THE DICHOTOMOUS SIZE VARIATION OF HUMAN-COMPLEMENT C4 GENES IS MEDIATED BY A NOVEL FAMILY OF ENDOGENOUS RETROVIRUSES, WHICH ALSO ESTABLISHES SPECIES-SPECIFIC GENOMIC PATTERNS AMONG OLD-WORLD PRIMATES

The human complement C4 genes in the HLA exhibit an unusual, dichotomous size polymorphism and a four-gene, modular variation involving novel gene RP, complement C4, steroid 21-hydroxylase (CYP21), and tenascin-like Gene X (RCCX). The C4 gene size dichotomy is mediated by an endogenous retrovirus, HERV-K(C4). Nearly identical sequences for this retrotransposon are present precisely at the same location in the long C4 genes from the tandem RCCX Module I and Module II. Specific nucleotide substitutions between the long and short C4 genes have been identified and used for diagnosis. Southern blot analyses revealed that HERV-K(C4) is present at more than 30 locations in the human genome, exhibits variations in the population, and its analogs exist in the genomes of Old World primates with species-specific patterns. Evidence of intrachromosomal recombination between the two long terminal repeats of HERV-K(C4) is found near the hunting-tin locus on chromosome 4. It is possible that members of KERV-K(C4) are involved in genetic instabilities including the RCCX modules, and in protecting the host genome from retroviral attack through an antisense strategy.