Human Genetic Variation
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Activity 2 - The Meaning of Genetic Variation

11. Point out the codon in which the first difference between the two sequences occurs and tell students that person A has normal hemoglobin, while Person B has an abnormal hemoglobin that is associated with sickle cell disease. Explain that the single base difference in this codon determines whether a person has normal hemoglobin or sickle hemoglobin.

If you wish to take the time, ask students to identify the actual amino acid difference between these two types of hemoglobin, based on the difference in the DNA sequence of the codon you identified. This is an opportunity for students to review the translation process and the genetic code. Remind them that the sequence they have is the same as the messenger RNA sequence, except it has Ts where the RNA would have Us. Normal hemoglobin has glutamic acid (RNA codon GAG) in the position where sickle cell hemoglobin has valine (RNA codon GUG).

12. Tell students that in the next part of the activity, they will consider the consequences of the genetic variation that results in sickle cell disease. Distribute Master 2.4, Exploring Sickle Cell Disease, and direct students to organize into their teams, view the mini documentary What Is Sickle Cell Disease? on the Human Genetic Variation Web site, and begin working on the questions.

Give the students about 30 minutes to complete their research. Notice that most of the information they need is located in the Reference Database on the Web site. If the students' textbooks have an adequate description of sickle cell disease, you may wish to assign certain questions on Exploring Sickle Cell Disease for them to complete at home.

When students reach Question 2 on the master, they should explain how they intend to test the Lindsey twins. Give the team a copy of the test results (Master 2.5, Results of the Lindsey Test ) after the students correctly explain the test they would have conducted.

Instead of giving students the results of the test they propose in Question 2 on Exploring Sickle Cell Disease, you may want them to complete the relevant laboratory themselves. Kits such as Ward's Identification of Genetic Diseases laboratory activity (catalog # 36WS374) are available that you can adapt to this purpose. If you plan to have your students complete the lab, schedule an additional one-half to one class period for the activity.

DAY 2

1. Open the second half of the activity by directing students to meet in their teams to complete or review their answers to the questions on Exploring Sickle Cell Disease. After they have completed their work, convene a class discussion in which you invite students to share their answers to the questions.

Question 1a What are the primary symptoms of sickle cell disease? What happens in a person's body to cause these symptoms?

People with sickle cell disease periodically experience symptoms that include severe pain and fever. The symptoms occur when the sickle hemoglobin (Hb S) inside red blood cells forms long crystals under conditions of low oxygen concentration. The red blood cells elongate and assume a "sickle" shape. The crystallized hemoglobin damages the cell membranes, causing them to burst easily. The misshapen cells also clog blood vessels. The result is the destruction of many red blood cells within a few hours and a disruption of oxygen transport that can lead to death.

Question 1b How is Hb S (sickle hemoglobin) different from Hb A (normal hemoglobin)?

Sickle hemoglobin (Hb S) has the amino acid valine in the position where normal hemoglobin (Hb A) has the amino acid glutamic acid.

Question 1c How can this difference in hemoglobin be detected in the laboratory?

Because of the difference in the amino acid sequence of Hb A and Hb S, the two forms of hemoglobin have different charges. The two forms can be separated using electrophoresis because Hb S moves more slowly in an electric field than Hb A.

Question 1d What does this difference in hemoglobin tell you about the DNA of people whose cells make Hb S as compared with people whose cells make normal hemoglobin?

The sequence of DNA that codes for hemoglobin in people whose cells make Hb S must be different from the sequence of DNA that codes for hemoglobin in people whose cells make Hb A. The allele that codes for Hb A has the nucleotide A at a place where the allele that codes for Hb S has the nucleotide T.

Question 1e What is the difference between sickle cell disease and sickle cell trait? Demonstrate in your answer that you understand how sickle cell disease is inherited.

People who have sickle cell disease have inherited two alleles for sickle cell hemoglobin, one from each of their parents. They are homozygous for the sickle cell hemoglobin allele. People who have sickle cell trait have inherited one allele for sickle cell hemoglobin from one parent and one allele for normal hemoglobin from the other parent. They are heterozygous and usually have no symptoms.

Möbius StripHighlight the contribution of basic science to the improvement of personal and public health by asking your students whether an early-20th-century physician would have answered Ms. Lindsey's question in this manner. The answer, of course, is no. The first observation of sickle-shaped cells was made in 1910, but the molecular basis of the disease was not worked out until 1949. You may also note that direct diagnosis of this disease through DNA analysis of a person's genotype was made possible in the mid-1980s.

Question 2 Use what you learned about sickle cell disease and trait to propose a way to determine whether Ms. Lindsey's twins have sickle cell trait. Explain your procedure to your teacher, then use the information provided on the handout your teacher will give you to determine the results of the test.

Students should explain the following procedure: Collect hemoglobin from Jason and from Sondra and determine the form(s) of hemoglobin each has using gel electrophoresis. "Standards," or controls, of normal and sickle hemoglobin should be included for comparison.

If a twin is normal, his or her hemoglobin will migrate on the gel in parallel with the Hb A standard. If a twin has sickle cell disease, his or her hemoglobin will migrate like the Hb S standard. If a twin is heterozygous (has sickle cell trait), his or her hemoglobin will contain two forms of hemoglobin, one that migrates like Hb A and one that migrates like Hb S.

Question 3 Write the dialogue for a brief (2-to-3-minute) scene in which you explain to Ms. Lindsey the results of the tests you ran on the twins, what these results say about the inheritance of the sickle cell trait in her family, and the implications of your findings for the twins' health.

Responses will vary, but students should indicate that Sondra has sickle cell trait and Jason has sickle cell disease. These results indicate that Ms. Lindsey has and her late husband had sickle cell trait; that is, they are both heterozygous for the sickle cell allele and the normal allele, because neither of them are or were ill, but each of them must have given a sickle cell allele to Jason. Sondra should be fine, but Jason has sickle cell disease.

assessmentCollect the students' written scenes or have each team perform its scene for the class as a way to assess students' understanding of the inheritance of sickle cell disease.

2. Ask students what their study of the beta globin gene and sickle cell disease has illustrated about human genetic variation.

Students should be able to describe the extent of genetic variation from one person to another and should be able to explain that most of these differences do not have a significant biological impact. Students should recognize, however, that some variation (for example, the single base change associated with sickle cell disease) produces negative consequences.

3. Summarize the students' answers by saying, "So you are saying that most variation does not make a difference and that some variation is negative. Is it possible that some variation also is positive?" Entertain several answers to this question.

Most students will recognize that it is possible that some variation is positive.

4. Ask students, as a final challenge, to imagine that they are doctors practicing in Cameroon, in west-central Africa. Direct them to return to the resources on the Web site 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.

The incidence of sickle cell disease among black Africans is as much as 16 times higher than the incidence among African Americans (4 percent compared with 0.25 percent). Scientists believe this difference is related to the occurrence of malaria in many parts of Africa. People who are homozygous for the normal allele for hemoglobin die of malaria more often than people who are heterozygous for the normal allele and the sickle allele for hemoglobin. Thus, more heterozygotes live than people who are homozygous for the normal allele, and they pass their allele for sickle hemoglobin on to many of their children. The result is that the proportion of this allele is higher in the population than it would be if there were no threat of malaria. In contrast, in the United States where there is practically no threat of malaria, people with sickle cell trait (heterozygotes) are no more likely to live than those who are homozygous for the normal allele for hemoglobin. So the proportion of the allele for sickle hemoglobin remains at a very low level in the population because those individuals who inherit two copies of this allele suffer with sickle cell disease and frequently die before passing their alleles on to any offspring.

5. 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.

6. Close the activity by challenging the class to answer the following questions:

. Will natural selection favor the survival of people who produce Hb S or people who produce normal hemoglobin?

The critical variable here is the environment in which the Hb S variation is expressed. In environments where malaria is endemic, those who are heterozygous for the Hb S allele (HbA/Hb S) will be more resistant to malaria than are those who are homozygous for the Hb A allele (Hb A/Hb A). Evidence indicates that natural selection has favored the heterozygous state in those environments, therefore maintaining the Hb S allele in relatively high frequencies in some populations during the course of human evolution. In a nonmalarial environment, there is no known selective advantage to carrying the Hb S allele in the heterozygous state. Those who are homozygous for the Hb S allele (Hb S/Hb S) likely will experience the symptoms of sickle cell disease in any environment.

puzzle pieceThis challenge will reinforce a major concept of this activity. Some genetic variation has negative consequences for individuals. However, some genetic variation improves the ability of the species to survive changes in the environment. Genetic variation is the basis for evolution by natural selection.

. 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.

Although most genetic variation is meaningless, some of it is harmful and some of it is beneficial because it improves the ability of the species to survive changes in the environment. The most likely explanation for these examples is the one that has been most clearly established for sickle cell disease: There is a survival/reproductive advantage for people who are heterozygous as compared with those who are homozygous for the normal allele.

In the case of cystic fibrosis, there is good evidence that those who carry one CFTR allele associated with the disease have increased resistance to typhus, a common killer in Europe in past centuries. There also is circumstantial evidence that those who have one allele associated with Tay-Sachs disease may be more resistant to tuberculosis than those who are homozygous for the normal allele.

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