Rh Terminology and Genetics
Befuddled expressions often result when people hear about the terminology and genetics of the Rh blood group system. This brief summary should get you started in the right direction.
The Rh blood group system is a complex set of red blood cell surface proteins that most likely serve the function of maintaining the integrity of the cell membrane. There are about fifty Rh antigens, but we spend most of our time concerned about only five of them. Those five (D, C, c, E, and e) account for the vast majority of clinical and laboratory issues in this blood group.
The D antigen is really the main Rh antigen. The presence or absence of D defines a person as "Rh positive" or "Rh negative," an extremely important distinction that establishes a person's basic blood type (in conjunction with their ABO type). Commonly, blood bankers will use the term "d" ("little d") to indicate the lack of the D antigen. Be sure to understand that there is no little d antigen; "little d" is merely a slang term to indicate that there is no D.
Initially, blood bankers believed (through the guidance of Drs. Fisher and Race in England) that these five main antigens were inherited as a combination of three different genes: One D gene, one gene for C or c (called "C/c" which coded for either C or c, not both), and one gene for E or e (called "E/e" and inherited in the same manner as C/c). Each child would receive a group of Rh genes from each parent (a so-called "haplotype"), and the combination of genes inherited from both parents resulted in the child's final Rh phenotype (at least for these five antigens). The eight possible haplotypes resulting from the possible combinations of the alleles of those three genes were given specific shorthand names by another famous early blood researcher, Dr. Alexander Wiener, which are outlined below. Turns out, the whole deal was kinda wrong, but here is what we thought, anyway:
| D Positive Haplotypes | D Negative Haplotypes |
| R1: DCe | r': dCe |
| R2: DcE | r": dcE |
| R0: Dce | r: dce |
| Rz: DCE | ry: dCE |
Even though this system, based on original Fisher-Race terminology as modified by Wiener, has been shown to be incomplete and not technically correct, any student of blood banking is expected to memorize it! To help you, notice that all the haplotypes in the left column are D-positive, as indicated by the "D" leading off every haplotype, and also indicated by the capital "R" as the first letter of the shorthand. Alternatively, it is easy to determine that a particular haplotype lacks D, simply by the presence of a "d" leading the shorthand name. Also note the following:
- 1 or ' after the R or r, respectively, gives a Ce combination
- 2 or " after the R or r, respectively, gives a cE combination
- 0 or nothing after the R or r, respectively, gives a ce combination
- Any letter after the R or r gives a CE combination
After years of further research, it is now clear that these five antigens are the result of the actions of two genes on chromosome 1 rather than three. As was thought before, the D antigen actually is the product of the actions of a single gene, but that gene is now known as RHD (note that RHD may be absent or mutated in D-negative haplotypes; there is no such thing as "RHd"). On the other hand, rather than the previous theory of a single gene controlling expression of C/c antigens and another gene regulating E/e antigens, both sets of antigens are derived from the actions of a separate, single gene, known as RHCE. The four possible alleles of the RHCE gene are RHce, RHcE, RHCe, and RHCE (note that the technically correct way to write the names of the alleles is as follows: RHCE*ce, RHCE*cE, etc., but everyone knows what you mean when you write them as above). Each parent contributes one RHD and one RHCE allele to make up a child's Rh type (expressed as the presence or absence of the main five Rh antigens above).
NOTE: This terminology can be confusing, especially with RHCE. Remember, the gene is known as RHCE, but that doesn't mean that all RHCE genes encode C and E antigens. Rather, four possible alleles (alternate forms of the gene) can occur at the RHCE locus on chromosome 1. Remember, only one of those alleles is inherited from each parent. For example, a person could inherit an RHCe allele at the RHCE gene site. See the table below.
| RHD Gene Possibilities | RHCE Gene Possibilities |
| RHD allele | RHce allele |
| Deleted RHD allele | RHcE allele |
| Mutated RHD allele | RHCe allele |
| RHCE allele |
Now that we know more about Rh genetics, we can modify the first table above to better describe the Wiener haplotype terminology. See the following:
| D Positive Haplotypes | D Negative Haplotypes |
| R1: RHD, RHCe alleles (DCe) | r': Absent or mutated RHD, RHCe alleles (dCe) |
| R2: RHD, RHcE alleles (DcE) | r": Absent or mutated RHD, RHcE alleles (dcE) |
| R0: RHD, RHce alleles (Dce) | r: Absent or mutated RHD, RHce alleles (dce) |
| Rz: RHD, RHCE alleles (DCE) | ry: Absent or mutated RHD, RHCE alleles (dCE) |
Here's an illustration of how this looks:
Note that each child inherits only one copy of chromosome 1 from each parent. In the example above, the child received the copy on the right from mom, and the one on the left from dad (obviously, just an example. Three other combinations are possible, of course). The child's final Rh phenotype is determined by the combination of genes he received from his parents. Note that the genes are "codominant," meaning that all of the C/c/E/e combinations are expressed (in other words, if a person has one RHCe and one RHcE allele, all four antigens are expressed). This is shown in the simple chart below showing the genotypes and phenotypes of the offspring of an R1R0 parent and an rr parent:
| R1 (RHD, RHCe) |
R0 (RHD, RHce) |
|
| r ("RHd", RHce) |
R1r (D+C+c+E-e+) |
R0r (D+C-c+E-e+) |
| r ("RHd", RHce) |
R1r (D+C+c+E-e+) |
R0r (D+C-c+E-e+) |
*NOTE that there is no "RHd" allele, as mentioned above. This term is used simply to imply a lack of a functional RHD gene.
The table below outlines the frequencies of the various haplotypes in various races (with the most common haplotype for each race in red and the second most common in blue):
| Haplotype | Caucasians | African-Americans | Asians |
| R1 | 42% | 17% | 70% |
| R2 | 14% | 11% | 21% |
| R0 | 4% | 44% | 3% |
| Rz | 0% | 0% | 1% |
| r' | 2% | 2% | 2% |
| r" | 1% | 0% | 0% |
| r | 37% | 26% | 3% |
| ry | 0% | 0% | 0% |
Source: AABB Technical Manual, 16th ed, pg 390
As you would expect from the genetics outlined above, two separate proteins carry these Rh antigens, with one protein carrying D and another carrying the various combinations of C/c and E/e. The proteins are very similar in appearance (and likely, in function), and both appear to be dependent on the presence of another protein known as "RhAG" for expression.
As mentioned above, this discussion only touches on the genetics of the five main Rh antigens. The other 45 or so antigens in this system cause far fewer clinical and immunohematologic issues for blood banks, and we will not discuss them here.
Written by DJC on 6/20/11; updated 9/6/11