C4 GENE POLYMORPHISM IN PRIMATES - EVOLUTION, GENERATION, AND CHIDO AND RODGERS ANTIGENICITY

Eleven new C4d genomic primate sequences of the fourth complement fact or (C4) have been obtained. Seven of them belong to five species not y et explored for this gene: Pan paniscus (pygmy chimpanzee), Cercopithe cus aethiops (green monkey), Macaca mulatta (rhesus monkey), Macaca fa scicularis (cynomolgus), and Saguinus oedipus (cotton top tamarin). Th e New World monkeys (tamarins, four individuals) sequenced for C4 have a single C4d sequence only, which shows a B isotypic specificity and a Rodgers 3 (Rg3), Chide 1 (Chi) antigenicity. Rg3 and Chi could thus be the oldest Rg/Ch specificity (at least 50 million years old) and Rg 1, Rg2, Ch3, and Ch6 could be more recent human-specific antigens. Mec hanisms of C4d polymorphism generation were analyzed by compiling all the presently available sequences. Examples of both point mutations an d crossing-over events among C4d primate sequences could be detected. The problem of a possible trans-species inheritance of C4d polymorphis m was addressed and two apparently contradicting dendrograms were obta ined. One of them, constructed by using both exon and intron sequences , does not support trans-species evolution, but supports the proposed theory of extensive homogenization of the C4 genes occurring within ea ch species, because alleles from each primate species cluster together . Another completely different dendrogram, obtained by using exon sequ ences only, suggests the existence of trans-species evolution for C4d polymorphism, because alleles belonging to different species cluster t ogether in a way similar to that found for HLA class I or II alleles. However, orangutan sequences group together in both kinds of C4d seque nce dendrograms and seem to have arisen from an ancestor different fro m that of chimpanzee, gorilla and man C4d sequences. Finally, further data have been obtained that support trans-species conservation of A-n ess and B-ness and the existence of trans-specifically conserved allel ic motifs, both in intronic and exonic sequences.