Mechanisms that limit the diversity of antibodies. II. Evolutionary conservation of Ig variable region genes which encode naturally occurring autoantibodies.

Antibody which reacts with phosphatidyl choline can be detected in all normal mice. Generation of this specificity requires the use of either the unmutated VH11 or VH12 genes, with constraints on the length and sequence of CDR3, and specific light chain association. Given that those parts of the antibody that are subject to somatically generated diversity are restricted, we hypothesized that the germline VH11 and VH12 genes may be evolutionarily conserved to a greater extent than other VH genes. The nucleotide sequence was determined from a panel of inbred strains and Mus species for VH11 and VH12. The results were compared to the three functional members of the S107 VH family and show that VH11 and VH12 have a total of 13 silent and three replacement mutations while the S107 genes have 11 silent and 20 replacement mutations. This implies that there has been strong selection to conserve the VH11 and VH12 gene products, which must reflect a substantial survival value to the individual. Sequence comparisons also show that the alleles present in the recently derived inbred strains arose prior to speciation. While there is polymorphism within the inbred strains, there are alleles which are shared between species which diverged 3-5 million years ago. Conservation at the amino acid and nucleotide levels argues against the idea that Ig genes evolve at a rapid rate and suggests that the rate at which mutations are incorporated may be determined by the importance of the encoded protein.