Structure and Evolution of Human Immunoglobulin Cγ Genes

In order to learn about the evolution of the human immunoglobulin Cγ gene family, the structural features of individual Cγ genes were examined. The complete nucleotide sequences were determined for three members of the gene family-the Cγ1, Cγ2, and Cγ4 genes. A comparison of these sequences with those of the three reported mouse Cγ genes (Cγ1, Cγ2a, Cγ2b) fails to reveal any pairs of corresponding genes in the two species. Moreover, the sequence homology shared by human Cγ genes in both coding and noncoding regions (about 95%) is significantly greater than that seen within the mouse Cγ family (about 70-80%). The presumably neutral mutations accumulated in the noncoding regions of the human genes have been used to estimate that approximately 6-8 million years have elapsed since the divergence of these genes from a common ancestral sequence. This divergence is considerably more recent than inferred for the mouse Cγ genes, and suggests that gene duplication or gene correction events have occurred more recently in humans than in mice. In contrast to the CH domain exons and adjacent noncoding regions, the hinge exons of human Cγ genes are quite divergent both in length and sequence. This coding sequence variability is seen to extend into the regions of CH domains which border the hinge in the polypeptide chain. This divergence is interpreted as being the result of natural selection for particular hinge structures in the IgG subclasses. The implication is that these polypeptide regions are important for immunologic effector functions carried out by IgG molecules. The arrangement of the Cγ2 and Cγ4 genes in human chromosomal DNA has been determined to be 5'-Cγ2-17 kilobase pairs-Cγ4-3'. The genetic processes generating hybrid IgG molecules from these two genes are discussed, along with the relationship of these processes to gene duplication and gene correction.