MAJOR HISTOCOMPATIBILITY COMPLEX (MHC)
Major histocompatibility complex (MHC) occupies 3.6Mb on chromosome 6. Genes present in the MHC bind peptides of either intracellular or extracellular origin and present them to T cells. When these peptides are recognised as foreign the T cells initiate an immune response. So far there are 128 functional genes in MHC which are known. The MHC is a multigene family which controls self/nonself recognition. They are supposed to control specific immune responses like humoral and cell mediated. There is a diverse classification of MHC namely class I, II and III. The MHC class I molecules have loci A, B and C in humans and the MHC is called as HLA in humans. HLA stands for Human Leucocyte Antigen. The loci A, B and C in humans are called classical MHC I molecules and these are monomers expressed on the surface of nucleated somatic cells. The molecules in the MHC which help in the peptide presentation are called as classical MHC molecules and those which do not function in peptide presentation are non classical MHC molecules. The class II molecules are hetrodimers which have two peptide chains where sequence variation occurs and DQA and DRB loci are correlated with MHC evolution. Polymorphism is the main distinguishing factor between classical and non classical MHC molecules. The MHC molecules are highly polymorphic due to polygeny of MHC and there is co- dominant expression of MHC genes. Poly means many and morph means shape change. This is called as gene variation at the locus and the gene variants which occupy some locus are called alleles. Polymorphisms in MHC double itself and increase diversity through polygeny.
ANTIBODY GENES AND TCR GENES
Antibodies are secreted form of B cell receptors. Membrane bound to the immunoglobulin on B cell surface serves as cell receptor for antigen and this is BCR. The main work of the BCR is to recognise the antigen exposed on the surface of the cell which is bound to the V region which leads to activation of B cell and thus produces antibody. There are two identical heavy and light chains present. The heavy chains are V, D and J which denotes variable, diversity and joining segments. The light chain has the V and J region. The V region of the light chain binds to antigen and these can bind to any one of the two CDRs or FRs. In the CDRs the antigen binding site are highly variable constant region called as Fc region. FRs is more preferential than CDRs. The T cell Receptor is a heterodimer and is generated in similar ways like B cell. The TCR has alpha and beta chains and these contain the variable amino terminal regions and constant regions. The three constant regions are CDR1, CDR2 and CDR3. CDR1 and CDR2 react mainly with more conserved regions of MHC and CDR3 interacts with central region of bound peptide. The TCRα locus has V and J gene segments and the TCRβ locus has D gene segments. This also has Vβ and Jβ gene segment.
There is genetic diversity occurring due to polymorphisms and this occurs because of various mechanisms observed in the MHC, Antibody and TCR genes. The polymorphisms are maintained by balanced selection and the evidence for this are:
(1) Linkage Disequilibrium
(2) dn/ds ratio
(1)Linkage disequilibrium: When genes are separated by large physical distances and they show high significant statistical values of linkage disequilibrium in humans. Linkage disequilibrium is the non random association of two or more alleles; they do not have to occur in the same chromosome. Non random associations between polymorphisms at different loci are measured using Linkage disequilibrium. If D' converges to zero it indicates linkage disequilibrium where D' = D/Dmin and D' is the correlation efficient. The linkage disequilibrium is affected by factors like genetic drift, rate of recombination, rate of mutation and genetic linkage. Linkage disequilibrium is explained by both demographic and selective pressures.
(2)Synonymous and Non synonymous substitution:
Dn/ds ratio is the ratio of the rate of synonymous substitution to the rate of non synonymous substitution. These provide information on the mode of selection. Selection which is purified eliminates harmful mutants and these are expected to accumulate higher rates of synonymous changes. If there is substitution then the amino acid changes and there is non-synonymous substitution occurring. Variation increases with increasing non-synonymous substitutions. Both HLA I and II have higher synonymous than synonymous substitution rates.
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