hypermutation of BCR provides a buffer between the germline and matured BCR specific for particular antigens.
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