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Griffiths AJF, Miller JH, Suzuki DT, et al. An Introduction to Genetic Analysis. 7th edition. New York: W. H. Freeman; 2000.

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An Introduction to Genetic Analysis. 7th edition.

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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 in 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:

Image ch4e11.jpg

Figure 4-3. Red (c+/c+), pink (c+/c), and white (c/c) phenotypes of four o’clock plants.

Figure 4-3

Red (c+/c+), pink (c+/c), and white (c/c) phenotypes of four o’clock plants. The pink heterozygote demonstrates incomplete dominance. (R. Calentine/Visuals Unlimited.)

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. By 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 4-3 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 produces most functional transcript and therefore most functional protein product; one dose produces less transcript and product, whereas zero dose has no functional transcript or product. In cases of full dominance, in the wild-type/mutant heterozygote either half the normal amount of transcript and product is adequate for normal cell function (the gene is said to be haplosufficient), or the wild-type allele is “upregulated” to bring the concentration of transcript up to normal levels.

Figure 4-3. Summary of dominance relations.

Figure 4-3

Summary of dominance relations. The ruler represents some sort of phenotypic measurement, such as amount of pigment.

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 one 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.

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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 antigens are two different 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 is a source of 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:

Image ch4e13.jpg

Figure 4-4 shows an electron micrograph of sickle cells. In regard to the presence or absence of anemia, the HbA allele is 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 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 by electrophoresis, a technique that separates macromolecules with different charge or size (Figure 4-5). It so happens that the A and S forms of hemoglobin have different charges, so they can be separated by electrophoresis (Figure 4-6). 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.

Figure 4-4. An electron micrograph of a sickle-shaped red blood cell.

Figure 4-4

An electron micrograph of a sickle-shaped red blood cell. Other, more rounded cells appear almost normal. (Meckes/Ottawa/Photo Researchers.)

Figure 4-5. Apparatus for electrophoresis.

Figure 4-5

Apparatus for electrophoresis. Each sample is placed in a well in a gelatinous slab (a gel). The molecules in the samples migrate different distances on the gel owing to their different electric charges. Several samples are tested at the same time (one (more...)

Figure 4-6. Electrophoresis of hemoglobin from a person with sickle-cell anemia, a heterozygote (called sickle-cell trait), and a normal person.

Figure 4-6

Electrophoresis of hemoglobin from a person with sickle-cell anemia, a heterozygote (called sickle-cell trait), and a normal person. The smudges show the positions to which the hemoglobins migrate on the starch gel.

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 made—organismal, 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.

The population analysis of the HbA and HbS alleles will be considered in Chapter 24.

MESSAGE

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

The leaves of clover plants show several variations on the dominance theme. Clover is the common name for plants of the genus Trifolium. There are many species. Some are native to North America, whereas others grow there 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 4-7 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 photographs 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 photographic evidence permit us to say anything about the dominance or recessiveness of allele v?

Figure 4-7. Multiple alleles determine the chevron pattern on the leaves of white clover.

Figure 4-7

Multiple alleles determine the chevron pattern on the leaves of white clover. The genotype of each plant is shown below it. (After photograph by W. Ellis Davies.)

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:

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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 that we 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:

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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 4-8 shows a typical litter from a cross between yellow mice.

Figure 4-8. A mouse litter from two parents heterozygous for the yellow coat-color allele, which is lethal in a double dose.

Figure 4-8

A mouse litter from two parents heterozygous for the yellow coat-color allele, which is lethal in a double dose. Not all progeny are visible. (Anthony Griffiths.)

The AY allele produces effects on two characters: coat color and survival. The AY allele 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.

The tailless Manx phenotype in cats (Figure 4-9) also is 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 the ML/ML homozygote, the double dose of the gene produces such an extreme developmental abnormality that the embryo does not survive.

Figure 4-9. Manx cat.

Figure 4-9

Manx cat. All such cats are heterozygous for a dominant allele that causes no tail to form. The allele is lethal in the homozygous condition. The dissimilar eyes are unrelated to taillessness. (Gerard Lacz/NHPA.)

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. We are all estimated to be 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, or Tay-Sachs disease, exert their effects in childhood. The time of death can even be in adulthood, as in Huntington disease. The total of all the deleterious and lethal genes that are present in individual members of a population 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. 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 4-10. Sickle-cell anemia, discussed earlier, is another example.

Figure 4-10. Diagram showing how one specific lethal allele causes death in rats.

Figure 4-10

Diagram showing how one specific lethal allele causes death in rats. (From I. M. Lerner and W. J. Libby, Heredity, Evolution, and Society, 2d ed. W. H. Freeman and Company, 1976; after H. Gruneberg.)

Whether an allele is lethal or not often depends on the environment in which the organism develops. Whereas certain alleles are lethal in virtually any environment, others are viable in one environment but lethal in another. For example, the human hereditary disease cystic fibrosis is a disease that would be lethal without treatment. Furthermore, 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 farmers 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 ratio of 50 percent A/a and 50 percent a/a, but we might consistently observe a ratio such as 55 percent:45 percent or 60 percent:40 percent. In such a case, 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 forms—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.

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2000, W. H. Freeman and Company.
Bookshelf ID: NBK21920

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