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Modern Genetic Analysis Chapter 6. Gene Interaction
Interactions Between the Alleles of One Gene

The alleles of one gene can interact in several different ways at the functional level, resulting in variations in the type of dominance and markedly different phenotypic effects in different allelic combinations.

Incomplete Dominance

Four-o'clocks are plants native to tropical America. Their name comes from the fact that their flowers open in the late afternoon. When a wild-type four-o'clock plant with red petals is crossed with a pure line with white petals, the F1 has pink petals. If an F2 is produced by selfing the F1, the result is

Because of the 1:2:1 ratio in the F2, we can deduce an inheritance pattern based on two alleles of a single gene. However, the heterozygotes (the F1 and half the F2) are intermediate in phenotype, suggesting an incomplete type of dominance. Inventing allele symbols, we can list the genotypes of the four-o'clocks in this experiment as c+/c+ (red), c/c (white), and c+/c (pink). Incomplete dominance describes the general situation in which the phenotype of a heterozygote is intermediate between the two homozygotes on some quantitative scale of measurement. Figure 6-3 gives terms for all the theoretical positions on the scale, but in practice it is difficult to determine exactly where on such a scale the heterozygote is located. At the molecular level, incomplete dominance is generally caused by a quantitative effect of the number of "doses" of a wild-type allele; two doses produce most functional transcript and therefore most functional protein product; one dose produces less transcript and product, whereas zero doses have no functional transcript or product. In cases of full dominance, in the wild-type/mutant heterozygote either half of the normal amount of transcript and product is adequate for normal cell function (the gene is haplo-sufficient), or the wild-type allele is "up-regulated" to bring the concentration of transcript up to normal levels.

Codominance

The human ABO blood groups are determined by three alleles of one gene that show several types of interaction to produce the four blood types of the ABO system. The allelic series includes three major alleles, i, IA, and IB, but of course any person can have only two of the three alleles (or two copies of one of them). There are six different genotypes, the three homozygotes and three different types of heterozygotes:

In this allelic series, the alleles IA and IB each determine a unique antigen, which is deposited on the surface of the red blood cells. These are two forms of a single protein. However, the allele i results in no antigenic protein of this type. In the genotypes IA/i and IB/i, the alleles IA and IB are fully dominant to i. However, in the genotype IA/IB each of the alleles produces its own antigen, so they are said to be codominant.

The human disease sickle-cell anemia gives interesting insight into dominance. The gene concerned affects the molecule hemoglobin, which transports oxygen and is the major constituent of red blood cells. The three genotypes have different phenotypes, as follows:

Figure 6-4 shows sickle cells. In regard to the presence or absence of anemia, the HbA allele is obviously dominant. In regard to blood cell shape, however, there is incomplete dominance. Finally, as we shall now see, in regard to hemoglobin itself there is codominance. The alleles HbA and HbS actually code for two different forms of hemoglobin differing by a single amino acid, and both these forms are synthesized in the heterozygote. The different hemoglobin forms can be visualized using electrophoresis, a technique that separates macromolecules with different charge or size (Figure 6-5). It so happens that the A and S forms of hemoglobin have different charges, so they can be separated by electrophoresis (Figure 6-6). We see that homozygous normal people have one type of hemoglobin (A) and anemics have type S, which moves more slowly in the electric field. The heterozygotes have both types, A and S. In other words, there is codominance at the molecular level.

Sickle-cell anemia illustrates that the terms dominance, incomplete dominance, and codominance are somewhat arbitrary. The type of dominance inferred depends on the phenotypic level at which the observations are being madeorganismal, cellular, or molecular. Indeed the same caution can be applied to many of the categories that scientists use to classify structures and processes; these categories are devised by humans for convenience of analysis.

MESSAGE
The type of dominance is determined by the molecular functions of the alleles of a gene and by the investigative level of analysis.

Clover is the common name for plants of the genus Trifolium. There are many species. Some are native to North America, while others grow here as introduced weeds. Much genetic research has been done with white clover, which shows considerable variation among individuals in the curious V or chevron pattern on the leaves. Figure 6-7 shows that the different chevron forms (and the absence of chevrons) are determined by multiple alleles. In this example we are dealing with a genetic polymorphism, so the wild-type/mutant allele symbolism is not used. Study the figure to determine the type of dominance of each allele in various combinations. List the alleles in a way that expresses how they relate to one another in dominance. Are there uncertainties? Does the evidence permit us to say anything about the dominance or recessiveness of allele v?

Lethal Alleles

Normal wild-type mice have coats with a rather dark overall pigmentation. A mutation called yellow (a lighter coat color) illustrates an interesting allelic interaction. If a yellow mouse is mated to a homozygous wild-type mouse, a 1:1 ratio of yellow to wild-type mice is always observed in the progeny. This observation suggests (1) that a single gene with two alleles determines these phenotypic alternatives, (2) that the yellow mouse was heterozygous for these alleles, and (3) that the allele for yellow is dominant to an allele for normal color. However, if two yellow mice are crossed with each other, the result is always as follows:

Note two interesting features in these results. First, the 2:1 phenotypic ratio is a departure from the expectations for a monohybrid self-cross. Second, because no cross of yellow × yellow ever produced all yellow progeny, as there would be if either parent were a homozygote, it appears that it is impossible to obtain homozygous yellow mice.

The explanation for such results is that all yellow mice are heterozygous for one special allele. A cross between two heterozygotes would be expected to yield a monohybrid genotypic ratio of 1:2:1. However, if all the mice in one of the homozygous classes died before birth, the live births would then show a 2:1 ratio of heterozygotes to the surviving homozygotes. The allele AY for yellow is dominant to the wild-type allele A with respect to its effect on color, but AY acts as a recessive lethal allele with respect to a character we would call viability. Thus, a mouse with the homozygous genotype AY/AY dies before birth and is not observed among the progeny. All surviving yellow mice must be heterozygous AY/A, so a cross between yellow mice will always yield the following results:

The expected monohybrid ratio of 1:2:1 would be found among the zygotes, but it is altered to a 2:1 ratio in the progeny born because zygotes with a lethal AY/AY genotype do not survive to be counted. This hypothesis is supported by the removal of uteri from pregnant females of the yellow × yellow cross; one-fourth of the embryos are found to be dead. Figure 6-8 shows a typical litter from a cross between yellow mice.

The AY allele produces effects on two characters: coat color and survivalit is pleiotropic. It is entirely possible, however, that both effects of the AY pleiotropic allele result from the same basic cause, which promotes yellowness of coat in a single dose and death in a double dose. (Note that in mouse genetics the + symbol is traditionally not used for wild-type alleles.)

The tailless Manx phenotype in cats (Figure 6-9) is also produced by an allele that is lethal in the homozygous state. A single dose of the Manx allele ML severely interferes with normal spinal development, resulting in the absence of a tail in the ML/M heterozygote. But in ML/ML homozygotes, the double dose of the gene produces such an extreme developmental abnormality that the embryo does not survive. There are indeed many different types of lethal alleles. Some lethal alleles produce a recognizable phenotype in the heterozygote, as in the yellow mouse and Manx cat. Some lethal alleles are fully dominant and kill in one dose in the heterozygote. Others (the much more frequent case) confer no detectable effect in the heterozygote at all, and the lethality is fully recessive. Furthermore, lethal alleles differ in the developmental stage at which they express their effects. Human lethals illustrate this very well. It has been estimated that we are all heterozygous for a small number of recessive lethals in our genomes. The lethal effect is expressed in the homozygous progeny of a mating between two people who by chance carry the same recessive lethal in the heterozygous condition. Some lethals are expressed as deaths in utero, where they either go unnoticed or are noticed as spontaneous abortions. Other lethals, such as those responsible for Duchenne muscular dystrophy, cystic fibrosis, and Tay-Sachs disease, exert their effects in childhood. The time of death can even be in adulthood, as in Huntington's disease. The total of all the deleterious and lethal genes that are present in individuals is called genetic load, a kind of genetic burden that the population has to carry.

Exactly what goes wrong in lethal mutations? In many cases it is possible to trace the cascade of events that leads to death. A common situation is that the allele causes a deficiency in some essential chemical reaction. The human diseases PKU and cystic fibrosis are good examples of this kind of deficiency, as we saw in Chapter 3. In other cases there is a structural defect. For example, a lethal allele of rats determines abnormal cartilage protein, and the effect of this abnormality is expressed phenotypically in several different organs, resulting in lethal symptoms, as shown in Figure 6-10. Sickle-cell anemia, discussed above, is another example.

Whether an allele is lethal or not often depends on the environment in which the organism develops. Whereas certain alleles would be lethal in virtually any environment, others are viable in one environment but lethal in another. Human hereditary diseases provide examples. Cystic fibrosis is a disease that would be lethal without treatment, and individuals with PKU would undoubtedly not survive in a natural setting in which the special diet would be impossible. As another example, many of the alleles favored and selected by animal and plant breeders would almost certainly be eliminated in nature as a result of competition with the members of the natural population. Modern grain varieties provide good examples; only careful nurturing by the farmer has maintained such alleles for our benefit.

Geneticists commonly encounter situations in which expected phenotypic ratios are consistently skewed in one direction by reduced viability caused by one allele. For example, in the cross A/a × a/a, we predict a progeny phenotypic ratio of 50 percent A/a and 50 percent a/a, but we might consistently observe a ratio such as 55%:45% or 60%:40%. In such cases, the recessive phenotype is said to be subvital, or semilethal, because the lethality is expressed in only some individuals. Thus, lethality may range from 0 to 100 percent, depending on the gene itself, the rest of the genome, and the environment.

MESSAGE
A gene can have several different states or formsthese are called multiple alleles. The alleles are said to constitute an allelic series, and the members of a series can show various degrees of dominance to one another.

© 1999 by W. H. Freeman and Company. All rights reserved.