Continuous Variation and Rh Blood Factor Multiple Gene (Polygenic) Inheritance Gamete ABC AbC aBC abC ABc Abc aBc abc s ABC 6 5 5 4 5 4 4 3 ABc 5 4 4 3 4 3 3 2 AbC 5 4 4 3 4 3 3 2 Abc 4 3 3 2 3 2 2 1 aBC 5 4 4 3 4 3 3 2 aBc 4 3 3 2 3 2 2 1 abC 4 3 3 2 3 2 2 1 abc 3 2 2 1 2 1 1 0 Table 1. Polygenic inheritance in people showing a cross between two mulatto parents (AaBbCc x AaBbCc). The offspring contain seven different shades of skin color based on the number of capital letters in each genotype. Polygenic Inheritance: Human skin color is a good example of polygenic (multiple gene) inheritance. Assume that three "dominant" capital letter genes (A, B and C) control dark pigmentation because more melanin is produced. The "recessive"alleles of these three genes (a, b & c) control light pigmentation because lower amounts of melanin are produced. The words dominant and recessive are placed in quotation marks because these pairs of alleles are not truly dominant and recessive as in some of the garden pea traits that Gregor Mendel studied. A genotype with all "dominant" capital genes (AABBCC) has the maximum amount of melanin and very dark skin. A genotype with all "recessive" small case genes (aabbcc) has the lowest amount of melanin and very light skin. Each "dominant" capital gene produces one unit of color, so that a wide range of intermediate skin colors are produced, depending on the number of "dominant" capital genes in the genotype. For example, a genotype with three "dominant" capital genes and three small case "recessive" genes (AaBbCc) has a medium amount of melanin and an intermediate skin color. This latter genotype would be characteristic of a mulatto. In the following cross between two mulatto genotypes (AaBbCc x AaBbCc), each parent produces eight different types of gametes and these gametes combine with each other in 64 different ways resulting in a total of seven skin colors. The skin colors can be represented by the number of capital letters, ranging from zero (no capital letters) to six (all capital letters). The approximate shades of skin color corresponding to each genotype are shown in Table 1. Note: Skin color may involve at least four pairs of alleles with nine (or more) shades of skin color. The cross in Table 1 can also be shown with the bionomial expansion (a + b)6 where the letter a = number of capital letters and the letter b = number of small case letters. Each term in the expression represents the number of offspring with a specific skin color phenotype based on the number of capital letters in the genotype. For example, 20 offspring have three capital letters in their genotype and have a skin color that is intermediate between very dark with all caps (AABBCC) and very light with no caps (aabbcc). (a + b)6 = a6 + 6 a5b + 15 a4b2 + 20 a3b3 + 15 a2b4 + 6 ab5 + b6 6 Caps 5 Caps 4 Caps 3 Caps 2 Caps 1 Cap 0 Caps Multiple gene (polygenic) inheritance explains many plant and animal traits where there is a wide variation between extreme phenotypes, with most individuals having intermediate phenotypes. Some examples of polygenic inheritance are: human skin and eye color; height, weight and inteligence in people; and kernel color of wheat. In fact, kernel color in wheat is nicely shown in Table 2. Table 2 is essential the same as Table 1, except the extremes in color are dark red and white, rather than black and white. In polygenic inheritance the "dominant" capital genes are additive, each capital gene adding one unit of color to the genotype. With more capital genes, the phenotype (appearance) gets darker. The garden peas studied by Gregor Mendel involved pairs of alleles with only three possible genotypes and two phenotypes per trait. For example, the gene for round pea (R) is dominant over the gene for wrinkled pea (r) and only three genotypes are possible: RR, Rr and rr. These three genotypes produce only two phenotypes: Round (RR and Rr) and wrinkled (rr). There are no intermediate traits between round and wrinkled. If all human characteristics were controlled by simple pairs of dominant and recessive alleles like the one Mendel studied, we would have tall and short people with no intermediates. Polygenic inheritance is yet another exception to Mendel's genetic ratios. Gamete ABC AbC aBC abC ABc Abc aBc abc s ABC 6 5 5 4 5 4 4 3 ABc 5 4 4 3 4 3 3 2 AbC 5 4 4 3 4 3 3 2 Abc 4 3 3 2 3 2 2 1 aBC 5 4 4 3 4 3 3 2 aBc 4 3 3 2 3 2 2 1 abC 4 3 3 2 3 2 2 1 abc 3 2 2 1 2 1 1 0 Table 2. Polygenic inheritance in wheat showing a cross between two intermediate parents (AaBbCc x AaBbCc). The offspring contain seven different shades of kernel color based on the number of capital letters in each genotype. Rh Factor: Another Example Of Polygenic Inheritance Rh Factor: Another interesting example of polygenic inheritance is the Rh factor. Unlike the A-B-O blood types where all the alleles occur on one pair of loci on chromosome pair #9, the Rh factor involves three different pairs of alleles located on three different loci on chromosome pair #1. In the following diagram, 3 pairs of Rh alleles (C & c, D & d, E & e) occur at 3 different loci on homologous chromosome pair #1. Possible genotypes will have one C or c, one D or d, and one E or e from each chromosome. For example: CDE/cde; CdE/cDe; cde/cde; CDe/CdE; etc. In order to determine how many different genotypes are possible, you must first determine how many different gametes are possible for each parent, then match all the gametes in a genetic checkerboard (See the following Table 3). Although the three pairs of genes are linked to one homologous pair of chromosomes, there are a total of eight different possible gametes for each parent: CDE, CDe, CdE, Cde, cDE, cDe, cdE, and cde. This number of gametes is based on all the total possible ways these genes can be inherited on each chromosome of homologous pair #1. [It is not based on the random assortment of these genes during meiosis in the parents because all three genes are closely linked together on the same chromosome; therefore, all three genes tend to appear together in the same two gametes: CDE and cde.] The possible different genotypes are shown in the following Table 3: Gametes CDE CDe CDE CDE/ CDE CDE/ CDE/ CDE/ CDE/ CDE/ CDE/ CDE/ CDe CdE Cde cDE cDe cdE cde CDe/ CDE CdE/ CDE Cde/ CDE cDE/ CDE cDe/ CDE cdE/ CDE cde/ CDE CDe/ CDe CdE/ CDe Cde/ CDe cDE/ CDe cDe/ CDe cdE/ CDe cde/ CDe CDe CdE Cde cDE cDe cdE cde CdE CDe/ CdE CdE/ CdE Cde/ CdE cDE/ CdE cDe/ CdE cdE/ CdE cde/ CdE Cde CDe/ Cde CdE/ Cde Cde/ Cde cDE/ Cde cDe/ Cde cdE/ Cde cde/ Cde cDE cDe CDe/ CDe/ cDE cDe CdE/ CdE/ cDE cDe Cde/ Cde/ cDE cDe cDE/ cDE/ cDE cDe cDe/ cDe/ cDE cDe cdE/ cdE/ cDE cDe cde/ cde/ cDE cDe cdE cde CDe/ CDe/ cdE cde CdE/ CdE/ cdE cde Cde/ Cde/ cdE cde cDE/ cDE/ cdE cde cDe/ cDe/ cdE cde cdE/ cdE/ cdE cde cde/ cde/ cdE cde Table 3. Polygenic inheritance in the Rh blood factor. Every genotypic combination with DD or Dd is classified as Rh Positive (red). This is about 85% of the U.S. population because the D gene is more common than the C and E genes. Every genotypic combination with dd is classified as Rh Negative (blue). Since the ratio of C and E genes is much less than D genes, approximately 15% of the U.S. population are Rh negative (dd). Consolidating the duplicates, a total of 10 genotypes are homozygous recessive for the d allele (dd); however, nine of these genotypes are actually positive for the C and E factors: Cde/cde (0.46%), Cde/Cde (0.0036%), cdE/cde (0.38%), cdE/cdE (0.0025%), Cde/cdE (0.006%), CdE/cde (0.008%), CdE/Cde (0.0001%), CdE/cdE (0.0001%), and CdE/CdE (0.00001%). Therefore, only about 0.86% of the U.S. population are positive for C and E. Expressed as a decimal, this is 0.0086 or 8.6 out of 1000. This is why Rh incompatibility involving the C and E genes is rare in the U.S. population. Antigen Immune Antibodies (In Blood Plasma) (RBC Membrane) anti-C anti--D anti-E C (RhC) ------ ------ ------ D (RhD) ------ RhoGAM & Biology TypingSerum ------ E (RhE) ------ ------ ------ Table 4. Rh antibodies primarily utilized in immunoglobulin serums. More than 98% of all cases of hemolytic disease of the newborn (maternal-fetal blood incompatibility) are caused by the D antigen, also referred to as RhD and Rh Positive (+). This is why RhoGam and standard blood typing kits for general biology labs only contain anti-RhD (anti-D) antibodies. Anti-C and anti-E antibodies against the C and E antigens can be associated with maternal-fetal blood incompatibility, but this is uncommon and only occurs in a small percentage of non-RhD cases. Apparently immune globulins (such as RhoGam) are not available to prevent these rare cases. According to Dr. Kenneth J. Moise, Jr., formerly of the University of North Carolina Medical School at Chapel Hill, more than 43 other RBC antigens have been implicated in the non RhD cases. Especially problematic are the Kell (K1), c, Duffy (Fya) and Kidd (Jka and Jkb) antigens. A recent study from a tertiary referral center in New York found 550 cases of antibodies associated with hemolytic disease of the newborn in 37,506 blood samples taken from women of reproductive age (1.1% incidence). Anti-D occurred in 25% of the samples, anti-Kell in 28%, anti-c in 7%, anti-Duffy in 7%, anti-Kidd in 2%, anti-E in 18%, anti-C in 6%, anti-MNS in 6%, and anti-Lutheran in 2%.