![]() ![]() ![]() The region of identity between RHD and Ce includes the exon 2 sequence responsible for C rather than c antigenicity the fact that this region extends into flanking non-coding sequence suggests that the Ce allele arose by non-reciprocal intergenic exchange (gene conversion) of RHD sequences into a ce allele. that ce is 96% homologous to Ce and RHD over the 4.26 kb that includes exon 2, and except for a single base change, identical to Ce in the 5′ and 3′ flanking sequence (see Fig. We have now sequenced the equivalent region of a ce allele of RHCE and find that the converse relationship holds, i.e. In the 304 and 935 bp of sequence flanking this region, the two genes are 96% homologous, a figure close to that previously determined for their coding regions ( 1– 5). We found that these two genes are completely identical over the 4.26 kb that includes exon 2. In an earlier study ( 12), we sequenced a 5.5 kb region that includes exon 2 and parts of introns 1 and 2 of both RHD and the Ce allele of RHCE. These sequences have been deposited in GenBank, accession numbers U66340 and U66341. The starred AflIII site in the RHD sequence is polymorphic (see text). Restriction sites relevant to the present study only are shown. A total of 5501 bp was sequenced around exon 2 of RHD and the Ce and ce alleles of RHCE (the limits of the region sequenced are denoted by vertical arrows). The relationship between the RHD gene and alleles of RHCE in the neighbourhood of exon 2. However, our evidence only supports crossing over where the order of antigen determining sites is C-E-D, and this arrangement was confirmed by direct analysis of genomic DNA. We now present evidence which suggests a probable origin for the common alleles of RHCE and which lends compelling support for the crossing over model for the origin of the less common RH haplotypes. There has been one suggestion ( 11), but no proven case, of recombination between RHD and RHCE within a single pedigree. Moreover, the imperfect homology between genomes that have and those that lack an RHD gene may impede pairing between them, and reduce the possibility of recombination in heterozygotes. The frequency ratios of the supposed parental and recombinant haplotypes suggested that the arrangement D-C-E was most likely under the crossing-over hypothesis.Īt the time, Fisher and Race assumed that the three series of antigens are encoded in three separate genes, whereas it is now known that there are only two recombination between the sites encoding C/c and E/e would therefore be intragenic, and occur between exons that are separated by ∼30 kb ( 10). In 1946 Fisher and Race ( 9) proposed a model for the evolution of the RH polymorphism in which the less common haplotypes (CDE, Cde, cdE and CdE) are generated and maintained by recombination from those found at higher frequency. In the presence and absence, respectively, of RHD, the four alleles of RHCE make up all possible haplotypes, although there are marked differences in their relative frequencies, both within and between populations (see Table 1). There are, in addition, rare variants of C, c, E and e, whose molecular basis is, for the most part, unknown. Only four of these result in amino acid substitutions, and that at nucleotide 307 (serine to proline, residue 103) is most consistently associated with C or c antigenicity, respectively. Alleles of RHCE that express the C antigen differ from those expressing c at six nucleotide positions, one in exon 1 and five in exon 2. A single C to G transition in exon 5 of RHCE results in a polypeptide that reacts with anti-e, rather than anti-E, antisera. ![]() Lack of D antigen expression is usually due to the absence of the entire RHD gene from the genome of RhD− individuals ( 7), whereas variant forms of the C and E antigens are generated by base substitutions in RHCE ( 5, 8). Alternative mRNA splicing is probably responsible for the production of two distinct polypeptides from the single RHCE gene ( 6). The Rh antigens are carried on three non-glycosylated transmembrane proteins that are encoded in only two genes, RHD and RHCE ( 1– 5). Incompatibility for the other products of the RH locus, the C-series and E-series antigens, can also occasionally give rise to hemolytic reactions. In addition to the problems caused by incompatibility for RhD type between transfusion donor and recipient, incompatibility between a multiparous RhD− mother and her unborn child can result in a severe immune reaction leading to neonatal hemolytic disease (HDN) or even intrauterine death. Although the Rh system is highly polymorphic, and comprises at least 44 distinct antigens, clinically the most significant polymorphism is due to the presence or absence of the RhD antigen on red cells. ![]() The Rh blood group, popularly referred to as Rhesus, is second only to the ABO system in its importance in transfusion medicine. ![]()
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