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Alleles of Rh boxes
A model for the RH locus on chromosome 1p34-1p36 was proposed by Wagner and Flegel (Blood, 2000, 95, 3662) based on deposited RHD and RHCE nucleotide sequences and PCR and nucleotide sequencing. It is proposed that the open reading frames of both RHD and RHCE genes are in opposite orientations, their 3' ends facing each other; they are separated by about a 30 kb region that contains the SMP1 gene. The RHD gene is flanked by two DNA segments, designated the Rhesus boxes, in identical orientation, each about 9000 bp long; the upstream box ends ~4900 bp from the 5' end of RHD and the downstream box originates ~104 bp after RHD stop codon. The sequence homology between the two segments is 98.6%. The model further suggests that this high level of homology may lead to unequal homologous recombination between the upstream and downstream Rhesus boxes resulting in the deletion of the RHD gene and formation of a single hybrid Rhesus box that shows characteristic sequences of both boxes. The region in which recombination may occur, or the breakpoint, is a stretch of 1463 bp in which the sequence is nearly identical in both boxes (position 5701 to 7163). This region is designated the identity region. It was further proposed that the presence of a hybrid box may be used as evidence for the deletion of the RHD gene and determination of the zygosity status.
PCR and PCR-RFLP methods were suggested as tools to detect the presence of the hybrid box. As shown more recently, a significant level of sequence variation in Rhesus boxes sequences may occur among individuals, rendering more difficult clear cut conclusions about the absence of the RHD gene and the zygosity status. Such sequence differences may be associated with distinct RHD alleles, and be more prevalent among certain ethnic groups (Blacks in particular). Here we document different alleles of upstream (U), downstream (D), and hybrid (H) Rhesus boxes some resulting from from gene conversions or recombinations and single mutations (Matheson and Denomme, Grootkerk-Tax et al., Wagner et al.). In addition to the table shown below, the article entitled "Genetic mechanisms of Rhesus box variation" by Wagner et al. in Transfusion, 2005, 45, 338, presents an excellent summary of representative DNA changes in a relatively large number of RHD-allele-associated Rhesus Boxes in some Eurasian and African populations.
Olga. O. Blumenfeld, Ph.D, Dept. of Biochemistry, Albert Einstein College of Medicine, New York, N.Y.,10461, USA. Email -
Updated February, 2012