MECHANISMS THAT LIMIT THE DIVERSITY OF ANTIBODIES .2. 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 eithe r the unmutated V(H)11 or V(H)12 genes, with constraints on the length and sequence of CDR3, and specific light chain association. Given tha t those parts of the antibody that are subject to somatically generate d diversity are restricted, we hypothesized that the germline V(H)11 a nd V(H)12 genes may be evolutionarily conserved to a greater extent th an other V-H genes. The nucleotide sequence was determined from a pane l of inbred strains and Mus species for V(H)11 and V(H)12. The results were compared to the three functional members of the S107 V-H family and show that V(H)11 and V(H)12 have a total of 13 silent and three re placement mutations while the S107 genes have 11 silent and 20 replace ment mutations. This implies that there has been strong selection to c onserve the V(H)11 and V(H)12 gene products, which must reflect a subs tantial survival value to the individual. Sequence comparisons also sh ow that the alleles present in the recently derived inbred strains aro se prior to speciation. While there is polymorphism within the inbred strains, there are alleles which are shared between species which dive rged 3-5 million years ago. Conservation at the amino acid and nucleot ide levels argues against the idea that Ig genes evolve at a rapid rat e and suggests that the rate at which mutations are incorporated may b e determined by the importance of the encoded protein.