Chapter 10 FROM PROTEINS TO PHENOTYPES

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1 Chapter 10 FROM PROTEINS TO PHENOTYPES Chapter Summary The effects of mutated genes on the phenotype of fungi, discovered by Beadle and Tatum, were the jumping-off point for an ongoing effort to identify the protein or polypeptide produced by each gene. Comparison of normal proteins from healthy individuals to abnormal proteins from persons with genetic disorders is an important step in identifying protein function and relating that to gene function. Once we know what is wrong with the protein that the abnormal allele is coding for, then the door is open wider for treatment of the symptoms, and even for replacing the abnormal allele with a copy of the normal one. In the simplest case of genes and their proteins affecting phenotypes, consider the usual basis for albinism: the colorless compound DOPA is not converted to melanins. Written as a reaction, the normal production of pigment would look like this: DOPA melanins whereas albinism would appear as: DOPA -----//-- (no melanins) The blockage in the reaction indicated by // represents the lack of a product from allele A, and this product is necessary to make the reaction proceed. Often the reason for the lack of a product is the presence of two recessive alleles in the genotype. Therefore the genotype of an albino is given as aa, whereas even one dominant allele is capable of coding for enough product to direct the formation of melanin and the pigmented phenotype.

2 78 Chapter 10 Lack of other enzymes may produce phenotypes with more severe departures from normal, and the cause may be a buildup of a substrate (on the left side of the arrow), as is the case in PKU. Blockages have been found in a number of biochemical pathways in people with abnormal phenotypes. Other gene changes may not produce faulty enzymes, but instead produce faulty receptor proteins (familial hypercholesterolemia), and transport proteins (abnormal hemoglobins),. In each case, a mistake in the DNA blueprint causes an error in the protein, which in turn causes the genetic disorder. These erroneous blueprints may in turn be passed from parent to child, resulting in pedigrees with the same disorder showing up in several generations. Small changes in genes that do not lead to disorders may affect the way a person responds to drugs and to chemicals in the environment. Learning Objectives By the conclusion of this chapter, you should have a thorough understanding of: a. the concept that proteins are the end product of genetic blueprints. b. how proteins that function as enzymes participate in metabolic pathways. c. how alterations in genes can produce defects in enzymes that affect metabolic pathways, producing altered phenotypes. d. how proteins perform in some of their other roles, such as transport of oxygen. e. how altering these protein functions causes abnormal phenotypes. f. the types of changes that can occur in the DNA sequence to produce an altered protein. Key Terms substrate product metabolism alkaptonuria inborn error of metabolism essential amino acids phenylketonuria (PKU) galactosemia pseudogenes hemoglobin variants thalassemias alpha thalassemia beta thalassemia pharmacogenetics ecogenetics

3 From Proteins to Phenotypes 79 Multiple Choice Circle the letter of the best answer. 1. The compound that is formed during a reaction is known as a. the product b. the reactant c. the catalyst d. the enzyme 2. A person with mental retardation, poor control of arm and leg movements, and light pigmentation would be suspected to have an inherited disorder called a. pentosuria b. phenylketonuria c. alkaptonuria d. xeroderma pigmentosum 3. The diagnosis of the disorder described in question #2 would be confirmed if _?_ were found. a. excess levels of an amino acid b. excess levels of hemoglobin c. anemia d. urine that turns black on standing 4. To prevent the symptoms of the disorder described in question #2 from developing a. the person receives periodic injections b. the person must undergo repeated surgery c. the person is put on a restricted diet d. the person is sent to a special school 5. The symptoms that develop if the disorder described in question #2 is not treated are the result of a. production of a toxin b. accumulation of fatty compounds within lysosomes c. over-accumulation of a normal diet component d. excessive amounts of an enzyme e. failure of a metabolic pathway to produce a needed product

4 80 Chapter The ability to taste PTC a. is found in a majority of U.S. residents b. is restricted to one ethnic group in this country c. makes sucrose taste better d. occurs in people with the genotype TT, but not those who are Tt e. makes children less picky eaters 7. Brent and Danielle differ in their responses to environmental chemicals. They would be good candidates for a study of a. ecogenetics b. succinylcholine activity c. wine tasting ability d. pharmacogenetics 8. Sugars and starches are considered to be part of the group of organic compounds called a. cellulose b. lipids c. proteins d. carbohydrates 9. If Louise develops gastrointestinal disturbances, cataracts, dehydration, jaundice, and mental retardation, she probably has a. G6PD deficiency b. thalassemia c. galactosemia d. lactose intolerance 10. The individual in question #9 would not have developed those symptoms if she had not been given _?_ as a baby. a. wheat b. soy products c. milk d. eggs 11. Sickle cell anemia a. is caused by insufficient iron in the diet b. is caused by low levels of transcription of the globin genes c. is the result of improper RNA splicing d. is caused by one incorrect amino acid out of 146

5 From Proteins to Phenotypes Thalassemias a. are caused by a missing enzyme b. are found in everyone who lives around the Mediterranean Sea c. cause a build-up of an essential amino acid d. are caused by proteins in which an incorrect amino acid has been substituted e. result from reduced synthesis of a polypeptide Fill-ins Supply the word or words to complete the statement. 1. A metabolic pathway is. 2. In a metabolic pathway, the initial unchanged substance that enters the reaction is known as a. 3. In a metabolic pathway, the product of one reaction may in turn serve as the of the next reaction. 4. In a metabolic pathway, the loss of activity of a single enzyme may produce abnormal phenotypes because of the build-up of or because of the lack of. 5. Sugar and starches are all classified in the group of organic compounds known as. 6. Animals, including humans, use excess glucose to make a storage carbohydrate known as. 7. The altered phenotype resulting from the lack of a functional protein can usually be traced to a in the individual s genotype. 8. The absence of the enzyme responsible for breaking down galactose (a milk sugar) causes toxic accumulation of. 9. The gene controlling production of the enzyme in question #8 has been found to occur in different forms or alleles. 10. Each different allele in question #9 produces a different of the enzyme. 11. An individual who is totally missing an enzyme (such as someone with PKU) has a genotype for that enzyme s gene.

6 82 Chapter If Kwaasi has sickle cell anemia, he inherited one abnormal allele from. 13. Todd needs only half the dose of a particular antihistamine to get the same allergy relief that Chris gets with the prescribed amount. This difference in reaction demonstrates that Todd and Chris have. 14. Her alleles of the paraoxonase gene affect Jenny s ability to Editing If the statement is true, label it T. If the statement is false, change the underlined word or phrase to make it true. Merely adding no or not is not an acceptable change. 1. Elsie is an adult who is homozygous for the recessive PKU allele and who wishes to have children. She should be sure to eat a balanced diet high in all amino acids. 2. The reason given for the recommendation in question #1 is that a heterozygous fetus may experience neurological damage from high levels of phenylalanine in the mother s blood. 3. Early diagnosis of individuals who are homozygous recessive for the alleles causing PKU and genetic goitrous cretinism is essential because they may transmit the disorder to their siblings. 4. Based on the information in Table 10.1, you could deduce that disorders that interfere with the glycogen metabolic pathway most frequently cause damage to the brain. 5. The biological reason that some people may not enjoy eating certain vegetables is that they don t like the color green. 6. Hemoglobin is an example of a protein that is made up of four amino acids. 7. Each hemoglobin molecule is the product of at least eight different genes. 8. Because the beta globin polypeptide is made up of 146 amino acids, the coding section of mrna that produces that polypeptide is 146 nucleotides in length. 9. Most variants of hemoglobin are caused by the substitution of an amino acid in the globin chain, indicating that the globin gene DNA has also been altered.

7 From Proteins to Phenotypes If Linda has low levels of the enzyme CYP2D6, she probably has alleles of the CYP2D6 gene that make Linda an ultrarapid metabolizer of the drug tamoxifen. 11. The phenotype produced by Linda s genotype with respect to CYP2D6 (question #10) is a higher risk of breast cancer recurrence. 12. The study of how genetically-different individuals vary in their responses to environmental chemicals has become known as pollution genetics. Short Discussion Questions/Problems 1. In the following metabolic pathway, a blockage resulting from the lack of an enzyme is shown by the symbol //. A disease phenotype develops if compound 4 is not made. Which of the following pathways would result in the production of the disease phenotype? a b // c // d // Why is testing of newborns done in all states for PKU but not for osteogenesis imperfecta? 3. Many states require that all newborns be tested for a variety of inherited disorders. Is this a good idea or is it just another example of government intervening in an area where it does not belong? Should newborn testing be voluntary? Present the pros and cons of the issue. 4. Knowing what you do about cell structure, what do you see as the difficulties involved in attempting to replace missing enzymes by pill or injection? How would gene therapy be preferable?

8 84 Chapter a. Explain what is meant by gene switching. b. Gene switching is only possible when several copies of the same gene exist in a linear array on the same chromosome. Discuss this statement, using examples from the information on globin genes. c. How is the drug hydroxyurea related to the problems of gene switching and thalassemia? 6. What is a pseudogene? 7. How is it possible for a single gene to cause all of the symptoms connected with osteogenesis imperfecta? 8. In this representation of a biochemical pathway, A, B, C, and D are compounds. M- ase, N-ase and P-ase are enzymes necessary for the indicated reactions to occur. M, N, and P are the dominant forms of the genes that produce the enzymes. M-ase N-ase P-ase A B C D a. What compounds will be made by a person whose genotype is mmnnpp? b. What compounds will be made by a person whose genotype is MmNNpp? c. If a normal phenotype is only achieved when compounds A, B, C, and D are all present, what is the minimum genotype necessary to produce all four compounds? 9. Why are some amino acids necessary for human protein production, such as histidine and lysine, called essential amino acids, whereas others necessary for human protein production are not called essential? 10. People vary a great deal in their ability to taste many substances. Brian puts a lot of salt on his mashed potatoes, while Rob uses much less. Is Rob afraid of the effects of salt on his blood pressure, or could there be another reason? 11. Latesha is a female baby who would have developed symptoms of PKU if the problem had not been detected at birth. a. What is Latesha s genotype? b. What treatment was recommended to Latesha s parents?

9 From Proteins to Phenotypes 85 Latesha marries Kareem, who is homozygous normal at the PKU locus. c. What will be the genotype of any baby born to Latesha and Kareem? d. What special precaution must Latesha take, beginning in the months before she becomes pregnant? Case Study Questions Case 1 1. If both the prospective parents in this case are achondroplastic dwarves with an alteration in the same gene, what is the probable genotype of each one? 2. What are their chances of having (a) a child of normal height? (b) a dwarf child? and (c) a child with homozygous achondroplasia? What is the prognosis for the child described in (c)? 3. What specific information about the fetus development will the serial ultrasounds give? 4. In what tissue might the normal FGFR3 gene be active during development? How could you find out if you are right? 5. If you wanted to do research to see if the percentage of dwarf children born to average-sized parents in your area is the same as that in the case study, how would you go about this? Where would you collect data? What safeguards for the patients privacy are required? Case 2 1. What are the probable genotypes of Tina and her parents? If Tina s parents have another child, what are the possible genotypes and phenotypes of that child? 2. If you were a genetic counselor, how would you explain the situation to Tina s parents to prevent them from feeling guilty for causing Tina s condition? 3. Why can t AMD be treated with dietary changes like PKU? 4. What is the inherent problem in enzyme replacement therapy? Why couldn t Tina just receive acid maltase shots?