Antibody molecules are made up of two heavy chains and two light chains. Each of these two chains is composed of variable region (V) and constant region (C).
The rate of nonsynonymous nucleotide substitution is greater than synonymous nucleotide substitution at the complementarity-determining regions of VH and VL genes and this is caused by directional selection. The human heavy variable chains of immunoglobulins are divided into seven distinct families. Each of these seven families builds a monophyletic cluster. Also, human heavy chains of immunoglobulins can be divided into three groups (A, B, and C). These three groups are shared by other species like amphibians and fishes too. Thus, these three groups have been intact in human lineage for more than 400 million years. As shown in figure 7, repeated gene duplication generated the VH genes (6, 7, 8).
DNA of humans has been sequenced and it is clear that divergence of polymorphism of immunoglobulins is lower than polymorphism of MHC class genes. On the contrary, sequence variation in VH loci is higher than MHC class genes (6, 7, 8).
As deletion, duplication, and translocation are important factors in revolution of immunoglobulins, haplotype polymorphism exists in VH and VL genes. In humans, there are two haplotypes, H1 and H2. Number of VK genes in H2 is more than H1. Gene sequencing showed us that these two sets of genes are very similar and H2 was produced by block duplication of H1. As other mammals do not have this duplication, the divergence happened about 5 million years ago (6, 7, 8).