Abstract
The correlation of many HLA-associated autoimmune and genetic diseases with the polymorphic complement C4 genes may be attributed to the presence of disease susceptibility genes in the close proximity of C4. We have cloned and characterized a pair of partially duplicated genes, RP1 and RP2, located 611 base pairs upstream of the human C4A and C4B genes, respectively. The putative RP protein, consisting of 364 amino acid residues, is basic and highly hydrophilic. There is a bipartite nuclear localization signal at residues 114-131 and therefore RP may be a nuclear protein. Northern blot analysis suggested that RP is ubiquitously expressed. The 5' region of the RP1 gene is CpG rich, which is a characteristic of housekeeping genes. The RP1 gene contains nine exons. Located in the fourth intron is a cluster of Alu elements, and a newly defined composite retroposon SVA with a SINE, multiple copies of GC-rich VNTRs and an Alu element altogether enclosed by direct terminal repeats. Members of SVA are also present in the complement C2 gene located about 20 kilobases upstream of RP1 in the HLA and in the cytochrome CYP1A1 gene. Determination of the DNA sequences for RP2 from two different HLA haplotypes revealed identical hybrid sequences which resulted 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 tandemly arranged genes RP, complement C4, steroid 21-hydroxylase (CYP21), and Gene X altogether form a modular structure, RCCX. The number of RCCX modules varies from one to three or more in the population. Absence of the truncated genes RP2 and Gene XA have been detected in genomes with single RCCX modules. Duplication of the RCCX modules probably occurred before the speciation of great apes and humans as they contain the same breakpoint region of RP and Gene X gene duplication.
Highlights
The correlation of many HLA-associated autoimmune Duplication of the RCCX modules probablyoccurred beand genetic diseases withthe polymorphic complement fore the speciation of great apes and humans as they
C4 genes may be attributed to the presence of disease contain the same breakpoint region of RP and Gene X
The5’ region of the RP1 geneis CpG rich, which with the major histocompatibility complex (MHC)’ in humans [1,2,3,4,5]. This may be attributed to: (i) the presence of disease susceptibility genes, oncogenes, or tumor suppressor genes in theMHC; or (ii) the variableefficiencies of the MHC class I, clas1s1,and possibly class I11molecules is a characteristic of housekeeping genes
Summary
0.8kb modified as revealed by these potential sites remained to be determined. Gene Structure of RPl-The human RP1 gene located upstream of a C4A3 gene in a cosmid clone was subcloned into plasmids (Fig. 3). The CpG sequences are generally under-represented in mammalian DNA and their presence (at the 5’ region of a gene) is strongly correlated with housekeeping genes [38]. There isa stretch of highly repetitive DNA sequences located betweennucleotides 5,717 and 6,579 (Fig. 4). Analysisof the RP, C2, and CYPlAlgenomic sequences reveals a more complex organization of the reiterative sequences than those of SINE-Rs. Located immediately downstreamof the VNTRs in each gene is a highly conserved region of 370-372 bp (Fig. 7) with sequence identities of about 95%. Located immediately downstreamof the VNTRs in each gene is a highly conserved region of 370-372 bp (Fig. 7) with sequence identities of about 95% Present ineach of these sequences are three stretches of Alu-related sequences of 25, 54, and 246 bp (Fig. 7) and a less well-defined sequence of 32 bp.
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