Year: 1999
Type: article
Abstract: The number and distribution of nucleotide substitutions in human VkappaJkappa genes were examined using a PCR technique that analyzed nonproductive and productive rearrangements amplified from genomic DNA of individual B cells. The results indicate that the mutational mechanism introduces replacement (R) mutations comparably throughout the length of the VkappaJkappa rearrangement, but tends to target specific triplets. Moreover, hotspots of mutational activity were identified in complementarity determining regions (CDR). A marked increase in the frequency of R mutations in CDR was noted when productive were compared to nonproductive rearrangements, indicating that these were selected into the expressed repertoire. Of note, amino acids encoded by codons adjacent to hotspots of mutation were also positively selected implying that similar regions were targeted for hypermutation and subsequent selection. In contrast to the distribution of CDR mutations, R mutations in the framework (FR) regions tended to be eliminated from productive VkappaJkappa rearrangements, implying that the somatic hypermutational machinery frequently introduced amino acid changes that were deleterious to the structural integrity of the kappa chain protein. The difference in the ratio of R to silent mutations in CDR and FR in the expressed repertoire, therefore, reflects the summation of positive selection of R mutations in the CDR and the elimination of R mutations in the FR. The data indicate that the balance between targeted mutation of VkappaJkappa rearrangements and subsequent selection and elimination governs the pattern of mutations manifest within the expressed kappa repertoire.
Source: European Journal of Immunology
Institution: The University of Texas Southwestern Medical Center
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
Award: G1460087149
OpenAlex ID: W1980800509