Mutation TN - Serendip Studio's One World



Teacher Notes for “Mutations and Muscular Dystrophy” This analysis and discussion activity begins with a brief video presenting the anchor phenomenon – a teenager who has Duchenne muscular dystrophy. Then, students learn about the normal role of the muscle protein, dystrophin, and how the lack of functional dystrophin results in the death of muscle fibers. Students analyze how different types of deletion mutations cause the more severe Duchenne muscular dystrophy vs. the milder Becker muscular dystrophy. During this analysis, students review basic molecular biology, learn how to use a codon wheel, and analyze the molecular effects of different types of point mutations and deletion mutations. Finally, students analyze the sex-linked recessive inheritance of muscular dystrophy.As background, students should understand the processes of transcription and translation. For this purpose, I recommend either of these activities:“How Genes Can Cause Disease – Introduction to Transcription and Translation" (a hands-on simulation activity available at ) or“How Genes Can Cause Disease – Understanding Transcription and Translation” (an analysis and discussion activity, available at ).Learning GoalsIn accord with the Next Generation Science Standards and A Framework for K-12 Science Education:Students will gain understanding of the Disciplinary Core Ideas:LS1.A: Structure and Function – “Genes are regions in the DNA that contain the instructions that code for the formation of proteins, which carry out most of the work of cells.”LS3.B: Variation of Traits – "Although DNA replication is tightly regulated and remarkably accurate, errors do occur and result in mutations, which are also a source of genetic variation." Students will engage in the Scientific Practices:Constructing Explanations – “Apply scientific ideas, principles and/or evidence to provide an explanation of phenomena…”Using Models – “… use a model to predict and/or describe phenomena.”This activity provides the opportunity to discuss the Crosscutting Concepts:Systems and system models, including “Models can be valuable in predicting a system’s behaviors.”Cause and effect: Mechanism and explanation, including understanding “causal relationships by examining what is known about smaller scale mechanisms within the system.”This activity helps to prepare students for the Performance Expectations:HS-LS3-1 – “Ask questions to clarify relationships about the role of DNA and chromosomes in coding the instructions for characteristic traits passed from parents to offspring.”HS-LS3-2 – "Make and defend a claim based on evidence that inheritable genetic variations may result from mutations…"Specific Content Learning GoalsDifferent versions of a gene result in different versions of a protein which can result in different characteristics. For example, a mutation in the DMD gene can result in no production of functional dystrophin protein in skeletal and heart muscles, which in turn results in the muscle breakdown which causes Duchenne muscular dystrophy.A gene provides the instructions to make a protein via the processes of transcription and translation.A codon wheel summarizes which mRNA codons specify which amino acids during translation. The codon wheel also specifies the start and stop codons.A change in a single nucleotide is a point mutation. Some point mutations result in a change in a single amino acid in the polypeptide produced by transcription and translation of the gene. Other point mutations change a codon to another codon for the same amino acid, which results in no change in the amino acid sequence of the polypeptide. In other cases, a point mutation results in a stop codon which terminates translation and can result in a drastically shortened, nonfunctional protein.If a deletion mutation results in the deletion from the mRNA molecule of any number of nucleotides that is not a multiple of 3, this causes a frameshift during translation of the mRNA. Every codon after this frameshift is changed, which usually results in the production of a nonfunctional protein. In contrast, a deletion mutation that results in the deletion of three nucleotides or a multiple of three nucleotides from the mRNA molecule will generally have less severe consequences since there is no frameshift and the subsequent codons will not be affected. The majority of cases of the more severe Duchenne muscular dystrophy result from frameshift deletion mutations, while deletion mutations that do not cause a frameshift generally result in the milder Becker muscular dystrophy.Because the DMD gene is located on the X chromosome and disease-causing mutations are recessive, muscular dystrophy is very rare in girls and most muscular dystrophy patients are boys.Suggestions for Implementation and Background BiologyTo maximize student learning, we recommend that you have your students work individually or in pairs to answer a group of related questions and then have a class discussion of student answers before moving on to the next group of related questions.The PDF of the Student Handout shows the correct format; please check this if you use the Word document to make revisions.A key is available upon request to Ingrid Waldron (iwaldron@upenn.edu). The following paragraphs provide additional instructional suggestions and background information – some for inclusion in your class discussions and some to provide you with relevant background that may be useful for your understanding and/or for responding to student questions.This activity begins with a 5-minute video () that introduces a teenager who is living a full life despite his Duchenne muscular dystrophy, together with an expert who briefly describes the biology of Duchenne muscular dystrophy. You might also want to view and possibly show an 8-minute video, “Duchenne muscular dystrophy and dystrophin”, (), which provides more detail about the biology of Duchenne muscular dystrophy. This video also discusses attempts to develop gene therapy to treat muscular dystrophy.Muscular dystrophy is currently incurable, but various treatments can reduce the symptoms. Researchers are trying to develop gene therapies that will provide effective treatments and even cures for muscular dystrophy (). Currently available techniques for genetic testing of carrier mothers and for prenatal diagnosis can provide the basis for avoiding births of affected sons or carrier daughters.Question 1 is intended to get students thinking about the question of how a mutation could result in muscle weakness. The anatomy of skeletal muscles is shown on page 1 of the Student Handout. Some students may need help to understand the relationships between the four increasingly magnified diagrams. If your students need help to interpret the figure, you can begin question 2 with the following.2a. Put the label “cell” next to the diagram of a muscle cell.2b. Put an * in the part of the bottom diagram that represents the inside of a muscle cell.Page 2 of the Student Handout reviews relevant molecular biology and introduces the distinction between the more severe Duchenne muscular dystrophy and the milder Becker muscular dystrophy.Page 3 of the Student Handout introduces students to the codon wheel and helps them to understand how the codon wheel is used to predict the outcome of translation. If you prefer a genetic code table, you can substitute the one shown below. An explanation of the advantages of the codon wheel is provided at . INCLUDEPICTURE "" \* MERGEFORMATINET ()Question 6 will help students understand how translation produces the correspondence between codons and amino acids which is summarized in the codon wheel. For each codon in the mRNA, a tRNA molecule brings the correct amino acid into the ribosome where the amino acid is joined to the growing protein molecule. There are multiple different types of tRNA molecules, each with an anticodon that matches a codon in the mRNA (by the base-pairing rules). Before a tRNA molecule enters the ribosome, a specific enzyme for each type of tRNA attaches the correct amino acid for that tRNA’s anticodon.During discussion of pages 4-5 of the Student Handout, the effects of the various mutations should be related to the students' understanding of the process of translation. The term allele is generally used for different versions of a gene that result in different characteristics, but different versions of a gene that result in a disease are often called mutations and the version of the gene that does not cause disease is called normal. There often are multiple different disease-causing mutations, as is observed for the DMD gene. The nucleotide sequences shown in the table are for the template strand (i.e. the DNA strand that RNA polymerase uses to make mRNA).Mutation 1 does not cause any change in the amino acid sequence, so it is typically called a silent mutation. However, recent research has shown that some so-called silent mutations are harmful because they affect RNA folding and thus the rate of breakdown of the RNA transcript or because they serve as a better or worse marker of the end of an exon. Mutation 2 illustrates a missense mutation since there is a change in one of the amino acids in the polypeptide. Some missense mutations have little effect, e.g. if an amino acid with similar chemical properties is substituted or the change in amino acid occurs in a region which is not crucial for the function of the polypeptide. Other missense mutations have a substantial effect, e.g. the substitution of a single amino acid which results in the difference between normal hemoglobin and sickle cell hemoglobin (analyzed in the prerequisite activities mentioned on page 1 of these Teacher Notes).Mutation 3 is called a nonsense mutation because it results in an early stop codon. An animation of the effects of a stop codon is available at . The deletion mutations shown are frameshift mutations that result in a shift in the reading frame in the ribosome. For an animation that shows how the reading frame is set up in the ribosome during the initiation of translation, see help students understand the difference in effects of deletion vs. point mutations you may want to use the following example:Normal sentenceThe big cat ate the fat rat.Point mutation sentence32385036195i replaced with o00i replaced with oThe bog cat ate the fat rat.Deletion mutation sentence36766545720 g deleted00 g deletedThe bic ata tet hef atr at.The mutations analyzed in questions 7-10 involve a change in a single nucleotide or the deletion of a single nucleotide. Of course there are many other types of mutation (e.g. deletion of multiple nucleotides). A helpful general introduction to mutations is available at (see section on Mutations and Health). Both Duchenne muscular dystrophy and Becker muscular dystrophy result from mutations in the DMD gene on the X chromosome. About two-thirds of cases are due to deletion mutations. The severity of the effects of these deletion mutations in the DNA depends in large part on the number of nucleotides deleted in the mRNA (). If the number of nucleotides deleted in the mRNA is not a multiple of three, the frameshift mutation generally results in no functional dystrophin protein, which results in more rapid breakdown of muscle cells and the more severe Duchenne muscular dystrophy. If the number of nucleotides deleted in the mRNA is a multiple of three, the mutation does not cause a frameshift, which typically results in a less defective version of the dystrophin protein, less rapid breakdown of muscle cells, and the milder Becker muscular dystrophy. Notice that the crucial factor is whether the mutation is a frameshift mutation, not the overall length of the deletion which can be quite long for some cases of Becker muscular dystrophy and quite short for some cases of Duchenne muscular dystrophy. The type of muscular dystrophy can be influenced by additional factors such as whether the mutation results in an early stop codon and the specific location of the mutation in the dystrophin gene. As preparation for question 12, students should be familiar with the basics of inheritance; for this purpose I recommend “Genetics” (). Because the dystrophin gene is on the X chromosome and because the alleles for defective dystrophin are recessive, both Duchenne and Becker muscular dystrophy are observed almost exclusively in boys. Duchenne and Becker muscular dystrophy together affect about one in every 3500-5000 newborn male babies. If your students are already familiar with X-linked inheritance, you may want to substitute the following more challenging version of question 12.12a. Duchenne muscular dystrophy is very rare in girls, and almost all Duchenne muscular dystrophy patients are boys. Based on this observation, fill in the blanks.The mutated DMD gene that causes muscular dystrophy is on ____________________________.(one of the autosomes / the X chromosome / the Y chromosome)A boy inherits the mutated version of the gene from his _________________. This parent does (father / mother)not have Duchenne muscular dystrophy.The normal version of the DMD gene is ____________________ and the mutated versions of the (dominant / recessive)DMD gene are __________________. (dominant / recessive)12b. Explain your reasoning.An estimated 10-50% of cases of muscular dystrophy are due to mutations during gamete formation in the mother or maternal grandparents (often called de novo mutations) (). The DMD gene is an extremely large gene, which contributes to a relatively high mutation rate. In the absence of new mutations, the prevalence of Duchenne muscular dystrophy would gradually decrease because it is disabling before reproductive age. If you want your students to learn how unequal crossing-over during meiosis results in new deletion mutations, you can use the Optional Additional Student Handout Page shown on the last page of these Teacher Notes.For more information on muscular dystrophy see:“About Duchenne Muscular Dystrophy” ()“Duchenne Muscular Dystrophy (DMD)” ()Additional ActivitiesAdditional molecular biology learning activities are suggested in "Molecular Biology: Major Concepts and Learning Activities" (). “Cut it out! Editing DNA with CRISPR-Cas9” () is an analysis and discussion activity that develops student understanding of current research on gene editing to treat muscular dystrophy in mice. For a high school class, you might want to use the first two pages of this case study with their links to two resources that should be appropriate for students who have a high school background in molecular biology. You may want to omit the last two pages of the case study since they depend on reading and understanding a technical review of the molecular biology of gene editing.Sources for Figures in Student HandoutFirst page – modified from page – modified from page top figure and fourth page: Third page bottom figure: modified from Krogh, Biology – A Guide to the Natural WorldFifth page: modified from Optional Additional Student Handout Page For about one third of boys with muscular dystrophy, there is no family history of muscular dystrophy. The mutation that causes the boy’s muscular dystrophy occurred during gamete formation in his mother or in one of his mother’s parents. To understand how a new deletion mutation in the DMD gene occurs, we will begin by reviewing meiosis.13. Label each number in the figure with the appropriate label from this list:DNA replicationfirst cell divisionhomologous chromosomes line upsecond cell division, which produces gametescrossing-overThis figure shows how unequal crossing-over can produce a chromosome with a deletion mutation. 14. The DMD gene is a very large gene represented in this figure by the part of the chromosome labeled B, C and D. Which chromosome or chromosomes on the right have a deletion mutation in the DMD gene?15. Suppose that a gamete with a deletion mutation in the DMD gene is fertilized to produce a zygote. Explain how this zygote would develop into a person who has this mutated DMD gene in every muscle cell. ................
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