STRUCTURE AND GENETICS OF THE PARTIALLY DUPLICATED GENE RP LOCATED IMMEDIATELY UPSTREAM OF THE COMPLEMENT C4A AND THE C4B GENES IN THE HLA CLASS-III REGION - MOLECULAR-CLONING, EXON-INTRON STRUCTURE, COMPOSITERETROPOSON, AND BREAKPOINT OF GENE DUPLICATION

The correlation of many HLA-associated autoimmune and genetic diseases with the polymorphic complement C4 genes may be attributed to the pre sence of disease susceptibility genes in the close proximity of C4. We have cloned and characterized a pair of partially duplicated genes, R P1 and RP2, located 611 base pairs upstream of the human C4A and C4B g enes, respectively. The putative RP protein, consisting of 364 amino a cid residues, is basic and highly hydrophilic. There is a bipartite nu clear localization signal at residues 114-131 and therefore RP may be a nuclear protein. Northern blot analysis suggested that RP is ubiquit ously expressed. The 5' region of the RP1 gene is CpG rich, which is a characteristic of housekeeping genes. The RP1 gene contains nine exon s. Located in the fourth intron is a cluster of Alu elements, and a ne wly defined composite retroposon SVA with a SINE, multiple copies of G C-rich VNTRs and an Alu element altogether enclosed by direct terminal repeats. Members of SVA are also present in the complement C2 gene lo cated about 20 kilobases upstream of RP1 in the DLA and in the cytochr ome CYP1A1 gene. Determination of the DNA sequences for RP2 from two d ifferent HLA haplotypes revealed identical hybrid sequences which resu lted from fusion of RP with the tenascin-like Gene X and truncation of the 5' regions of both genes. Cumulative data suggest that the four t andemly arranged genes RP, complement C4, steroid 21-hydroxylase (CYP2 1), and Gene X altogether form a modular structure, RCCX. The number o f RCCX modules varies from one to three or more in the population. Abs ence of the truncated genes RP2 and Gene XA have been detected in geno mes with single RCCX modules. Duplication of the RCCX modules probably occurred before the speciation of great apes and humans as they conta in the same breakpoint region of RP and Gene X gene duplication.