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Proc. Nat. Acad. Sci. USA Vol. 70, No. 5, pp. 1303-1307, May 1973 Genetic Model for the Rh Blood-Group System (conjugated operons/repressors/quantitative blood typing) RICHARD E. ROSENFIELD*, FRED H. ALLEN, JR.t, AND PABLO RUBINSTEIN*t *Department of Pathology, Mount Sinai School of Medicine, 5th Ave. and 100th Street, New York, N.Y. 10029; tNew York Blood Center, 310 East 67th Street, New York, N.Y. 10021 Communicated by P. Levine, February 26, 1173 ABSTRACT Inherited quantitative aspects of the Rh No such studies have been possible with membrane anti- blood-group system and susceptibility of Rh to the effects gens, perhaps because their actual isolation from lipid mem- of independently segregating suppressor genes can be cause serious accounted for with a conjugated operon model. This brane constituents might degradation (17). assumes the existence of four operator or promotor (con- Recent studies of the microstructure of human erythrocyte trol) genes for these functions, while closely linked struc- membranes revealed moveable protein particles embedded in tural regions determine the qualitative characteristics of the lipid phase (18); they were associated with blood-group A Rh antigens. Observed restriction of antigenic crossre- activity (18) and with receptors for both phytohemagglutinin activity to the products of adjacent genetic regions and data from blood typing of nonhuman primates both and influenza virus (19). The number of these particles was suggest that Rh complexity arose from a series of gene estimated to be 4200 (18)-4500 (19) per /Am2 of the surface of duplications and independent mutations. erythrocyte ghosts or about 6 X 105 for an average intact cell. The 33 qualitatively different antigenic specificities of the Rh Membrane protein particles are likely to consist of several blood-group system (1, 2) have become extraordinarily dif- polypeptides, some of which may be wholely or partly re- ficult to organize systematically. Each allele at the Rh locus sponsible for the expression of blood-group antigens. If such a determines a variable number of different antigens (3, 4), and polypeptide were directly determined by a single blood-group recombination has been observed in just one family (5). In gene, alloantigenic variation could be the result of single addition, quantitative differences in the expression of Rh anti- amino-acid substitutions similar to the situation for Gml of gens are also under the control of Rh genes (6). Accommoda- IgG heavy chains (20). However, tertiary structures arising tion of quantitative data by genetic theories devised to ac- from interaction between a polypeptide and either other poly- count only for qualitative alloantigenic variants (3, 4, 7, 8) peptides or other membrane structures could also give rise to results in a vast increase in an already overwhelmingly large blood-group antigens. For instance, Rh antigenic activity was number of complex alleles. lost when ghosts were extracted with lipid solvents, but Rh In this report, Rh data have been arranged in a manner that distinguishes qualitative from quantitative information. From this arrangement, a consistent genetic model emerges that may TABLE 1. Glossary of Rh terminology* provide a biologically sounder conceptual basis for this com- (refs. 26 and 27, text) plex system. In the Rh system (see Table 1 for glossary of terms) Rh: wl - 12 - rhG or G 23 - Dw (Rh or DU) was the first quantitative variant found (9). I Rho or D A most interesting situation was shown to involve allelic 2 - rhI or C 13 a RhA 24 w ET interaction, with the R-",2 -3 (r' or dCe) gene being suppres- 3 - rh" or E 14 - RhB 26 a Deal sive of RI alleles (R or D) in trans position (10). Quantitative 4 a hr' or c 15 - RhC 27 - cis cE variants of RI were documented quantitatively by Silber et 5 - hr" or e 16 n Rh0 28 - hrH al. (11) and Masouredis (12), but Gibbs and Rosenfield (6) 6 a hr or f or cis ce 17 a Hr0 29 - 'total Rh' found that the quantitative "degree of expression" was under 7 - hr1 or cis Ce 18 a Hr 30 u Goa the strict genetic control of Rh genes and so was the inter- 19 a hrs 31 - hrB allelic depressive effect of R-1"2 -3. Within an extensive pedi- 8 - rhWl or CW gree, identical genotypes were quantitatively identical for 9 - rhX or CX 20 a VS 32 a determined by RN four different Rh antigens, whereas qualitatively similar geno- 10 = hrt or V or eS 21 a CG 33 - determined by R0 Har types in the general population varied over a significant range 11 - rht or Ew 22 a cia CE 34 a Bas. (6). Using a different method, Berkman et al. (13) con- firmed these observations and extended the findings to the * Antigens shown as "Rh" followed by corresponding number. other blood groups. Phenotypes shown as "Rh: " followed by numbered antigens Studies of the chemistry of secreted human blood-group separated by commas for which tests were performed. Negative substances have provided detailed insight into the chemical or weak result of test shown by minus (-) or "w," respectively, of and Lewis antigens (14, 15), while evalua- preceding number. Alleles shown by R with antigens produced genetics ABO, H, or not produced given as for phenotype but in superscript. Rh25 tion of N-acetyl-galactosaminyl transferases established both (LW) is the main antigen shared by human and rhesus eryth- the nature and the mechanism of production of quantitative rocytes. In man Rh25 is determined by genes that segregate variants of the A antigen through the Km value of the specific independently of the Rh locus. Rh34 has been assigned to the transferase (16). specificity of the total immune response of Mrs. Bas (32). 1303 Downloaded by guest on September 25, 2021 1304 Genetics: Rosenfield et al. Proc. Nat. Acad. Sci. USA 70 (1973) activity of ghosts treated with n-butanol was restored by gens are expressed, while XQ/XQ depresses slightly less and addition of "nonspecific" phosphatidyl choline (21). In- produces "pseudo rhG" (34). Furthermore, all known ex- terestingly, F. A. Green found that Rh.,,1 cells reported in amples of either blood type are associated with congenital ref. 22 were neither deficient in "restorative" phosphatidyl hemolytic anemia characterized by cup-shaped erythrocytes choline nor could their ghosts be rendered Rh-antigenic by (stomatocytes) rather than normal discoid erythrocytes (35, addition of n-butanol extracts of normal cells (personal com- 36). Rhnull also arises from the homozygous state of "amor- munication to R.E.R.). Tertiary structure interactions appear phic" Rh genes (r or -) (37), and this, too, is associated with to underly the HI and AI determinants (3) and may explain stomatocytic hemolytic anemia (38). Thus, one adequately (see Rh25 of Table 1) the phenotypic association between Rh functioning Rh gene appears to be needed for production of and LW (3, 23). normal erythrocyte membranes. Whether the erythrocyte Strongly suggestive evidence that Rh is protein in nature changes associated with RhnuiI and "pseudo rhG" are a direct (24) includes its reversible inactivation by p-chloromercuri- consequence of the altered expression of Rh antigens or the benzoate (25), inactivation by N-ethylmaleimide (25), de- result of an epistatic effect of Rh genes is as yet unknown. struction by heating to 56' (26), susceptibility to proteolytic The expression of all Rh antigens from one Rh gene can be digestion (27), and denaturation by urea (25, 28) or exposure depressed by certain paired genes, especially those determin- to pH 3.0 (29). The role of phosphatidyl choline and the high ing Rh2 (rh' or C) (6). This effect, too, is more readily com- lability of Rh indicate that the tertiary structure of a protein- prehensible when a main point of regulation is assumed. lipid complex is essential to the formation, orientation, and/or The main regulatory locus of Rh may display allelic alterna- stabilization of the expression of Rh determinants. tives. If R29 is considered the "normal" allele, R-29 can be Table 1 gives the 33 antigenic specificities described in the assumed for cis Rhnun1 and RI' can be used for an abnormal Rh system. The genetics of Rh, however, is far more com- expression of all structurally specified antigens with coinciden- plicated because the qualitative combination of antigens tal emergence of a rare and otherwise unobserved antigen, within each allotype and the degree to which each antigen is Rh33 (39). These allelic possibilities, however, are not obliga- expressed are both under the control of the Rh locus. In fact, tory because similar effects would obtain with selected cis to account for the thousands of resulting Rh allotypes, no less conditions at other regions of the Rh system. These and other than four conjugated and coordinated systems, or operons problems relating to the main point of regulation will be con- (30), appear to be needed on chromosome 1 (31). This is shown sidered later. in Fig. 1. The serology of the Rh blood-group system can be divided A main point of regulation, although not an absolute neces- into two parts, one concerning Rhl (Rh. or D) and the other sity, clearly indicates how all of Rh is susceptible to suppres- non-Rhl antigenic specificities. Indeed, this is the basis of sion, especially by independently segregating, partially reces- Wiener's Rh-Hr terminology (4). However, Rhl is not likely sive genes. The known independent suppressors are called to be a discrete antigenic determinant but, rather, a series of X~r (33) and XQ (34) although neither is associated with the distinct antigens inherited en bloc and all determined by X chromosome.

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