Length polymorphism of the human complement component C4 gene is due to an ancient retroviral integration

The fourth component of the complement system, C4, is encoded by two highly homologous MHC-linked genes expressing the two isotypes C4A and C4B. A gene size polymorphism (either 22.5 or 16 kb) has been described which depends on the presence or absence of a 6.5-kb insertion in intron 9 of the C4 gene. By sequencing a C4A-specific lambda clone from a human genomic library containing the long intron 9 as well as PCR-amplified DNA containing the short intron, the DNA sequences of both introns were determined. The long and short introns have lengths of 6,787 bp and 415 bp, respectively. The sequence of the short intron is almost identical (96%) to the corresponding parts of the long intron. At position 282 of the short intron, a 6,372-bp insertion is present in the long intron which has all characteristics of a full-length endogenous retrovirus. The proviral DNA is flanked by two 6-bp target site repeats. The orientation of the proviral sequence is opposite to that of the C4 coding strand. Long terminal repeats (LTRs) of 548 bp were found at both ends of the provirus. A TATA box and an SV40 enhancer core as well as a polyadenylation signal are present in the LTR. A 5' primer binding site for lysine tRNA was identified. The strongest sequence homologies were found in comparison to human endogenous retrovirus (HERV-K): between 65-88% for gag, pol and env genes. However, a search for open reading frames in these regions indicated the presence of multiple stop codons in all three reading frames.(ABSTRACT TRUNCATED AT 250 WORDS)