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Cookie-ase Excerpted and Adapted by Drs. Jennifer Doherty and Ingrid Waldron, University of Pennsylvania, 20111 From “Cookie-ases: Interactive Models for Teaching Genotype-Phenotype Relationships” By Rebecca L. Seipelt, the American Biology Teacher, Online Publication, May 2006 Today you will simulate the changes in a protein that can result from mutations in a gene. A mutation is a permanent change in the DNA of a gene. A mutated gene may result in the production of a protein that is less able to do its job. The protein you will simulate is a hypothetical enzyme, cookie-ase, which opens sandwich cookies. ★ What is a gene? ★ Complete the following flowchart to show how a gene can influence the structure and function of a protein enzyme. Use the terms: DNA, protein, RNA. nucleotide sequence in the _________ of a gene nucleotide sequence in messenger ___________ transcription amino acid sequence in ____________ translation structure and function of the protein enzyme One type of mutation is a change in one or more nucleotides in the nucleotide sequence of a gene. Changes in the nucleotide sequence of a gene can result in the placement of the wrong amino acid in a protein when the protein is made. This error can make the protein defective so it cannot do its job as well or at all. Mutations result in different versions of a gene. Each different version of a gene is a different allele. 1 Teachers are encouraged to copy this student handout for classroom use. A Word file (which can be used to prepare a modified version if desired) and teacher notes are available on the molecular biology page of https://sites.google.com/site/biologypd/home . 1 The figures below show the nucleotide sequence in the DNA of a gene for a hypothetical very short protein.2 The resulting mRNA and protein are also shown. Remember that each group of three nucleotides makes up a triplet codon. Each triplet codon is then translated into a single amino acid. Translation of a piece of mRNA begins when the ribosome recognizes the start codon AUG. AUG also codes for the amino acid methionine. Translation stops when the ribosome recognizes one of three stop codons that do not code for an amino acid: UGA, UAG, UAA. Normal allele = A T A C T T C A A A C C G A T T DNA mRNA This allele is able to generate a fully functional protein. A U G A A G U U U G G C U A A protein Met Lys Phe Gly Stop Met ★ Circle the triplet codon in the mRNA that codes for the amino acid phenylalanine (Phe). Point Mutation a1 allele A point mutation changes a single nucleotide in a strand of DNA and changes one triplet codon in mRNA which is translated into a different amino acid in the protein. Sometimes an important area of the protein is changed so that it cannot function properly. C replaced with T T A C T T C A A A T C G A T T DNA mRNA protein A U G A A G U U U A G C U A A Met Met Lys Phe Ser Stop ★ Circle the codon that has been changed by the point mutation. Insertion Mutation a2 allele An insertion mutation inserts an extra nucleotide into a strand of DNA. The DNA shown below has an insertion mutation. Extra A DNA T A C A T T C A A A C C G A T T C mRNA_____________________________________ protein_____________________________________ ★ Write in the results of transcription for this DNA. Mark off each codon in the mRNA. Compare the codons in this mRNA to the codons in the mRNA for the normal allele shown above. Notice that the insertion mutation results in a change in every codon after the insertion. An insertion mutation has the potential to change every amino acid in the protein. ★ Write in the results of translation for the mRNA. Remember that the codon UAA is a stop codon. 2 Real proteins typically have 50-2000 amino acids, and even a short polypeptide has more amino acids than our hypothetical protein. 2 As you saw, an insertion mutation can result in a stop codon instead of a codon for an amino acid. This results in a much shortened protein which may be extremely defective. ★ In general, do you expect point mutations or insertion mutations to result in the most severe defects? Explain why. To help you understand why an insertion mutation typically has such a big effect, you can imagine that when a ribosome makes a protein, the ribosome reads a strand of mRNA as you would read a sentence on a piece of paper. Look at the three sentences below. Normal sentence The big cat ate the fat rat. Point mutation sentence i replaced with o The bog cat ate the fat rat. Insertion mutation sentence a inserted The bai gca tat eth efa tra. ★ Which mutated sentence is more difficult to read? ★ Write a deletion mutation sentence which has the letter i deleted from the word big. Procedure for simulation In your simulation, you will work in groups of two or three. One of you will be the enzyme cookie-ase that breaks down the substrate (sandwich cookies) into product molecules (sandwich cookie halves). The table on the next page explains the different ways you will use your hands to simulate the normal enzyme and the enzymes produced by the gene with the point mutation or the insertion mutation. 1. Get a stack of job cards, a stop watch, a package of cookies, and three paper plates. 2. Each of you should select a job card. All jobs should be taken. If necessary, the recorder can also be the timekeeper. a. Enzyme: The enzyme will try to break down as many substrate molecules (sandwich cookies) into product molecules (sandwich cookie halves) as possible in 10 seconds. The two halves of the sandwich cookie must be completely separated to count (broken cookie halves don’t count). Make sure you wash your hands thoroughly before you start. 3 b. Recorder: The recorder records the numbers of cookies split in 10 seconds for each allele in the table below and makes sure the enzyme does not cheat and use fingers that are not allowed. c. Timekeeper: The timekeeper starts and stops the enzyme at the correct time. 3. The simulation is run three times: first with the normal genotype AA, then with the point mutation genotype a1a1, then with the insertion mutation genotype a2a2. Genotype How you will simulate this enzyme type Cookies split in 10 seconds You can use all the fingers on both of your hands to AA (Normal) pick up and open a cookie. You can only use your pointer and middle fingers to a1a1 (Point Mutation) pick up and open a cookie. You can only use your fists a2a2 (Insertion Mutation) (thumb inside the other four fingers). Cookies split in 10 s (phenotype) Questions 1. Create a bar graph of your data in the figure below. Be sure to label your Y axis. AA a1a1 Genotype a2a2 2. Did the point mutation or insertion mutation results in the most severe defect? Are the results of your simulation in agreement with your predictions at the top of page 3? Next, we will apply what you have learned to understanding the genetic basis for two human characteristics: albinism and muscular dystrophy. 4 Albinism Albinism is a genetic disorder that results in very pale skin and hair color. One form of albinism is caused by mutations in the gene which codes for the protein enzyme tyrosinase. Tyrosinase (together with other enzymes) acts on the substrate tyrosine to make melanin, the pigment found in the hair, skin, and eyes. When the enzyme tyrosinase is defective, not enough melanin is made. The resulting deficiency in melanin causes the characteristic pale hair and skin of albinos. The lack of pigment may also cause visual problems. In a person who is homozygous for the gene that codes for the enzyme tyrosinase, both copies of the gene have the same allele. Tushana and Raymond are both homozygous for a mutated tyrosinase allele, but they are homozygous for different alleles and they look different. Raymond is very pale, but he does have a slight yellow color in his hair, eyes, and skin. Tushana is extremely pale with white skin and hair. 1. How might the differences between Tushana and Raymond be explained? (Hint: Think about the different mutations for the cookie-ase gene.) In a person who is heterozygous for the tyrosinase gene, with one allele coding for a normal tyrosinase enzyme and one allele coding for a defective tyrosinase, enough normal tyrosinase enzyme is produced by the one normal tyrosinase allele to make enough melanin to give normal skin and hair color. So, the heterozygous individual has a normal phenotype. 2. Based on this information, which allele is dominant -- the allele for normal tyrosinase or the allele for defective tyrosinase? Explain your reasoning. 5 Muscular Dystrophy You can use the information you have learned so far to understand the genetic basis for two different types of muscular dystrophy. Muscular dystrophy is caused by harmful alleles of the gene that codes for the muscle cell protein, dystrophin. If dystrophin is defective or missing, muscle cells gradually break down so the child with muscular dystrophy becomes weaker and loses the ability to walk. Eventually the muscles in the internal organs also fail so the person dies. Duchenne muscular dystrophy is more severe. A child with Duchenne muscular dystrophy begins showing symptoms of loss of muscle function by about age 3 and needs to use a wheelchair by about age 10. A person with Duchenne muscular dystrophy typically dies as a young adult, due to failure of the muscles in the internal organs. Becker muscular dystrophy is milder. Symptoms do not begin until age 12 or later, and the person can live into their 40s or 50s. 1. Complete the following table to indicate which type of muscular dystrophy you think would be caused by each type of mutation. Type of Mutation Type of Muscular Dystrophy Deletion Mutation # nucleotides deleted from mRNA is a multiple of 3 Deletion Mutation # nucleotides deleted from mRNA is not a multiple of 3 Point Mutation stop codon 2. Explain your reasoning. 3. In a heterozygous individual, the single copy of the normal allele results in enough normal dystrophin protein to prevent muscular dystrophy. Which allele is recessive: the allele for normal dystrophin or the allele for defective dystrophin? 4. Muscular dystrophy is an X-linked disorder; the gene for dystrophin is on the X chromosome. Explain why boys are much more likely than girls to have muscular dystrophy. 6