B cell variable genes have evolved their codon usage to focus the targeted patterns of somatic mutation on the...

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Adaptive immunity relies on B cells diversifying their receptors to recognize diverse antigens.
• Somatic mutation in B cell receptors (BCRs) is crucial for affinity maturation but is not uniformly distributed.
• Specific micro-sequence preferences and codon usage influence mutation patterns in BCR Variable (V) genes.

Purpose of the Study:

• To investigate the interplay between somatic mutation targeting and codon usage in human BCR V genes.
• To determine how these factors shape mutation patterns within complementarity determining regions (CDRs).
• To explore the implications of mutation bias for V gene usage and repertoire stability in different immune states and age groups.

Main Methods:

• Analysis of mutation distribution in human BCR V genes across four datasets.
• Modeling of mutation biases based on codon usage and micro-sequence specificities.
• Comparison of mutation patterns in B cell receptors (BCRs) versus T cell receptors (TCRs).
• Examination of V gene usage in resting and activated B cell repertoires, including in older patients.

Main Results:

• A significant correlation was found between predicted V gene mutation biases and actual mutations in CDRs across all datasets.
• BCR V genes exhibit a distinct codon usage bias that, combined with mutation targeting, focuses changes within CDRs.
• T cell V genes show mutation skewing but lack the codon bias seen in BCRs, suggesting amino acid usage influences TCR mutation patterns.
• Resting B cell repertoires favor V genes with high CDR mutation bias, a trend that diminishes during acute immune responses but persists in older individuals.

Conclusions:

• The combination of mutation targeting and codon bias in BCR V genes drives focused diversification of CDRs, enhancing antigen recognition.
• Mutation bias in V genes is linked to their long-term survival and selection within human B cell repertoires.
• Age-related inflexibility in V gene usage biases older individuals towards highly skewed V genes, potentially limiting immune response diversity.