Mutations and selection in the generation of class II histocompatibility antigen polymorphism

Area of Science:

• Immunogenetics
• Molecular Anthropology

Background:

• Human leukocyte antigen (HLA) class II molecules (DR and DC) play a crucial role in immune responses.
• Allelic variation within these genes contributes to diverse immune system functions and disease susceptibility.

Purpose of the Study:

• To compare the magnitude of allelic variation in human DR and DC class II beta-chain genes.
• To analyze nucleotide substitutions and amino acid replacements in relation to functional domains of class II molecules.
• To investigate the role of selective pressure on different domains of class II molecules.

Main Methods:

• Comparative analysis of seven human DR and DC beta-chain amino acid sequences.
• Analysis of silent and replacement nucleotide substitutions in human (DR and DC beta-chain) and murine (I-A beta and I-A alpha) class II sequences.
• Assessment of mutation rates and amino acid replacement patterns in the first and second external domains.

Main Results:

• Allelic variation is of comparable magnitude in both human DR and DC beta-chain genes.
• Mutation rates are similar in nucleotide sequences encoding the first and second external domains of class II molecules.
• Amino acid replacements are predominantly located in the first external domains, suggesting differential selective pressures.

Conclusions:

• Conservative selective pressure acts on the second external domains of class II molecules.
• Replacement substitutions in the first external domains are often selectively neutral or favored.
• Differential selection is the primary driver for the observed differences in amino acid replacements between the first and second domains.