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Alleles of Rh boxes

Rh box

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.

Box DNA alteration Region of
alteration
Association
with RHD allele
Accession
number
Reference
upstream reference (URH)     AJ252311 Wagner & Flegel
upstream (RHD pseudo) gene conversion downstream sequence at 7618-8081 RhD pseudogene   Wagner et al.
upstream (DAU-1) gene conversion downstream sequence at 7385-8081 DAU-1 & DAU-3   Wagner et al.
upstream+downstream identity (nt. 5701-7163) + 5' and 3' regions (3209-5703+7167-8804) single mutations+ deletions +insertions 103 total: 6 in identity region; remaining in others     Wagner et al.
upstream (URH1) gene conversion or recombination? downstream sequence at 5406 + 7649-7723     Grootkerk-Tax et al.
upstream (URH2) gene conversion or recombination? downstream sequence at 5406 + 7416-7723     Grootkerk-Tax et al.
downstream reference (DRH)     AJ252312 Wagner & Flegel
downstream (Ccde) gene conversion upstream sequence at 4144-4292+ 5703-7350 Ccde   Wagner et al.
downstream (weakD type 4.1) gene conversion upstream sequence at 3947-7385 weak D type 4.1   Wagner et al.
downstream (weakD type 4.2) gene conversion upstream sequence at 7167-7888 weak D type 4.2   Wagner et al.
downstream (DAU-0) gene conversion upstream sequence at 7167-8794 DAU-0   Wagner et al.
downstream (DRH1) gene conversion or recombination? upstream sequence at 5136-7416     Grootkerk-Tax et al.
downstream (DRH2) gene conversion or recombination? upstream sequence at 7287-7649     Grootkerk-Tax et al.
downstream (DHR3) gene conversion or recombination? upstream sequence at 7287-7678     Grootkerk-Tax et al.
downstream (DRH4) gene conversion or recombination? upstream sequence at 7416     Grootkerk-Tax et al.
downstream (DRH5) gene conversion or recombination? upstream sequence at 7287-7381 +7678     Grootkerk-Tax et al.
hybrid HRHB1 (standard, reference,UDRH) recombination breakpoint nt. 5703-6594 5' and 3' parts from Euresian with E AJ252313 Wagner & Flegel
hybrid HRHB2 recombination breakpoint nt. 5703-7167 5; and 3' parts from Euresian with e   Wagner et al.
hybrid HTHB3 recombination breakpoint nt. 6594-7271 5' and 3' parts from Ccde   Wagner et al.
hybrid HTHB4 recombination breakpoint nt. 6594-7256 5' and 3' parts from Euresian with E   Wagner et al.
hybrid HTHB5 recombination breakpoint nt. 3254-3282     Wagner et al.
hybrid UDRH1 gene conversion or recombination? upstream sequence 7287-7416+7678     Grootkerk-Tax et al.
hybrid UDRH2 gene conversion or recombination? upstream sequence 7287-7381+7678     Grootkerk-Tax et al.


Contributors

Olga. O. Blumenfeld, Ph.D, Dept. of Biochemistry, Albert Einstein College of Medicine, New York, N.Y.,10461, USA. Email -

Updated February, 2012


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