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Non-human orthologs of the Rh blood group system

Recent studies of RHAG and RHCED genes in a number of different mammalian and non-mammalian organisms indicate that both loci arose from a common origin and evolved into an ever-expanding gene family. Whereas products of RHAG and RHCED are expressed in erythrocytes of all mammals examined so far, homologs of RHAG only have been identified both in erythroid and non-erythroid tissues, and all RH-like genes recently identified in lower species such as C. elegans or the slime mold, are more homologous to RHAG than to RHCED, and may represent the prototype of the ancestor gene.

Thus it appears that, early in evolution, RHCED arose from RHAG via a chromosomal translocation event and the divergence of both loci then proceeded at distinct rates; RHCED (ultimately gave rise to RHCE and RHD) evolved at a rate about twice faster than RHAG and remains polymorphic at the level of populations, whereas RHAG remains monomorphic. It appears that both loci experienced different selective forces, that possibly relate to their functional conservation during evolution. The discovery of RH orthologs and paralogs in slime mold and non-erythroid tissues supports the idea that RH proteins fulfill an important function in the physiology of the organism that is not confined to erythocytes only. This function still needs to be clarified. (Learn about primates here.)

phylogeny of Rh

Figure above shows a dendrogram of 30 Rh protein homologues obtained from representative organisms.  For details, see C.-H. Huang and P.Z. Liu, Blood Cells Mol. Dis. 2001. 27(1); 90-101(with permission from the journal).

In most primates and mammals such as mouse, rat or cow (only mammals examined so far) a single gene, a homologue of RHCED, is present. This gene encodes counterparts of human Rh30 polypeptides that are expressed at the erythocyte surface and, like in man, seem to be integral membrane proteins with multiple transmembrane spanning segments. As deduced from the hydrophobicity profiles they most probably display twelve transmembrane segments delineating six external loops (see the human Rh site).

In the course of primate evolution, in the common ancestor of man, chimpanzee and gorilla, the RHCED ancestor gene duplicated and the two resulting genes further diversified; one resulted in the RHCE ancestor and the other gave rise to the RHD ancestor gene. Thereafter, due to multiple unequal crossings-overs favored by the homology of the RH genes, a polymorphism of RH gene number appeared at the locus. In man, two types of haplotypes are known. The first type is characterized by the presence of two closely linked genes: one called RHD, responsible for the expression of the antigen D, the second, called RHCE, possesses four different alleles, responsible for the expression of the two antithetical series of antigens C/c and E/e. The second haplotype (occurs with a frequency of 39% in Caucasians), is characterized by the complete deletion of the RHD gene but the presence of RHCE, in form of the four alleles. Chimpanzees and gorillas possess,respectively, three and two RH-like genes per haplotype.

Only chimpanzee and gorilla possess antigen D counterparts. Other apes, orangutan and gibbon possess more distantly related antigens. In the case of the Chimpanzee, the D counterpart is carried by proteins which define the chimpanzee blood group antigens of the R-C-E-F system. This blood group system is as complex at that of man and it depends on the polymorphism of the chimpanzee Rh-like genes. In gorilla, Rh-like gene polymorphism is related to the expression of the Dgor antigen which is the gorilla couterpart of the human D antigen. Counterparts of the human antigen c are expressed by chimpanzee, gorilla and gibbon. However in these species, in contrast to man, the expression of the c-like antigen is monomorphic The other human Rh antigens (C, e, E) have no counterparts among apes or other primates.

In the case of the mouse RHCED gene, the only species in addition to human whose gene organization was studied, the exon-intron structure and arrangement appear identical to the human gene. The deduced protein sequence is consistent with an integral membrane protein showing a high level of sequence homology among family members and across the species. Mouse and all lower mammalian and non-mammalian species do not express Rh antigen counterparts, eventhough their red cell membranes contain the Rh30 proteins.

hydropathy model of Rh

Above is a model for the vertebrate Rh glycoprotein homologues constructed with the consensus amino acid sequences: The consensus sequence was derived by aligning 16 proteins. Hydropathy analysis was done using Kyte-Doolittle method. Red denotes identical residues present in 14-16 protein sequences; black, conserved; and crosses, non-conserved residues. Conserved charge distribution is in yellow and E/Q (Glu/Gln) alternation is in green. [(x)]n denotes length variation in the N- or C- terminal sequence.

Rh30 are erythrocyte integral membrane nonglycosylated, palmitoylated proteins, with an apparent molecular weights, by SDS-PAGE, between 32 and 35 kDa (actual MW ~ 45 kDa). Rh30 polypeptides are components of a membrane complex of erythrocyte membrane proteins including Rh50 glycoprotein and LW, Fy, CD47 and GPB proteins. Interaction with Rh50 is essential for the expression of RhCED antigens.

Literature reference

Blancher & Socha. The Rhesus System. In Blancher, Klein, Socha Eds. Molecular Biology and Evolution of Blood Group and MHC antigens in Primates, p93-164. Heildelberg, Springer Verlag. 1997; Kitano et al. BBRC. 249, 78, 1998; Matassi et al. J. Mol. Evol. 48, 151, 1999; Westhoff et al. Genomics. 57:451, 1999; Liu & Huang. Biochem. Genet. 37:119, 1999; Huang et al. J. Mol. Evol. 51: 76. 2000; Huang et al. Seminars in Hematol. 37:150. 2000.

Rh30 orthologs

Species Human Rh
antigens
counter-
parts
Simian
blood
group
antigens
No. of
genes
% identity:
cDNA vs
human
RHD/RHCE
% identity:
protein vs
human
RHD/RHCE
Accession
numbers
Reference
Chimpanzee D, c R-C-E-F 3 96.3 / 96.2
96.4 / 95.6
93.0 / 89.7
91.1 / 90.
92.6 /90.2
93.0 / 89.7
L37048
L37049
L37050
related:
AF045542, AF071198,
AF071199
Salvignol et al.;
Apoil & Blancher,
Gorilla D, c R-C-E-F and Dgor 2

95.7 / 95.1
96.8 / 95.4
95.3 /95.2
89.9 / 89.7
92.8 / 89.9
88.1 / 89.8
L37052
L37053

AF201369, AF049913
AF071197
Salvignol et al.; Apoil et al.;
Orangutan D (more distant) R-C-E-F 1 92.7 / 93.5 82.8 / 84.2 AF 012425 Apoil & Blancher
Gibbon c R-C-E-F 1 94.1 / 94.1   L37051 Salvignol et al.;
Rhesus monkey none none 1 89.7 / 89.9 77.4 / 78.4 S70343
AF045541
Mauro et al; Apoil & Blancher,
Crab-eating macaque none none 1 90 / 90 78.1 / 79.1 L37054 Salvignol et al.
Baboon none none 1 89.7 / 89.8 76.9 / 78.1 AF012426 Apoil & Blancher
Squirrel monkey none none 1 87.3 / 88.0 74.8 / 75.5 AF012427
AF012428
AF081795
Apoil & Blancher;
Apoil & Blancher
Marmoset none none 1 87.2 / 88.1 76.0 / 77.0 AF012429
AF045540
Apoil & Blancher;
Apoil & Blancher
Capuchin monkey none none 1 88.0 / 88.6 76.2 / 76.7 AF101479
AF102876
Westhoff &Wylie; 1998, unpublished; Blancher & Apoil, J Heredity, in press.
Lemur none none 1 77.9 / 79.0 63.5 / 63.4 AF021845
AF045544
Apoil & Blancher;
Apoil & Blancher
Mouse none none 1 71.6 / 72.0 58.5 / 58.7 AF012430; AF57524;
AB015189; AB015190; AF069311; AF045543; AF057525
Kitano et al.; Liu & Huang; Apoil & Blancher;
Westhoff et al.
Rat none none 1
/ 70.8
/ 56.7
AB015191
Kitano et al.
Cow none none 1 73.0 / 73.0 58.0 / 57.0 U59270 Meteniet-Delisse et al. Animal Genetics, 28, 202, 1997

About Rh50 orthologs

In most primates and mammals such as mouse or rat a single gene, a homologue of RHAG, is present. In contrast to RHCED, RHAG remains invariant at the population level. The gene encodes counterparts of human Rh50 glycoprotein that is expressed at the erythocyte surface and also in some non-erythroid tissues and, like in man, seems to be an integral membrane protein with multiple transmembrane-spanning segments.It shares ~ 36% identity with Rh30 polypeptides but, its disposition across the membrane is similar to Rh30; thus, as deduced from the hydrophobicity profiles, it most probably displays twelve transmembrane segments delineating six external loops (see the human RHAG site).

Rh50 is a glycosylated membrane protein with an apparent molecular weight, by SDS-PAGE, between x and x kD; heterogeneity of the glycosylation is responsible for this range of sizes but the molecular weight of the protein moiety is ~ 45 kDa. The human Rh50 locus is located on chromosome 6p11-21.1 and, in mouse, its counterpart resides on chromosome 17 in a syntenic region. Its chromosomal location has not been determined in primates.

The Rh50 protein is a component of a membrane complex of erythrocyte membrane proteins which includes, in man, RhCED, LW, Fy, CD47 and GPB proteins. In man, Rh50 is essential for the surface expression of the Rh30 polypeptides which carry the Rh blood group antigens. The absence of the Rh50 (or some specific point mutations) is responsible for the absence (or very low expresion) of the Rh antigens. This syndrome in man,is referred to as Rhnull of regulator type.

In the case of mouse, the only species in addition to human in which gene organization was studied, the exon-intron structure and arrangement appear identical to the human gene. The deduced protein sequence is consistent with an integral membrane protein and shows a high level of sequence homology to the primate counterparts. It shows about 40% identity to other family members (Rh30) across the species.

Rh50 proteins display homology with proteins deduced from cDNA sequences of Caenorrhabditis elegans, of the marine sponge and green algae. Also,the Rh50 proteins share some homology with ammonium transporters of bacteria, yeast and C. elegans. Yet, the Rh50 and ammonium transporter genes of C. elegans are different (accession numbers of the latter: U53338; M195.3; Z66498). At this time, the function of the Rh50 and Rh30 proteins remains elusive.

Also see, Kitano et al. BBRC. 249, 78, 1998; Huang et al. J. Mol. Evol. 51: 76, 2000, Huang and Liu. Blood Cells Mol. Dis. 27, 90, 2001.


Orthologs of RHAG (Rh50) genes

Species Percent
identity
cDNA (vs
human RHAG)
Percent
identity
protein (vs
human RHAG)
genomic
coding
sequence
(accession
numbers)
intron
sequences
(accession
numbers)
References
Man 100 100 AF031548 introns
2-AF179687
4-AF179691
9-AF179707
Huang et al.
Chimpanzee 98.5   AF177621 introns
2-AF179688
4-AF179692
9-AF179708
Huang et al.
Gorilla 98.5   AF177622 introns
4-AF179693
9-AF179709
Huang et al.
Orangutan 94.5   AF177623 introns
4-AF179694
9-AF179710
Huang et al.
Gibbon 93.6   AF177624 introns
4-AF179695
9-AF179711
Huang et al.
Rhesus monkey 90.5   AF177625 introns
2-AF179689
4-AF179696
9-AF179712
Huang et al.
Crab-eating macaque 95   AB015467   Salvignol et al.
Baboon 90.0   AF177626 introns
4-AF179697
9-AF179713
Huang et al.
Capuchin monkey     AF132980   Huang et al.
Mouse 87 70 AB015192; AB015193
AF057526
  Kitano et al.
Liu & Huang
Rat 82   AB015194   Kitano et al.
Cattle     AY013260   Huang & Liu
Rabbit     AY013263   Huang & Liu
C. elegans     U64847; Z74026
AF183390; AF183391
  Wilson et al.
Liu & Huang
Geodia cydonium (marine sponge)   33 Y12397   Seack et al.
Drosophila melanogaster (fruit fly)     AF193812   Liu et al.
Chlamydomonas reinhardtii (green algae)     AYO13257   Huang et al
Danio renio (zebrafish)     AF209468   Liu et al.
Oryzias Latipes (Japanese rice fish)     AB036511   Kitano & Saitou

Contributors

Antoine Blancher, MD, PhD, Laboratoire d'Immunologie, Hopital Rangueil Av.Jean Poulhes 31403 Toulouse CEDEX 4, France. Email -

Cheng-Han Huan, MD, PhD, Laboratory of Biochemistry and Molecular Genetics. Lindsley F.Kimball Research Institute. New York Blood Center. New York, N.Y. 10021. Tel.: 212 570-3388. Fax: 212 570 3251. Email -

Updated June, 2005


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