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Chapter 5: Extensions of Mendelian Inheritance Student Learning Objectives Upon completion of this chapter you should be able to: 1. Understand the relationship between gene expression and the dominant/recessive phenotype. 2. Understand the different patterns of Mendelian inheritance involving single genes and how to solve relevant problems. 3. Recognize how traits can be influenced by the environment. 4. Differentiate between sex-linked, sex-limited, and sex-influenced patterns of inheritance. 5. Understand how lethal alleles may result in inheritance patterns with unexpected results. 6. Recognize how gene interactions, such as epistasis, can alter the predicted 9:3:3:1 ratio of a dihybrid cross. 5.1 Overview of Simple Inheritance Patterns Overview The first section of this chapter introduces the various patterns of inheritance that involve single genes. These will be discussed in detail in the remaining sections. At this point, study Table 5.1 closely to become familiar with all these patterns. It is important to note that pure Mendelian inheritance is rare. Instead, patterns of inheritance are clouded by many factors, including the environment and protein function. One of the most important things to consider as you progress through this chapter is the relationship between the observed inheritance pattern and its molecular basis. By doing so, you will quickly come to realize that the behavior of the proteins encoded by genes is the major factor in determining the phenotype of the individual. Outline of Key Terms Mendelian inheritance (Simple Mendelian inheritance) Focal Points Types of Mendelian inheritance patterns involving single genes (Table 5.1) Exercises and Problems Name the pattern of inheritance based on its description: _______ _______ _______ _______ _______ 1. 2. 3. 4. 5. The heterozygote’s phenotype is intermediate between those of the homozygotes. The heterozygote has a trait that is more beneficial than either homozygote. The heterozygote expresses both alleles simultaneously. The allele has the potential to cause the death of an organism. The trait occurs in only one of the two sexes. - 46 - 5.2 Dominant and Recessive Alleles Overview The second section examines two main ideas: 1) what makes an allele dominant or recessive; and 2) how dominant alleles may not always exert their effects. The section opens with a discussion of wild-type and mutant alleles. In some instances, more than one wild-type allele can occur (Refer to Figure 5.1). This phenomenon is termed genetic polymorphism (Figure 5.1). In general, recessive alleles are due to mutations that result in a reduction or loss-of-function of the encoded protein. Dominant alleles, on the other hand, are most commonly caused by gain-of-function mutations, dominant negative mutations, or haploinsufficiency. The last part of this section addresses two phenomena that can influence traits: 1) incomplete penetrance, where an allele that is expected to be expressed is not expressed (Figure 5.3); and 2) expressivity, which refers to the degree to which a trait is expressed. Outline of Key Terms Dominant mutant alleles Gain-of-function mutations Dominant negative mutations Haploinsufficiency Incomplete penetrance Expressivity Wild-type alleles Genetic polymorphism Mutant alleles Focal Points A comparison of protein levels among various genotypes of flowers (Figure 5.2) Polydactyly, a dominant trait that shows incomplete penetrance (Figure 5.3) Exercises and Problems For questions 1 to 5, match each of the following to its correct definition. _____ 1. Wild-type allele _____ 2. Incomplete penetrance _____ 3. Dominant negative mutation _____ 4. Mutant allele _____ 5. Haploinsufficiency a. These are altered alleles that tend to be rare in natural populations. b. A heterozygote (with one functional and one inactive allele) exhibits an abnormal phenotype. c. The protein encoded by the mutant gene acts antagonistically to the normal protein. d. The dominant phenotype is not expressed even if a dominant allele is present. e. The most prevalent form of an allele in a population. - 47 - 5.3 Environmental Effects on Gene Expression Overview It is important to note that genes are not the only determinant of an organism’s phenotype. This section discusses three examples: 1) coat color in the arctic fox, which is white in the winter and brown in the summer (Figure 5.4A); 2) the disease phenylketonuria in humans, which can be avoided if individuals are diagnosed early and follow a restricted diet free of phenylalanine (Figure 5.4B); and 3) facet number in the eyes of fruit flies, which can change based on the temperature, even in genetically-identical individuals (Figure 5.4C). Outline of Key Terms Norm of reaction Focal Points Variation in the expression of traits due to environmental effects (Figure 5.4) Exercises and Problems Complete the following sentences with the most appropriate word or phrase: 1. 2. 3. 4. Coat color in the arctic fox is caused by a ______-______ allele. Phenylketonuria (PKU) is caused by a defect in the gene that encodes the enzyme _______. Individuals with PKU are placed on restricted diets that are free of _______. The term _______ refers to the effects of environmental variation on a phenotype. 5.4 Incomplete Dominance, Overdominance, and Codominance Overview This section takes a closer look at three types of inheritance patterns in which the heterozygote shows a phenotype that is different from those of the two homozygotes. The first of these types is incomplete dominance, where the heterozygote exhibits an intermediate phenotype. Indeed, it is important at this point to note the description of a trait as dominant or incompletely dominant actually depends on the level at which phenotype is examined (Refer to Figure 5.6). The second type is overdominance, which occurs when heterozygotes have superior traits to those of the corresponding homozygotes. Three possible explanations for this are given in Figure 5.8. The third inheritance pattern discussed in this section is codominane. It refers to the phenomenon in which a heterozygous individual expresses both alleles. The text first addresses the concept of multiple alleles, using the ABO blood type. These blood types are determined by antigens on the surface of red blood cells (Refer to Figure 5.9). The synthesis of these antigens is controlled by three alleles (IA, IB, and i), which exhibit various levels of dominance: IA and IB are codominant, and i is recessive to both of them. 47 Outline of Key Terms Incomplete dominance Overdominance Heterozygote advantage Homodimer Codominance Multiple alleles Focal Points Incomplete dominance in the four-o’clock plant (Figure 5.5) Inheritance of sickle cell disease (Figure 5.7) ABO blood type (Figure 5.9) Exercises and Problems 1. Is incomplete dominance an example of blending? Explain your answer. 2. If a red and pink four o’clock plant are crossed, what will be the phenotypic and genotypic ratio of the F1 generation? For questions 3 to 5, complete the following sentences with the most appropriate word or phrase: 3. In ABO blood groups, type _____ is the universal donor and type ____ the universal recipient. 4. The IA and IB alleles encode enzymes called _________. 5. Overdominance is also also called ________. For questions 6 to 8, select the molecular basis of each of the following patterns of inheritance. _____ 6. Codominance _____ 7. Incomplete dominance _____ 8. Overdominance a. Heterozygotes produce proteins that function over a wider range of conditions. b. The proteins produced different alleles function in slightly different ways resulting in both being expressed in the heterozygote. c. The amount of protein produced by a single dominant allele is not sufficient to produce the normal phenotype. For questions 9 to 11, use the following information: Jack has blood type A, and his father has blood type O. Jill, Jack’s wife, has blood type AB? 9. What is the probability that the couple’s first child has blood type A? 10. What is the probability that the couple’s first child is a son with blood type AB? 11. What is the probability that the couple’s first two children have blood type B? 48 5.5 Sex-Influenced and Sex-Limited Inheritance Overview In Chapter 4, we discussed sex-linked inheritance in humans, which is based on genes located on the sex chromosomes. It follows three basic models: X-linked, Y-linked, and pseudoautosomal. This chapter addresses sex-influenced and sex-limited inheritance, both of which involve genes found on autosomes. In sex-influenced traits, heterozygous males and females have different phenotypes. An example is pattern baldness in humans. Sex-limited traits, on the other hand, are expressed in only one sex. An example is the feathering pattern in chicken. Outline of Key Terms Sex-influenced inheritance Sex-limited inheritance Sexual dimorphism Focal Points Sex-influenced trait: Pattern baldness in humans (Figures 5.10 and 5.11) Sex-limited trait: Feathering pattern in chicken (Figure 5.12) Exercises and Problems Complete the following sentences with the most appropriate word or phrase: The gene that affects pattern baldness encodes an enzyme called (1) _______, which converts the hormone testosterone to (2) _______. The allele that causes pattern baldness results in overexpression of this enzyme. A rare tumor of the (3) _______ can cause the secretion of abnormally large amounts of testosterone. If this occurs in a woman who is (4) _______, she will become bald. Questions 5 and 6 refer to a bald woman and a nonbald man who are planning a family. 5. What is the probability that the couple’s first child is a son that will become bald as an adult? 6. What is the probability that the couple’s first child is a daughter that will be bald as an adult? 5.6 Lethal Alleles Overview This section addresses the concept of lethal alleles, which can potentially lead to the death of an organism. These alleles come in different forms, including temperature-sensitive, conditional, and semilethal. Lethal alleles may result in inheritance patterns that yield unexpected ratios (Refer to Figure 5.13). 47 Outline of Key Terms Lethal alleles Essential gene Non-essential gene Age of onset Conditional lethal alleles Temperature-sensitive (ts) lethal alleles Semilethal alleles Focal Points The Manx cat, which carries a lethal allele (Figure 5.13) Exercises and Problems For questions 1 to 5, match each of the following to its correct definition. _____ 1. Conditional lethal allele _____ 2. Nonessential gene _____ 3. Essential gene _____ 4. Semilethal allele _____ 5. Lethal allele a. An allele that kills an organism only in certain environments. b. An allele that causes the death of an organism. c. A lethal allele that only acts in some individuals. d. A gene that encodes a protein that when absent causes the death of the organism. e. A gene which is not absolutely required for survival. 5.7 Pleiotropy Overview This short section deals with pleiotropy, the phenomenon where a single gene can have multiple effects on the phenotype of the organism. Pleiotropy can occur for several reasons, including: 1) A gene may affect cell function in more than one way; 2) A gene may be expressed in different cell types in a multicellular organism; and 3) A gene may be expressed at different stages of development. Outline of Key Terms Pleiotropy 48 Exercises and Problems Complete the following sentences with the most appropriate word or phrase: An example of a pleiotropic mutation involves the disease (1) ________. The gene in question encodes a protein called CFTR, which transports (2) ______ ions across epithelial cell membranes. The mutation that causes this genetic disease affects several parts of the body. The most severe symptoms is thick (3) _______ in the lungs, that occurs because of a water imbalance. In addition, affected males may be infertile, because the (4) ______, the tubules that transport sperm from the testes, may be absent or undeveloped. 5.8 Gene Interactions The previous sections examined deviations from Mendelian inheritance based upon single genes. You should now also recognize that many of these patterns of inheritance were due to the proteins that were being produced by the genes. However, many traits are under the influence of more than one gene. In many cases, several genes produce enzymes that are involved in metabolic pathways. If a mutation in a gene early in the pathway produces a loss of function, then this may mask the phenotype of genes that contribute alleles later in the pathway (for example, see the left column on page 105). This is called epistasis. As you progress through this section, note how the gene interactions being described alter the 9:3:3:1 ratio of a Mendelian two-factor (dihybrid) cross. Before proceeding, carefully examine the table below of a two-factor cross involving two heterozygous individuals. Gene A A– aa A– aa Gene B B– B– bb bb Phenotypic Ratio 9/16 3/16 3/16 1/16 Notice that the 9/16th aspect of ratio occurs if a dominant allele is inherited for both traits, while a 3/16th ratio occurs if a dominant allele is inherited for only one of the traits. 1/16th of the time the phenotype is recessive. By recognizing these numbers it is usually easy to identify epistatic interactions, since the masking of one of the traits will cause the ratios to be combined. For example, a 9:7 ratio indicates that the A–bb, aaB–, and aabb ratios have been combined together. This will be useful later in additional discussions of gene interactions. Another example of a gene interaction is complementation (Refer to Figure 5.14). This refers to the production of offspring with a wild-type phenotype from parents that both display the same or recessive phenotypes. This section concludes with a discussion of gene redundancy, which is the phenomenon where a gene compensates for lack of function of another. The text provides a molecular explanation (Figure 5.15) and an example (Figure 5.16). Outline of Key Terms Gene interaction Epistasis Recessive epistasis Complementation Gene redundancy Paralogs Gene knockout 49 Focal Points Types of Mendelian inheritance patterns involving two genes (Table 5.3) A cross between two different white varieties of the sweet pea (Figure 5.14) The phenomenon of gene redundancy (Figures 5.15 and 5.16) Exercises and Problems For questions 1 to 4, complete the following sentences with the most appropriate word or phrase: 1. ________ occurs when the alleles of one gene mask the phenotypic effects of another gene. 2. ________ occurs when two different parents that express the same phenotype produce offspring with a wild-type phenotype. 3. ________ occurs when one gene compensates for the loss of function of another gene. 4. ________ are duplicated genes which are not identical due to the accumulation of mutations. 5. In crosses involving the sweet pea, two white flowered plants are crossed. Indicate whether the following offspring are possible. a. all white offspring b. all purple offspring c. a combination of purple and white offspring For questions 6 and 7, use the following information: In the shepherd’s purse plant, capsule shape is determined by two gene loci, T and V. Triangular shape requires at least one dominant allele. Plants that are ttvv homozygotes have ovate capsules. 6. A plant with genotype TtVv is self-fertilized. What is the phenotypic ratio in the offspring? 7. A plant with genotype TtVv is test-crossed. What is the phenotypic ratio in the offspring? Chapter Quiz 1. The Manx phenotype in cats is caused by a dominant allele that is lethal in the homozygous state. If two Manx cats are crossed, what phenotypic ratio is expected in kittens that are born? a. all Manx b. 3 Manx : 1 normal c. 2 Manx : 1 normal d. 1 Manx : 1 normal e. all normal 2. Expressivity is most often associated with which of the following? a. multiple allele systems b. heterozygote advantage c. incomplete penetrance d. incomplete dominance e. none of the above 46 3. The ABO blood groups in humans are an example of ________. a. multiple allele systems b. epistatic interactions c. gene dosage d. simple Mendelian inheritance e. incomplete dominance 4. The most common allele in the population is called the _______. a. mutant allele b. essential allele c. dominant allele d. wild-type allele e. recessive allele 5. A trait that produces a 9:7 ratio in the F2 generation of a two-factor cross is most likely exhibiting which of the following? a. gene redundancy b. epistatic interactions c. overdominance d. multiple allele systems e. sex-limited inheritance 6. An autosomal gene in humans has four alleles. How many different genotypes are possible? a. 4 b. 8 c. 10 d. 12 e. 16 7. A heterozygote that has a selective advantage over the homozygous dominant individual is an example of ________. a. gene interaction b. codominance c. temperature sensitive lethals d. overdominance 8. Which of the following CANNOT possibly be the offspring of a man with type A blood and a woman with type B blood? a. a child with type A b. a child with type B c. a child with type AB d. a child with type O e. choose this answer if all of the above are possible 9. A pattern-bald woman is married to a man with normal hair. Which of the following statements about their adult offspring is TRUE? a. All of their children are expected to be nonbald b. Half of their children of either sex are expected to be bald c. Half of their sons are expected to be bald, but none of their daughters d. All of their sons are expected to be bald; but none of their daughters e. All of their daughters are expected to be bald; but none of their sons 47 10. Phenotypic blending is the result of ________. a. incomplete penetrance b. incomplete dominance c. codominance d. overdominance e. epistasis Answer Key for Study Guide Questions This answer key provides the answers to the exercises and chapter quiz for this chapter. Answers in parentheses ( ) represent possible alternate answers to a problem, while answers marked with an asterisk (*) indicate that the response to the question may vary. 5.1 1. Incomplete dominance 2. Overdominance 3. Codominance 4. Lethal allele 5. Sex-limited inheritance 5.2 1. e 2. d 3. c 4. a 5. b 5.3 1. temperature-sensitive 2. phenylalanine hydroxylase 3. phenylalanine 4. norm of reaction 5.4 1. It is an example of phenotypic blending since the heterozygote produces an intermediate phenotype. However, the genotypes are not blended. 2. Phenotypic ratio is ½ red to ½ pink. The genotypic ratio is ½ CRCR to ½ CRCW. 3. O (donor); AB (recipient) 4. glycosyl transferases 5. heterozygote advantage 6. b 7. c 8. a 9. 1/2 10. 1/8 11. 1/16 5.5 1. 5--reductase 2. 5--dihydrotestosterone (DHT) 3. adrenal gland 4. heterozygous 5. 1/1 (100%) 6. 0% 48 5.6 1. a 2. e 3. d 4. c 5. b 5.7 1. cystic fibrosis 2. chloride (Cl-) 3. mucus 4. vas deferens 5.8 1. Epistasis 2. Complementation 3. Gene redundancy 4. Paralogs 5. a. yes b. yes c. yes 6. Ratio is 15 triangular : 1 ovate 7. Ratio is 3 triangular : 1 ovate Quiz 1. c 2. c 3. a 4. d 5. b 6. c 7. d 8. e 9. d 10. b 46