Allelic forms of rat kappa chain genes: evidence for strong selection at the level of nucleotide sequence.

The genes that code for two allotypic forms of the rat kappa light chain constant region (C(kappa)) have been cloned and the nucleotide sequence of 1172 base pairs of coding and flanking sequence has been determined for both alleles. These sequences have been compared to each other and to the corresponding sequences found in the mouse and human. Comparison of the LEW allele with mouse C(kappa) reveals two surprising features: (i) There is an unusually large number of amino acid substitutions (21) relative to the total number of nucleotide changes (37) in the coding region. Comparision among several other mammalian genes reveals a larger proportion of "silent" changes. (ii) The rate of accumulation of base substitutions is the same within the coding region as it is in some 870 base pairs of noncoding sequence (including 3' untranslated, 3' flanking, and 5' intervening sequences). Comparison of the two allelic forms of rat C(kappa) shows the same unusual features in more extreme form. (i) Twelve base substitutions in the coding region determine 11 amino acid differences-only one "silent" change exists. (ii) There are 12 base substitutions in the 318 base pairs of coding sequence (3.7% difference) and only 9 in the remaining 854 base pairs of noncoding DNA (1.1%), a highly significant difference. This degree of conservation of noncoding sequences and of "silent" sites within the coding region is unique among the mammalian genes studied thus far. These patterns suggest that there has been strong selection for conservation of nucleotide sequences, both inside and outside the coding region, independent of the selection required to maintain the function and characteristic structure of the immunoglobulin domain itself. The functions of the nucleotide sequences that account for this selective pressure are unclear at the present time.