1. How are polymorphisms and mutations alike?  How are they different?

2. What are some of the ways a substitution can occur in a DNA sequence?

3. What are some of the ways a deletion can occur in a DNA sequence?

4. What are some of the ways an insertion can occur in a DNA sequence?

5. The chapter on Translation has a figure that shows the structures of amino acids. Use that figure to predict which mutation would have a bigger effect on the function of a protein.

1. An alanine-to-glycine missense or an alanine-to-asparagine missense.
2. An alanine-to-asparagine missense or a nonsense mutation in the second-to-last codon.
3. An alanine-to-asparagine missense or a nonsense mutation in the 10^th codon.
4. A nonsense mutation in the second-to-last codon or a frameshift mutation in the 10^th codon.

6. Choose your favorite superhero or fictional character who has extraordinary abilities due to a mutation. How would you describe the mutation that gives them those abilities, using the terms in this chapter? Justify your reasoning with character traits. If you need some ideas, you could use Spiderman, Incredible Hulk, Teenage Mutant Ninja Turtles, or X-men, but you’re not limited to these characters. (My personal favorites are from Kipo and the Age of Wonderbeasts.)

7. If you sequenced your genome, you’d find that you probably have between 40-80 germline mutations compared to your parents’ DNA. The differences aren’t evenly distributed between your maternal and paternal half-genomes. On average, you will have about 15 mutations in your maternal chromosomes, regardless of your mom’s age when she had you. But the number of mutations carried by sperm increases with paternal age: if your dad had kids at age 20, he likely passed on an average of 25 mutations, but if your dad had kids at age 40, the average number of mutations per sperm is 65^[2].

1. What does that suggest about the number of cell divisions needed to produce an egg or sperm?
2. Why do mutations accumulate with the age of the father but not the mother? Compare and contrast oogenesis and spermatogenesis during development, using outside resources as necessary.

8. Microsatellite instability is frequently seen in certain kinds of colorectal cancer. The tumor cells have acquired somatic mutations in the MSH family of proteins, which repair the kinds of lesions generated by strand slippages.

What kinds of mutations would you expect to see if you looked at the sequence of MSH genes in the tumor cells? Would you also expect to see the same mutations in healthy cells from the same patient?

9. Coagulation Factor IX (F9) is an important factor in blood clotting. The OMIM entry for Factor IX is *300746. Use this entry to answer the following questions.

1. The Gene-Phenotype Relationships Table at the top of the entry lists multiple phenotypes associated with mutations in this gene, including Hemophilia B and Thrombophilia 8.
2. Click the links in the table to explore the phenotype listings for these traits.
   1. Describe Hemophilia B in terms a non-biologist would understand. You may need to look up some vocabulary words in the entry to answer this question! Is it caused by a gain or loss of function in the F9 gene? Is it a dominant or recessive disorder?
   2. Describe Thrombophilia 8 in terms a non-biologist would understand. Again, you will need to look up some vocabulary to answer this question! Is it caused by a gain or loss of function in the F8 gene?  Is it a dominant or recessive disorder?
3. Can mutations in a single gene cause different phenotypes? Explain your reasoning based on what you’ve learned from this exercise.

10. There are many variations in the gene Factor XIII (F8) that cause the excessive bleeding disorder Hemophilia A.

1. Open OMIM entry *300841. The Table of Contents menu at the left of the page has a link to Allelic Variants. Click on the Table View to bring up a list of variants that have been observed in humans. Scroll through the table.
   1. About how many alleles are listed?
   2. Are all of the alleles mutations, or are some polymorphisms?
2. How many alleles of a gene is any one individual expected to have?
3. Do you expect all alleles to be evenly represented in the human population, or do you expect that some are more common than others? Explain your reasoning.

11. Many mutations in the Factor XIII gene cause Hemophilia A. Click on the Allelic Variants link in OMIM entry *300841 to bring up a detailed listing of alleles associated with this disorder.

1. What type of mutation is .0208?
2. What type of mutation is .0209?
3. What type of mutation is .0210?
4. What kind of mutation is .0079?
5. Explain why all four of these mutations give a similar phenotype.

12. Lists of single-gene disorders can be found online. Choose one, and look up the disorder in the database Online Mendelian Inheritance in Man (www.omim.org).

1. Describe the phenotype associated with the disorder.
2. What gene is linked with the disorder? This information is found in the Gene-Phenotype Relationships table at the top of the page and in the text of the entry. [Look carefully! Other genes may be listed that modify the main phenotype.]
3. The Gene-Phenotype Relationships table has a link to the gene page. Click through to that reference.
4. What is the function of the gene?
5. Look at the Allelic Variants for this gene. What types of mutations cause the disorder you initially chose? Describe each mutation by the effect on gene function, change to DNA sequence, and impact on protein sequence.

Science and Society

13. In genetics, and science in general, we often learn a lot from exceptional situations: what is different genetically, molecularly, and cellularly in people with genetic disorders like Ehlers-Danlos Syndrome can teach us about the workings of a cell. And people with Ehlers-Danlos Syndrome can benefit from research into their conditions. But how do we balance the benefit of having the information with the risks to those who participate in medical studies and whose stories are told in textbooks like this? These risks might include physical health risks from participating in medical research, but they also can include risks to privacy, self-esteem, and mental health. Would you want your image to be used in a medical journal or textbook? Why or why not?

14. One of the challenges of modern genetics is distinguishing between rare polymorphisms and pathogenic (disease-causing) mutations. The majority of the original human reference genome was assembled primarily from one individual’s DNA. However,  later projects have looked to catalog variations. Why is it important that such projects look at genomes from individuals of varied ancestry?