Detecting Genetic Variation - Sickle Cell Trait

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Students will investigate variation in the beta globin gene by identifying base changes that do and do not alter function and consider the significance of the base change associated with sickle cell disease.

Big Idea

Our understanding of the basic biochemical mechanisms underlying the symptoms associated with sickle cell disease has provided important clues about possible strategies for clinical intervention such as treatment and new drug therapies.


5 minutes

In this lesson, students will investigate human genetic variation at the molecular level and examine the impact of that variation on biological function. Introduce the lesson by asking students to identify the ultimate source of the variation. Students should recognize that the ultimate source of genetic variation is differences in DNA sequences as seen in the following PowerPoint presentation.


15 minutes

Engage (Activate Student Thinking)


Introduce the lesson by asking students to identify the ultimate source of the variation they observed and discussed in the PowerPoint presentation found in the Introduction section of this lesson. Students should recognize that the ultimate source of genetic variation is differences in DNA sequences. If students do not arrive at this response review the introductory presentation focusing on the changes and variation in DNA, the blueprint of all human life.


60 minutes

Explore (Guided/Student-Centered Activity)

Distribute the "How Much Variation?" student pages containing the gene sequences for the Beta Globin Gene. 

1. Ask students to read the narrative at the top of each page and then estimate the total number of bases on each page.

2. Direct students to write their estimate in the space provided on the masters. The total number of bases on each page is 1,691. Students will need this number to complete their calculations. 

3. Point out that this sequence is only 1,691 bases long and the complete human genome is about three billion bases long.

a. Ask the students how they might use the sequences from person A and person B and the total size of the human genome to estimate the extent of variation (the number of bases that differ) between the two people

b. Ask what assumption they would be making as they arrived at their estimate.

(Students could estimate the extent of variation across the entire genome by calculating the percentage of difference between the two sequences shown for person A and person B, and then multiplying this percentage by 3 billion (the approximate number of bases in the human genome). This estimate assumes that the sequence shown displays a typical amount of variation.)

4. Provide a copy of the student page "How Much Variation? Doing the Math" to each student and direct the students to use this guide to estimate the values requested. If your students need help completing this estimate, suggest that they first try the example at the bottom of the master.

5. Ask students what their estimates indicate about the extent of human genetic variation at the molecular level.

(Students should recognize that at the molecular level, humans are far more alike (about 99.9 percent of the bases are the same) than they are different (only about 0.1 percent of the bases are different). Students should also realize, however, that even a small percentage difference can represent a very large actual number of differences in something as large as the human genome.)

6. If students have difficulty reaching these conclusions, help them by asking probing questions such as, “Based on this comparison, do you think that at the molecular level, people are more alike than they are different or vice versa?” and “How can a difference of only 0.1 percent (1 in 1,000) result in such a large number of differences (3 million differences)?” 


45 minutes

Explain (Formulate Ideas)


Explain that the rest of the lesson focuses on this 0.1 percent difference between people. Ask students questions such as: “Do you think these differences matter? What effect do you think they have? What might affect how much a specific difference matters?” 

1. Explain that studying the beta globin gene more closely will help students begin to answer these questions for themselves. Have students examine the sequences Beta Globin Gene sequences again. Explain that the regions that show bases grouped in triplets are from the coding regions (exons) of the gene, while the other regions are from the noncoding regions (introns). Then, ask students which of the two base differences in bold is most likely to matter, and why.

2. Explain that although 3 million base differences sounds like a lot, most of these differences have no significant impact on individuals, either because they occur in a noncoding region or for another reason. Point out that most of these 3 million differences can only be detected by examining the DNA sequence.

3. Tell students that in the next part of the lesson, they will consider the consequences of the genetic variation that results in sickle cell disease. Distribute the Exploring Sickle Cell Disease student pages, and direct students to organize into small groups.

4. Have students view the documentary “What Is Sickle Cell Disease?” on the student section of the Human Genetic Variation Web site completing the Focus for Media Questions as they view the video excerpt. 

For classes without access to the internet, provide each student with printed copies of the Sickle Cell Disease Reference Database in which to base their research and completion of the "Exploring Sickle Cell Disease" student pages.

5. Give the students about 30 minutes to complete their research. Notice that most of the information they need is located in the Sickle Cell Reference Database student page as well as the Database website however if the students’ textbook has an adequate description of sickle cell disease, you may wish to assign certain questions for them to complete at home with their textbook.

6. Collect the students’ written scenes or have each group perform its scene for the class as a way to assess students’ understanding of the inheritance of sickle cell disease.


15 minutes

Elaborate (Apply and Extend Understanding)

Ask students, as a final challenge, to imagine that they are doctors practicing in Cameroon, in West-Central Africa.

1. Direct students to return to the resources used in the Explain portion of the lesson and to compare the incidence of sickle cell disease in Cameroon with its incidence in the United States and to determine how scientists explain the difference. Students should access the database.

(For classes without access to the Internet: Ask students, as a final challenge, to imagine that they are doctors practicing in Cameroon, in west-central Africa. Direct them to return to Reference Database: Sickle Cell Disease to compare the incidence of sickle cell disease in Cameroon with its incidence in the United States and to determine how scientists explain the difference.)

2. When students reach Question 2 on the "Exploring Sickle Cell Disease" student page they should have explained how they intend to test the Lindsey twins.  Instead of giving students the results of the test they propose you may want them to complete the relevant laboratory activity themselves. Kits from Bio-Rad and Carolina Biological are available that you can adapt to this purpose. Some use proteins that represent hemoglobin from normal, sickle cell, and sickle cell trait (heterozygous) individuals. The test results on the student page, "Results of the Lindsey Test", are based on DNA from such individuals. If you use a kit, be sure to make this distinction clear to students. If you plan to have your students complete the lab, schedule an additional half to whole class period for the activity.


15 minutes

Evaluate (Monitor Understanding)

Based on the gel electrophoresis result, ask students how this information would change what they would say to Ms. Lindsey. The only thing that would change is the implication of the findings for the twins’ health. Jason will still have sickle cell disease, but Sondra should have enhanced resistance to malaria. 

Close this lesson with the following challenge questions:

1. Will natural selection favor the survival of people who produce Hb S or people who produce Hb A? 

2. All populations have genetic variations that lead to increased incidence of particular disorders (for example, cystic fibrosis among Caucasians of European ancestry, Tay-Sachs disease among Eastern-European Jews, and a particular type of Thalassemia—a blood disorder—among Asians).

Challenge students to explain why such apparently harmful variations have been maintained in those populations.