Trends in antibody sequence changes during the somatic hypermutation process

Area of Science:

• Immunology
• Computational Biology
• Structural Biology

Background:

• Antibodies (Abs) undergo somatic hypermutation to mature and improve antigen binding.
• Understanding the germline gene repertoire and mutation processes is crucial for Ab engineering.

Purpose of the Study:

• To computationally infer germline gene sequences from mature antibody sequences.
• To analyze the factors influencing residue mutation patterns during antibody maturation.
• To investigate the role of germline composition versus selection in shaping mature antibody interfaces.

Main Methods:

• Inferred germline gene sequences using computational matching to known V(D)J genes.
• Compared germline and mature antibody sequences structurally.
• Analyzed mutation patterns based on germline biases, accessibility, hotspots, and selection pressures.

Main Results:

• Germline antibody repertoires at antigen-contacting positions are biased towards tyrosine, serine, and tryptophan.
• These residues are enriched in mutation hotspots and decrease in abundance during maturation.
• Mature antibody interfaces reflect germline composition; tyrosine abundance is not solely due to selection. Histidine usage increases across all regions. Stabilizing mutations like proline increase, and disulfide bonds form via cysteine mutations.

Conclusions:

• Antibody maturation involves a conversion from non-specific binding residues to diverse types that enhance affinity and stability.
• Germline composition significantly influences mature antibody structure and function.
• Somatic hypermutation introduces stabilizing changes, contributing to antibody efficacy.