2 CLOSELY RELATED-KAPPA VARIABLE REGION PSEUDOGENES POSE AN EVOLUTIONARY PARADOX

Two pseudogenes belonging to the Igk-V1 variable region group have been isolated from BALB/c mice. The genes share > 96.5 % identity of nucleotide sequence in a 1800 base pair (bp) region surrounding the coding region, but deletions of 221 bp and 84 bp have removed essential sequences from the two genes. As the deletions are different in the two pseudogenes, they must have occurred independently in each gene during or subsequent to the duplication event which gave rise to the genes from a common ancestral gene. Polymerase chain reaction analysis was used to identify the pseudogenes in inbred strains of mice. BALB/c (Igk(c)) and AKR (Igk(a)), prototype strains representative of the predominant kappa-haplotypes, possess both pseudogenes but no intact copy. Only one of the pseudogenes was present in SJL (Igk(a)). Strains C58, c.C58 (Igk(d)) and NZB (Igk(b)) possessed an intact version of the gene. This distribution of haplotypes is consistent with a close linkage of the pseudogenes with other Igk-V1 genes on chromosome 6. The translated amino acid sequence of the pseudogenes indicates that prior to their acquiring deletions they encoded typical Igk-V1 variable regions except for an unusual FR2 region, in which the conserved proline at position 44 is replaced by leucine and the normally hydrophobic position 36 was occupied by histidine. Possible mechanisms to explain the occurrence of deletions in both of the pseudogenes in the recent evolution of BALB/c are discussed. One explanation would be that the two genes were already nonfunctional at the time of the duplication so that the subsequent deletions represent neutral events which became fixed in the inbred strains by a process of genetic drift. Alternatively, if the genes were functional at the time of duplication, their rapid loss due to deletion events suggests that negative selection may have acted to eliminate the genes from the V-region repertoire.