C4 gene polymorphism in primates: evolution, generation, and Chido and Rodgers antigenicity

Area of Science:

• Genomics
• Immunogenetics
• Primate Evolution

Background:

• The fourth complement factor (C4) plays a crucial role in the immune system.
• Understanding C4d polymorphism provides insights into immune system evolution and disease associations.
• Primate C4 gene evolution remains incompletely understood, particularly regarding mechanisms of polymorphism generation and inheritance.

Purpose of the Study:

• To sequence and analyze novel C4d genomic sequences from various primate species.
• To investigate the evolutionary mechanisms driving C4d polymorphism, including point mutations, crossing-over, and trans-species inheritance.
• To determine the evolutionary age of specific C4d antigen specificities (Rg/Ch) and their conservation across primate lineages.

Main Methods:

• Genomic DNA sequencing of the C4d gene from eleven primates across five species, including New World monkeys (Saguinus oedipus) and Old World monkeys (Cercopithecus aethiops, Macaca mulatta, Macaca fascicularis), and great apes (Pan paniscus).
• Phylogenetic analysis using two distinct dendrograms constructed from both exon/intron and exon-only sequences to assess C4d evolutionary patterns.
• Comparative analysis of C4d sequences to detect evidence of homogenization, point mutations, crossing-over, and trans-species evolution.

Main Results:

• Seven new C4d sequences from five previously unexplored primate species were obtained.
• New World monkeys exhibit a single C4d sequence with B isotypic specificity and Rodgers 3 (Rg3)/Chido 1 (Ch1) antigenicity, suggesting these are ancient specificities (≥50 million years old).
• Phylogenetic analyses yielded conflicting results: one dendrogram supported species-specific homogenization, while another suggested trans-species evolution of C4d polymorphism. Orangutan C4d sequences formed distinct clusters, indicating a separate ancestral origin.
• Evidence for trans-species conservation of A-ness, B-ness, and specific allelic motifs in both intronic and exonic sequences was found.

Conclusions:

• The study provides novel genomic data on C4d in diverse primate species, expanding our understanding of complement factor evolution.
• C4d polymorphism appears to be shaped by a combination of intra-species homogenization and inter-species (trans-species) evolutionary processes.
• The findings suggest that Rg3/Ch1 represent ancient C4d specificities, while other Rg/Ch specificities may be more recent and human-specific. Orangutan C4d evolution followed a distinct path compared to other great apes.