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Lesson 3


Evolutionary Processes and Patterns Inform Medicine

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Explain


At a Glance

Overview

Lesson 3 is divided into two activities. In Activity 1, students use data to solve the mystery of a disease, and then they notice that the disease, alpha-thalassemia, occurs most frequently in the same places that malaria is a serious health issue. Students then use data and the principles of natural selection to explain the relatively high frequency of the disease in certain populations.

In Activity 2, students continue in the role of medical investigators as they learn how comparisons of genetic sequences help researchers studying cleft lip and palate. Students work in small groups to better understand the causes of cleft palate. They then learn how to compare sequences for a gene among a large number of species. Mutations in the gene they analyze cause a syndrome that includes cleft lip and palate. Through this comparison, students identify regions of the gene that have not changed over vast amounts of time. Students apply their understandings of evolution to explain how natural selection has conserved these sequences. Students also reflect on the importance of understanding common ancestry to explain the value of experiments in model species.


Activity 1: Investigating a Mystery Disease

Estimated time: 100 minutes

Major Concepts

  • A genetic disease that causes health problems in humans can influence the severity of other human diseases.
  • Variation in genotypes can cause differences in phenotype.

Objectives

After completing this lesson, students will

  • be able to explain how different genotypes cause different phenotypes for a disease;
  • understand that, in specific cases, mutations in genes that lead to human disease may also benefit the individual by influencing the severity of another disease; and
  • be able to explain how natural selection can act on a human disease.

Activity 2: Using Evolution to Guide Research

Estimated time: 50 minutes

Major Concepts

  • Evolutionary comparisons are important for studying biomedical problems.
  • Rates of evolutionary change in genetic sequences show that natural selection can conserve some sequences in numerous lineages across vast timescales.
  • Other species are used as model systems for studying health-related issues in humans.
  • Descent with modification suggests that modern organisms inherited their traits from ancestors and that modern species all share common ancestors at some point in time. The characteristics of living organisms are shaped by this history.

Objectives

After completing this lesson, students will

  • understand the importance of studying the genomes of a large number of humans and other organisms and
  • appreciate the value of using other organisms as model systems for studying health-related issues in humans.

Teacher Background

Consult the following sections in Information about Evolution and Medicine:
1.0 Fundamentals of Evolution and Medicine
2.0 The Value of an Evolutionary Perspective for Medicine
3.0 Specific Applications of Evolution in Medicine
4.0 Students’ Prior Conceptions about Evolution
5.0 Featured Examples of Evolution and Medicine


In Advance
Web-Based Activities
Activity Web Component?
1 Yes
2 Yes
Photocopies, Transparencies, Equipment, and Materials
Photocopies and Transparencies
Activity 1: Investigating a Mystery Diease
For Classes Using Web-Based Activity:
1 transparency each of Masters 3.1, 3.5, 3.6, 3.7, and 3.9
1 copy each of Masters 3.2, 3.8, 3.12, and 3.13 (optional) for each student
1 copy of Master 3.10 for each student in half of the class
1 copy of Master 3.11 for each student in the other half of the class
For Classes Using Print-Based Activity:
1 transparency each of Masters 3.1, 3.5, 3.6, 3.7, and 3.9
1 copy each of Masters 3.2, 3.8, 3.12, and 3.13 (optional) for each student
2–3 copies of Master 3.3 (see Preparation, print version only)
1 copy of Master 3.4 for each group of 3–4 students
1 copy of Master 3.10 for each student in half of the class
1 copy of Master 3.11 for each student in the other half of the class
Activity 2: Using Evolution to Guide Research
For Classes Using Web-Based Activity:
1 copy each of Masters 3.14 and 3.17 for each student
1 transparency each of Masters 3.15 and 3.16
For Classes Using Print-Based Activity:
1 copy each of Masters 3.14 and 3.19 for each student
1 transparency each of Masters 3.15, 3.16, and 3.18
1 copy of Master 3.20 for each group of 3 students
Equipment and Materials
Different-colored pens or pencils (optional)
Preparation

Activity 1

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For classes using the web version, verify that the computer lab is reserved for your classes or that the classroom computers are set up for the activities.

Refer to Using the Web Site for details about hardware and software requirements for the Web site. Check that the Internet connection is working properly. Set the computers to the opening screen for Activity 1. Log on to the “Student Activities” section of the Web site by entering the following URL:

http://science.education.nih.gov/supplements/evolution/student

Select “Lesson 3: Evolutionary Processes and Patterns Inform Medicine.” This allows students to begin the activity directly.


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For classrooms using the print version of Activity 1, prepare two to three photocopies of Master 3.3, Blood Test Data. Each master includes blood test data for 10 patients. Each group will need one set of blood test data for two patients. Cut each master apart to separate the blood test results for each patient. Place the cut copies on a desk or table where students can pick up the information for their assigned patients when they are ready for that part of the investigation.

Make enough copies of the Master 3.4, Reference Manual, for each group to have one copy. You can print these two-sided if you wish. If you have multiple class sections, ask students to return their copies to a common area when they have completed the activity. In this way, other classes can use the same copies of the reference manual.

Make other photocopies and overhead transparencies as needed.

Activity 2

Make the necessary photocopies and overhead transparencies.

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For classrooms using the Web version of Activity 2, follow the same preparation steps as described for Activity 1.

 

 



Procedure

Activity 1: Investigating a Mystery Disease

Estimated time: 100 minutes

Note: In this activity, we formally introduce students to the five major principles of natural selection (variation, inheritance, origin of variation, fitness, and evolutionary change in populations) through the context of a human disease, alpha-thalassemia. Students develop an explanation of how mutations in a human gene can lead to disease. Then they consider how variation for this trait in the human population can help them understand how a deleterious trait (mutations resulting in alpha-thalassemia) can also provide a benefit (resistance to malaria) in some environments.

1.

Begin by explaining that you read a news story about a medical mystery on a Web site and want to share it with the class. Project Master 3.1, A Medical Mystery, and read the information with the class. Explain to students that exploring this scenario and figuring out what is happening is a way for them to apply and demonstrate their skills and abilities in science.

The scenario involves a population of people in Papua New Guinea. A relatively large number of people in the population are anemic. Anemia is a condition in which a person doesn’t have enough red blood cells to carry an adequate supply of oxygen to the body’s cells. Many conditions cause anemia, so the students’ challenge is to determine why so many people in this population have it.

2.

Give each student one copy of Master 3.2, Investigating a Medical Mystery. Ask them to work in their groups of three to four students. Explain that each group will investigate two cases (patients) to determine the cause of the medical mystery. Assign two cases to each group. Tell students to write the case (patient) numbers they will investigate on Master 3.2 handout.

Explain that the cases represent a subset of a larger number of cases in the population. You can use any of several methods to determine which cases each group explores. Groups can

  • count off until all groups have 2 of the 10 patient cases,
  • draw numbers out of a hat, or
  • choose two numbers ranging from 1 to10.

Be sure that each case is assigned to at least one group. Depending on the number of students in your class, it is likely that more than one group will investigate some of the cases. If necessary because of time constraints, groups could investigate only one case, but again, make sure that all cases are covered by at least one group.

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Tip from the field test: Students can work in pairs for the data analysis if that works better for your class in terms of its size, availability of computers, and familiarity with group work.



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(For print version, skip to Step 3-p.)

In classrooms using the Web version of this activity:

3-w.

Briefly explain to groups that there are two main parts to the investigation for each case. Groups will use the virtual microscope on the Web site to look at images of blood samples from the different patients. They will also examine the laboratory results of blood tests. Point out that a reference manual on the Web site will help them determine what the likely problem is in each case.

Groups should use the online virtual microscope first and then analyze the laboratory blood test data. Students must do both parts to be able to diagnose the problem.

The laboratory blood test data include a variety of data for each patient. The units specified are typical for the measurement of each blood component. Many of these units will be unfamiliar to students, but for this activity, students don’t need to know the units. They will simply compare the values for their patients with the normal range for that blood component.

4-w.

Instruct students to proceed to http://science.education.nih.gov/supplements/evolution/student.

Students should click on “Lesson 3: Evolutionary Processes and Patterns Inform Medicine,” then “Activity 1: Investigating a Mystery Disease.” Allow time for groups to work through the cases.

As groups work, circulate among them to respond to questions and monitor their progress. Remind students to use the information in the Reference Manual to help them diagnose the cases. (They access it by clicking on the “Reference Manual” button.) If students have trouble determining what data to focus on, prompt them that hemoglobin and anemia relate most directly to red blood cells (RBCs). In the microscope, students may see white blood cells (WBCs) in addition to the RBCs. WBCs tend to be larger than RBCs and irregularly shaped. The nuclei of WBCs are darkly stained.

Continue with Step 5.



In classrooms using the print version of this activity: Logo5.eps


3-p.

Briefly explain to groups that they will examine the results of blood tests to make a diagnosis. Point out where students can pick up the blood test data for their assigned patients (see the Preparation section about preparing Master 3.3, Blood Test Data). Explain to students that the microscopic analysis of red blood cells was completed by the lab technicians. These results are reported with the blood test data. They do not need to fill in the diameter of four different red blood cells (the first line on the master).

4-p.

Give each group one copy of Master 3.4, Reference Manual, and explain that they can use the information in it to help determine what the likely problem is in each case.

Students need to analyze blood test data to diagnose the problem.The blood test data include a variety of data for each patient. The units specified are typical for the measurement of each blood component. Many of these units will be unfamiliar to students, but for this activity, students don’t need to know the units. They will simply compare the values for their patients with the normal range for that blood component.

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Content Standard A: Communicate and defend a scientific argument.


5.

After groups complete the investigations, conduct a class discussion to synthesize their conclusions. Project Master 3.5, Summarizing the Mystery Disease Data, to help guide the discussion.

Ask for volunteers from the different groups to share their conclusions for each patient. Ask students to provide the diagnosis and share the evidence that led them to decide the cause for the anemia in each case and how they eliminated the other possibilities.

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Tip from the field test: Don’t let this discussion drag. It isn’t necessary to go over every piece of data for each patient. Focus instead on the data that led students to distinguish the different diseases. For example, if the diagnosis is alpha-thalassemia, what are the important pieces of data that led students to this diagnosis and what data ruled out other diseases? Some teachers in the field test asked students to provide one or two pieces of evidence for the first cases of alpha-thalassemia. As the teachers proceeded through additional patients, students stated additional pieces of evidence.

In Table 3, we present some key evidence that distinguishes one disease from another for each patient. Students may also list other data (from the Reference Manual) that are characteristic of the disease but aren’t included in the sample answers provided.

Patient Diagnosis Key evidence used for diagnosis
1 Alpha-thalassemia
  • Smaller-than-normal RBCs (microcytic; normal cells average 7–8 micrometers in diameter.)
  • Decreased RBC count (It could be within the normal range in mild cases.)
  • MCV:RBC ratio less than 13 (A ratio above 13 would indicate iron deficiency anemia.)
  • Hematocrit below normal
  • TIBC normal (It would be low in iron deficiency anemia.)
  • RDW normal (It would be high in iron deficiency anemia.)
2 Alpha-thalassemia
  • See Patient 1.
3 Iron deficiency anemia
  • In microscope, RBC variation in size and pale in color compared with normal
  • High RDW (This indicates a great deal of variation in the size of the RBCs.)
  • Serum ferritin concentration less than 12
  • Elevated TIBC
  • MCV:RBC ratio greater than 13 (These blood test criteria distinguish iron deficiency anemia from thalassemia.)
4 Alpha-thalassemia
  • See Patient 1.
5 Alpha-thalassemia
  • See Patient 1.
6 Alpha-thalassemia
  • See Patient 1.
7 Sickle cell disease
  • In microscope, some blood cells sickle shaped (This is a definitive sign for sickle cell disease.)
  • Elevated white blood cell count
  • TIBC below normal
8 Alpha-thalassemia
  • See Patient 1.
9 Normal—
no disease
  • Red blood cells with normal appearance: normal biconcave shape and normal color
  • All blood test data within normal ranges
10 Alpha-thalassemia
  • See Patient 1.
Note: Students may or may not measure a difference in size between normal RBCs and RBCs in thalassemia patients. While small RBCs (microcytic) are one characteristic of alpha-thalassemia, the degree of microcytosis depends on the severity of the disease. Individuals who are silent carriers (one nonfunctional allele of the alpha-globin gene) may not show any difference in RBC size, while individuals who have three nonfunctional copies are more likely to have measurable microcytosis. For this activity, students may not be able to detect a difference in size, but they should observe that the RBCs do not have a normal appearance.

The patients represent a sample of the individuals in Papua New Guinea who have (or are suspected of having) anemia. Make sure that students understand that this does not mean that 70 percent of the population has anemia.

6.

Inform students that they will focus on thalassemia for the rest of this activity. Initiate a class discussion with the following questions:

  • “Have you heard of thalassemia?”
  • “Do you think thalassemia is a common disease?”

Most students have probably not heard of thalassemia and probably don’t think it is very common.

7.

Project Master 3.6, The Distribution of Thalassemia Across the Eastern Hemisphere. Ask students to draw conclusions about thalassemia from this map.

Epidemiology is the study of the incidence, distribution, and control of disease in a population. Scientists look for patterns in a disease to determine its cause and to find ways to prevent the disease.

Students should conclude that thalassemia is more common in certain parts of the world. For example, thalassemia is more common in Mediterranean and Asian countries and in certain parts of Africa than elsewhere.

Inform students that the shading on the map indicates the regions of the world where thalassemia is most common. That doesn’t mean that it never occurs in the unshaded areas, just that it is much less common there. Also, it doesn’t mean that everyone who lives in one of the shaded areas has thalassemia.

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Step 8 is an opportunity to assess students’ current thinking about variation.



8.

Students have now seen that thalassemia is more common in some places in the world than others. They should also recognize that most of the people who live in an area where thalassemia is more common do not have thalassemia. Ask students for a brief statement about variation for thalassemia in the human population.

The fact that the frequency of thalassemia is higher in some places in the world suggests that there is variation for this trait. In addition, students should note that many people living in an area where thalassemia is more prevalent do not have the disease. This further suggests that there is variation in the population. In the following steps, students broaden their understandings of this variation.

If students have difficulty relating to variation among humans for thalassemia, ask, “If there were no variation in the thalassemia trait among humans, wouldn’t everyone have thalassemia?” and “If there were no variation among people, how could you explain why some people have thalassemia and others do not?”

9.

Project Master 3.7, The Alpha-Globin Gene and Alpha-Thalassemia. Briefly review the information in Part 1 about what alpha-thalassemia is and how problems with the function of the alpha-globin gene cause alpha-thalassemia. Then project Part 2, which correlates the number of functional alleles of the alpha-globin gene with thalassemia symptoms. Ask students whether they can see any relationship between the number of nonfunctional alleles of the alpha-globin gene and the severity of the symptoms of alpha-thalassemia.

As you review Part 1 of Master 3.7, point out to students how the genes and alleles are represented, both in the diagrams and as a genotype. In the diagrams, a shaded area without an x represents a normal or functional allele. A shaded area with an x represents a mutated, nonfunctional allele of the gene.

Figure 11. Schematic of chromosome 16 pairs showing functional and nonfunctional alpha-globin alleles.


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The alpha-globin gene codes for the alpha-globin protein. In adults, two alpha-globin protein chains combine with two beta-globin protein chains (coded for by beta-globin genes) to form hemoglobin. Though extra detail is included, students only need a basic understanding that alpha-thalassemia is a genetic disease that results from mutations in the alpha-globin gene.

From Part 2 of Master 3.7, students do not need to know the specific symptoms for the different types of alpha-thalassemia. Students should focus on the fact that the severity of the disease depends on an individual’s number of nonfunctional alleles of the alpha-globin gene. A “normal” individual has four functional alleles of the alpha-globin gene and makes normal hemoglobin. Individuals who have one, two, or three nonfunctional alleles of the alpha-globin gene produce less of the alpha-globin protein and have mild to moderate symptoms. More nonfunctional alleles increase the severity of the symptoms. Individuals with no functional alleles of the alpha-globin gene are seriously ill and almost always die around the time of birth.

Help students conclude that there is a relationship between the number of functional and nonfunctional alleles of the gene (the genotype) and the severity of the disease (the phenotype). If you wish (based on your students’ knowledge of genetics), inform students that the most common types of mutation to the alpha-globin gene are deletions. (Other types of mutations, such as point mutations, also result in thalassemia, but this is beyond what students need to know.)

Note: If you wish to include the extension activity and Master 3.13, Inheriting Thalassemia (described here), you could insert it here, after Step 9.

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Content Standard F: The severity of disease symptoms is dependent on many factors, such as human resistance and the virulence of the disease-producing organism.


10.

Give each student one copy of Master 3.8, Alpha-Globin and Variation. Ask students to work with their groups to answer the questions. Inform them that they need to explain their answers.

Answer key for questions on Master 3.8, Alpha-Globin and Variation

1.

What might cause the alpha-globin gene not to function?

Mutations in the alpha-globin gene cause it not to function.

2.

How are differences in the thalassemia trait (phenotype) passed from parents to offspring?

Differences in the thalassemia phenotype are passed from parents to offspring through inheritance. An individual inherits half of his or her alleles from the father and half from the mother.

3.

Now you know the genetic basis for alpha-thalassemia. What can you add to your description of the variation for thalassemia in humans?

From examining the map in Step 8, students know that the incidence of thalassemia is higher in certain areas of the world. With the information about the genetic basis of thalassemia, students can add the idea that different genotypes result in different forms of the disease, and each form has different symptoms and severities (phenotypes). These different forms of the disease result from variation in the genotype.

11.

Ask students to think about why a mutant alpha-globin allele would be maintained in the human population if it causes disease.

At this point, accept reasonable responses from students. This is another point at which you can gauge students’ thinking and prior knowledge about evolution and natural selection.

12.

Inform the class that a link in the original news story referred to another disease that has many symptoms, including anemia. This disease is malaria. Project Master 3.9, The Epidemiology of Malaria. Ask students to make observations about the occurrence of malaria.

Malaria is another disease that causes anemia. It is caused by a parasite that is passed to humans through the bite of a mosquito. Malaria is usually diagnosed by using a microscope to find the parasites in a blood sample. Students should notice that malaria is most common in Africa and Asia. The cases of malaria diagnosed each year in the United States are usually in people who were infected elsewhere.

13.

Overlay the transparencies of thalassemia and malaria (Masters 3.6 and 3.9). Ask students what conclusions they can draw from considering these maps together.

Students should notice that the occurrence of the two diseases is similar. Areas in which malaria is most common are also more likely to have a higher incidence of alpha-thalassemia.

14.

Explain to students that in the late 1940s, a scientist hypothesized that people who have thalassemia may have an advantage in survival over people who do not have thalassemia if they contract malaria. Recent scientific investigations collected evidence to test this hypothesis.

Students will examine data that relate to this hypothesis in Steps 17 and 18.

15.

Provide some brief information to students about malaria:

  • Malaria is caused by a parasitic infection (a plasmodium causes the disease, which is spread to humans through the bite of a mosquito). Malaria is not a genetic disease.
  • The parasites invade human red blood cells, causing them to burst. These red blood cells live a much shorter time than the normal 120-day life span.
  • Parasitic infection leads to a reduction in the number of red blood cells in the bloodstream. The fewer the red blood cells, the more severe the anemia (and the more problems a person has getting adequate oxygen to body cells).

Students do not need much background information about malaria for this activity, but a brief overview is helpful. Anemia can be a very serious problem for people with malaria. Some of the data that students will analyze relate to anemia being a key symptom of malaria.

Although malaria is not a health problem in the United States, about a million people die from malaria each year worldwide and many more are infected but survive.

16.

Inform students that they will look at data that relate to the hypothesis that individuals with thalassemia have an advantage over individuals without it in terms of how they are affected by malaria. Have students again work in their groups. Half the groups will use Master 3.10, Alpha-Thalassemia and Malaria in Papua New Guinea, and the other half will use Master 3.11, Alpha-Thalassemia and Malaria in Kenya. Point out the questions on the masters, which should help them analyze the data appropriately.

Briefly review the task and then allow time for groups to analyze the data. As they work, circulate among groups to answer questions or assist if they have trouble with the data. Reinforce to students that they need to be able to support their conclusions with data.

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Content Standard A: Formulate and revise scientific explanations and models using logic and evidence.


17.

After giving students time to analyze the data and write a few conclusions, hold a class discussion to review the conclusions and check understanding. Because groups analyzed different sets of data, they should begin the discussion by briefly explaining their cases to the other students.

For the Papua New Guinea investigation, the data suggest that individuals with malaria who have one or two nonfunctional alpha-globin alleles have a lower risk for severe malarial anemia than do individuals with the normal genotype for alpha-globin. Unless treated with blood transfusions, severe malarial anemia is a life-threatening condition. The odds ratio statistic used in this study will be new for students. However, the main thing they need to know is that it is a comparison. Students need to compare the statistical value for each genotype with 1 to determine whether it is more or less likely that a person with thalassemia will have severe malarial anemia compared with a normal individual.

Table 4. Alpha-Thalassemia and Severe Malarial Anemia

Risk factor One nonfunctional allele of the alpha-globin gene Two nonfunctional alleles of the alpha-globin gene
Risk for developing severe malarial anemia 0.74 0.52


Source: Data from F.J.I. Fowkes et al. 2008. Increased microerythrocyte count in homozygous α+-thalassaemia contributes to protection against severe malarial anaemia. PLoS Medicine 5(3): 494-501: e56. doi:10.1371/journal.pmed.0050056

The main idea for students to understand from this analysis is that individuals with thalassemia are less likely to have severe malarial anemia than are normal individuals (no thalassemia). However, students may ask about comparing the risk of severe malarial anemia in individuals who have one nonfunctional alpha-globin allele compared with individuals who have two nonfunctional alpha-globin alleles. The further away a value is from 1 indicates how much more or how much less risk the individual has. For example, the person who has two nonfunctional alleles of the alpha-globin gene has a lower risk for severe malarial anemia than does the person who has one nonfunctional allele of the alpha-globin gene because the statistical value is further away from 1 (0.52 compared with 0.74).

For the investigation of thalassemia and malaria in Kenya, the data indicate that thalassemia has a protective effect against malaria.

In this study, for each consequence of malaria (coma, severe anemia, or death), a lower percentage of individuals who have one or two nonfunctional alleles of the alpha-globin gene have the consequence than do people with the normal genotype (no thalassemia).

Table 5. Alpha-thalassemia and the Consequences of Malaria (percent of people with each genotype that had a certain consequence)

Consequence of malaria All alleles of the alpha-globin gene function (%) One nonfunctional allele of the alpha-globin gene (%) Two nonfunctional alleles of the alpha-globin gene (%)
Coma 45.1 43.2 39.8
Severe anemia (hemoglobin less than 5 g/dL) 25.8 22.4 18.1
Death 12.5 10.4 8.4

Source: Data from T.N. Williams et al. 2005. Both heterozygous and homozygous α+ thalassemias protect against severe and fatal Plasmodium falciparum malaria on the coast of Kenya. Blood 106(1): 368-371.

The last question on both Masters 3.10 and 3.11 asks students to summarize what they have learned about the relationship between alpha-thalassemia and malaria. The completed sentences should be similar for both sets of data.

18.

Give each student one copy of Master 3.12, Summing Up Thalassemia, Malaria, and Evolution. Ask students to answer the questions. Tell them that they will return to this master during the last activity in the supplement.

Questions 1–3 ask students to think about how and why a disease-causing mutation may persist in the human population. The remaining questions have been covered in this lesson and should be straightforward but will help students compare thalassemia with other medical conditions discussed in this supplement. (This will be important for Lesson 5.) Ask students to include the reasons for their answers. After students have answered the questions, hold a class discussion to allow them to compare their responses. Reemphasize the major principles of natural selection (see Lesson 1) and make them explicit. Students should recognize that the same principles apply to MRSA, lactase persistence, and alpha-thalassemia.

Answer key for questions on Master 3.12, Summing Up Thalassemia, Malaria, and Evolution

1.

Do the data from the studies in Papua New Guinea and Kenya support the hypothesis that individuals who have thalassemia might have some advantage over other individuals when living in an area where malaria is common? Explain.

Both sets of data support the hypothesis. In each investigation, the data show that the symptoms of malaria are less severe in individuals who have thalassemia.

2.

Depending on their genotype, individuals with nonfunctional alpha-globin alleles may have symptoms that range from mild to more serious, including anemia, fatigue, enlarged spleen, liver problems, or even death. If the alpha-globin mutations are passed from parent to child, and individuals with four nonfunctional alpha-globin alleles die, how is the mutation maintained in the population?

Even though alpha-thalassemia can cause severe health problems and death (if the individual has three or four nonfunctional alleles of the alpha-globin gene), the condition apparently provides some benefit to individuals in areas where malaria is common. Malaria is one of the leading causes of death in the world. Individuals who are affected less severely by malaria are more likely to survive and reproduce and pass their genes on to future generations.

3.

The human population shows variation for alpha-thalassemia. How did the variation arise?

Some individuals in the population have alpha-thalassemia and others do not. In addition, different individuals have different forms of the disease depending on the number of nonfunctional alleles of the gene. Alpha-thalassemia has a genetic basis. Mutations in the alpha-globin gene, which occur randomly, result in variation in the population. You may want to emphasize to students that the mutations that cause alpha-thalassemia mostly occurred in the past. Many students think that the mutations that cause genetic variation are made anew each generation. The most likely explanation for why these mutations have been maintained in some groups of humans is that they have beneficial effects with respect to malaria.

4.

A common misconception related to evolution is that individuals develop mutations because the mutations fulfill some “need” or the individuals gain some benefit. In this case, this reasoning would suggest that individuals develop a mutation in the alpha-globin gene because they want or need protection from malaria. On the basis of your understanding of evolution and natural selection, explain why this reasoning is faulty.

Mutations to the alpha-globin gene arise by chance. Individuals with the mutations have alpha-thalassemia and, depending on their genotype, have symptoms and health problems because of the genotype. This is another opportunity for students to recognize that mutations don’t occur because individuals want protection against malaria. Mutations are maintained in the population because the people with specific mutations had an advantage over individuals without the mutation (in terms of survival and reproduction).

5.

In certain environments, did alpha-thalassemia affect an individual’s ability to survive and reproduce? Explain.

In certain cultural or environmental contexts, individuals who have alpha-thalassemia had relatively higher survival rates and left relatively more offspring. Alpha-thalassemia offers some protection against malaria. In areas with high rates of malaria, individuals with alpha-thalassemia may have a lower chance of developing severe malarial anemia or dying from malaria.

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After students complete Master 3.12, you may wish to collect their papers to assess their understandings. Use this information to guide the class discussion and clarify any remaining misconceptions.

19.

Ask students to revisit their responses to the questions on Master 1.1 in Lesson 1, Activity 1, and Masters 2.5 and 2.10 in Lesson 2. Ask them to revise their answers if the new information about natural selection caused their thinking to change.

It may be helpful for students to make their revisions with a different-colored pen or pencil so that they have evidence of how their ideas have changed. You could assign this task as homework.

Extension Activity (Optional)

Estimated time: 20 minutes

Note: This activity is related to Activity 1. Although this extension reinforces the genetic basis for alpha-thalassemia and its heritability, students who have not reviewed basic inheritance recently may find it challenging. Students can learn the most important concepts of the lesson without completing this optional activity.

If you choose to include this activity, one option is to insert it after Step 9 of Activity 1.

1.

Project Part 1 of Master 3.7, The Alpha-Globin Gene and Alpha-Thalassemia. Remind students that each individual usually has four functional alleles of the alpha-globin gene. Introduce students to the way the alpha-globin gene is written when working with genotypes:

  • The functional allele of the gene is written as an alpha symbol (α).
  • The nonfunctional allele of the gene (shown as an x on the chromosome picture) is written using a minus sign (–).

2.

Continue the introduction by providing examples of how an individual’s genotype for the alpha-globin gene is written:

  • The genotype for a normal individual is αα/αα.
  • The genotype for someone who has a mutation in one of the four alpha-globin genes would be αα/α –.

Provide other examples if helpful for your students.

3.

Explain that students will work through the problems on Master 3.13, Inheriting Thalassemia, to learn how mutated, nonfunctional alleles of the alpha-globin gene are passed from parent to offspring. Give each student one copy of Master 3.13.

Decide how you want the class to work through the problems. You may want to work through the first problem as a class. To save time, each group can work on one problem and then share the solutions with the class.

These problems should be relatively straightforward for students if they have studied basic genetics. Students should recognize that a child inherits his or her genotype from the parents, and the genotype specifies the health or disease state of the child. Students should view this as an example of probability—we can predict the probability that children of specific parents will have thalassemia. Also, this exercise helps students understand that the variation for the thalassemia phenotype has a genetic basis, which is important when considering how natural selection can act on this trait.

4.

Hold a class discussion to review the problems with the class. Allow different groups to present their results and explain their conclusions.

Depending on the strategy you use, you may have more than one group complete each problem. If so, ask one group to present the offspring’s genotypes for a problem and another group to complete the other information.

Answer key for problems on Master 3.13, Inheriting Thalassemia

Problem 1

Figure 1. The upper part of the diagram shows a schematic of chromosome 16 pairs from Father #1 and Mother #1 with the alpha globin alleles in each parent. Each chromosome carries two copies of each allele, meaning that each person has a total of four copies of each allele. The lower part of the diagram shows the possible combinations of chromosome 16 pairs in offspring from the parents. Students fill in possible combinations of alpha-globin alleles.

NIHFT10.EM.PR.032.jpg


Problem 2

Figure 2. The upper part of the diagram shows a schematic of chromosome 16 pairs from Father #2 and Mother #2 with the alpha globin alleles in each parent. Each chromosome carries two copies of each allele, meaning that each person has a total of four copies of each allele. The lower part of the diagram shows the possible combinations of chromosome 16 pairs in offspring from the parents. Students fill in possible combinations of alpha-globin alleles.

NIHFT10.EM.PR.033.jpg


Problem 3

Figure 3. The upper part of the diagram shows a schematic of chromosome 16 pairs from Father #3 and Mother #3 with the alpha globin alleles in each parent. Each chromosome carries two copies of each allele, meaning that each person has a total of four copies of each allele. The lower part of the diagram shows the possible combinations of chromosome 16 pairs in offspring from the parents. Students fill in possible combinations of alpha-globin alleles.

NIHFT10.EM.PR.034.jpg

Procedure

Activity 2: Using Evolution to Guide Research

Estimated time: 50 minutes

Note: This activity is the second part of the Explain lesson. Its focus is to help students explain why understanding common ancestry is important for medical research. The role of common ancestry is often underemphasized in teaching about evolution, leaving students with the impression that natural selection is equivalent to evolution. However, the fact of common ancestry explains many aspects of medical research, such as the importance of using model organisms to study disease processes. The main connection between Activities 1 and 2 is that both help students build explanations for the role of evolution in medicine, though the two activities emphasize different aspects of evolution.

1.

Begin the activity by congratulating students on their work in the thalassemia case. Their work showed how the process of natural selection helps explain why some diseases are more common in certain parts of the world. Explain that now, students will undertake a new challenge. They will investigate how understanding common ancestry helps medical researchers solve problems. The students’ goal in this activity is to use an understanding of common ancestry to identify sections of a gene that have not changed over vast amounts of time. Mutations to this gene cause some cases of cleft lip and palate.

2.

Ask, “Have you heard of a condition called cleft lip and palate?” and “What do you think causes cleft lip and palate?” Ask two or three students to share their ideas in a brief class discussion.

Some students may think that cleft lip and palate are more common in the developing world, and they may therefore conclude that environmental factors cause the condition. Be open to a range of ideas, but ask students to use logic when considering the cause. Remind students that they will have the opportunity to improve understanding throughout the activity. If students have not heard of cleft palate, tell them they will learn more about it in this lesson.

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Tip from the field test: Students tend to be very interested in cleft lip and palate. Nevertheless, keep this discussion brief.


3.

Explain to students that researchers are trying to understand how clefts form and how to prevent the condition or more effectively treat it. Form student groups of three. Give each student one copy of Master 3.14, Cleft Lip and Palate. Ask students to read the questions at the end of the handout first, then read the information about cleft lip and palate, and then work together to answer the questions.

Having students read the questions they will answer before they complete the reading helps them anticipate the kinds of information they will encounter in the reading. Anticipation reading strategies help students read more successfully.

Note: The convention for three-letter code names for genes differs across species. In humans, the three-letter symbol for a gene has all the letters capitalized. In other species, only the first letter is capitalized (for example, mouse and rat), and in others, all the letters are lowercase (for example, zebrafish). To avoid confusion in this supplement, all gene symbols are in italics and have the first letter capitalized.

Answer key for questions on Master 3.14, Cleft Lip and Palate

1.

Use the following steps to calculate the number of people expected to be born with cleft lip and palate in the United States each year.

a.

The worldwide incidence of cleft lip and palate is 14 out of 10,000 births. Calculate the frequency of cleft lip and palate by dividing the number of babies with the condition by the number of births.

The following equation shows how frequency is calculated.

b.

Assume that there are 4,000,000 births per year in the United States. Multiply the number of births by the frequency of cleft lip and palate you calculated in Question 1a to determine the expected number of babies born with cleft palate each year in the United States.

The number of babies with cleft lip or palate can be calculated as follows.

0.0014 babies with cleft lip or palate per birth × 4,000,000 births = 5,600 babies with cleft lip or palate born in the United States per year

2.

How could a change to a gene cause cleft lip and palate? How might a change in an environmental signal cause cleft lip and palate?

Many genes play a role in the development of the head and face. Mutations to a number of these genes could disrupt the fusion of the two developing sides of the lip and palate.Similarly, a growing embryo responds to many environmental cues. Not having necessary nutrients or other environmental signals at the proper time could affect the fusion of the lip and palate.

Together, these answers imply that changes in any of many different genes and the environment may lead to the development of cleft lip and palate. This question is included to help students avoid the common misconception that many phenotypes have a simple genetic basis. In fact, most phenotypes, including disease-related ones, have a complex genetic basis and interact with the environment.

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Content Standard C: Cells can differentiate, and complex multicellular organisms are formed as a highly organized arrangement of differentiated cells. In the development of these multicellular organisms, the progeny from a single cell form an embryo in which the cells multiply and differentiate to form the many specialized cells, tissues and organs that comprise the final organism. This differentiation is regulated through the expression of different genes.

3.

Assume that one parent has an allele of the Irf6 gene with a mutation that causes cleft lip and palate and a second allele that is normal. Also assume that the second parent has two normal alleles for this gene. What is the probability that a child born to this couple will have a cleft lip and palate? Mutated Irf6 acts in a dominant fashion.

Because Irf6 acts in a dominant fashion, there is a 50 percent chance that a child from this couple will have a cleft lip and palate.

Strictly speaking, Irf6 does not act in a simple dominant fashion. It has incomplete penetrance and variable expression. However, this is beyond what students need to know. For the purposes of this activity, students can assume that the mutated allele acts in a dominant fashion.

4.

Explain how studies from mice are helpful to scientists trying to understand cleft lip and palate in humans.

Scientists learned that the gene that causes Van der Woude syndrome in humans is active in the cells that line the two sides of the forming mouth in mice. The gene is turned on and makes protein just before and during fusion of the two sides. Mice and humans inherited Irf6 from a common ancestor, and both use a similar process to develop major structures like the head. Many lines of evidence show that mice and humans share a common ancestor. Because of common ancestry, the processes that occur in the development of the face and head of mice are similar to processes in humans.

In general, scientists are able to perform experiments with mice that would not be possible or ethical in humans. What scientists learn from these experiments is helpful because humans share many chemical pathways and other physiological processes with mice due to shared ancestry.

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Students’ responses to Question 4 will help you assess their understanding of one of the major learning goals for this activity.


4.

Ask one or two groups to share their ideas in a brief class discussion of the questions from Master 3.14.

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Tip from the field test: Classes that had a large number of students who struggle with math benefited from the teacher walking through the calculations in Question 1.



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(For print version, skip to Step 5-p.)

In classrooms using the web version of this activity:

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Content Standard C: The millions of different species of plants, animals, and microorganisms that live on Earth today are related by descent from common ancestors.

5-w.

Explain to students that they will learn a technique that scientists use to identify regions of DNA that have not changed in different organisms over long periods of time. To begin the investigation, students need to complete a tutorial on comparing genes across multiple species. They will learn a general technique that they will apply later to a gene involved in cleft palate.

Instruct students to proceed to

http://science.education.nih.gov/supplements/evolution/student

Students should click on “Lesson 3: Evolutionary Processes and Patterns Inform Medicine,” then “Activity 2: Evoprint Tutorial.”

The tutorial lasts approximately five minutes. Ask students to take notes during the tutorial and give them time to ask questions about it after they finish. Allow students to review segments of the tutorial they found confusing.

After the tutorial, make sure that students understand that a capital letter represents a nucleotide that is identical in all the species included in the comparison. A lowercase letter represents a nucleotide that is different in at least one of the species in the comparison.

One potentially confusing section of the animation deals with calculating times in an evoprint. When comparing sequences between species, we need to consider that the sequences are evolving separately in each lineage in parallel time. So, to calculate the total amount of time, we need to add up all the times associated with each branch on the tree. It’s difficult for many students to comprehend parallel time for these comparisons. For this reason, we include the following step, where students practice adding up the time on all the branches on the tree.

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Content Standard C: In all organisms, the instructions for specifying the characteristics of the organism are carried in DNA, a large polymer formed from subunits of four kinds (A, G, C, and T). The chemical and structural properties of DNA explain how the genetic information that underlies heredity is both encoded in genes (as a string of molecular “letters”) and replicated (by a templating mechanism). Each DNA molecule in a cell forms a single chromosome.

6-w.

Project Master 3.15, Calculating Times for an Evoprint. Ask students to calculate the amount of time that would be represented in evoprints that include all the species on the two different trees.

Answer key for questions on Master 3.15, Calculating Times for an Evoprint

1.

How many years are represented in an evoprint constructed from sequences from the three species shown in the evolutionary tree below?

The time since common ancestry for each pair of species is shown below:

  • Human/orangutan = 15 million years
  • Human/guinea pig = 90 million years

To calculate the total amount of time represented in an evoprint of these three species, students need to add the time from the common ancestor of humans and guinea pigs to modern humans (90 million years) + the time from the common ancestor of humans and guinea pigs to modern guinea pigs (90 million years) + the time from the common ancestor of humans and orangutans to modern orangutans (15 million years) = 195 million years.

Note: If students struggle with this calculation, consider walking through it with them. As students view the evolutionary tree in Figure 1 of Master 3.15, explain that to find the total time, they need to add up the time associated with every branch on the tree (excluding the root lineage). In other words, they need to account for every vertical line on the tree. Use a transparency pen to trace the lineage from humans to the common ancestor of humans and guinea pigs. Then write “90 million years.” Ask students what vertical lines are not accounted for. Students should note that the line leading from the common ancestor of guinea pigs and humans to modern guinea pigs is not included. Highlight this branch and ask how much time this branch represents. Write another “90 million years” on the projected master. Ask again what line or lines are not included. Students should note that the lineage leading from the common ancestor of humans and orangutans to modern orangutans is not included. Again, highlight this branch and write “15 million years.” Explain to students that to find the total number of years in the evoprint, they need to add 90 million years + 90 million years + 15 million years = 195 million years. Ask students to use the same process to decipher the amount of time represented on the second tree.

2.

If you constructed an evoprint from sequences from the four species represented in the evolutionary tree below, how many years would be represented in the evoprint?

The time since common ancestry for each pair of species is calculated as follows:

  • Human/rhesus monkey = 30 million years
  • Human/horse = 97 million years
  • Human/platypus = 220 million years

To calculate the total amount of time represented in an evoprint of these four species, students need to add the time from the common ancestor of humans and platypuses to modern humans (220 million years) + the time from the common ancestor of humans and platypuses to modern platypuses (220 million years) + the time from the common ancestor of humans and horses to modern horses (97 million years) + the time from the common ancestor of humans and rhesus monkeys to modern rhesus monkeys (30 million years)= 567 million years.

The times to the last common ancestor presented in this activity are estimates, but, for the sake of simplicity, they can be used here as though they were measured without error. In fact, these dates are measured with error, and they can change as we gain new information. Time estimates are from the TimeTree Web site, http://www.timetree.org.

7-w.

To help students get a sense of the vast amount of time represented on an evolutionary tree, ask the following questions. Let students make a few guesses, and then quickly provide the answers:

  • “How long ago was 1,000 seconds?”
    Answer: About 17 minutes ago
  • “How long ago was 1 million seconds?”
    Answer: About 11½ days ago
  • “How long ago was 1 billion seconds?”
    Answer: About 32 years ago

Ask students to reflect on how 1,000 years ago seems like such a long time. Then compare that with the 567 million years they calculated in Step 6. The difference is like comparing 17 minutes (about a third of a 50-minute class period) with 18 years (longer than most of students have been alive).

This step helps students get some perspective on geologic time, which is difficult for many people to grasp. This step is meant to be brief.

8-w.

Project the questions on Master 3.16, Interpreting Evoprints, one at a time. Ask students to use their notes and their understandings from other activities in the supplement to answer the questions. After giving students time to think about their answers, discuss the questions as a class.

Try to not simply provide the answers to students. Instead, use probing questions to help students make the connections necessary to answer the questions. If they are struggling, ask questions such as, “Do you think mutations occurred in the regions that did not change?” and “If so, why don’t they show up in this comparison?”

Answer key for questions on Master 3.16, Interpreting Evoprints

1.

How does an evoprint help identify regions of DNA that have not changed over large amounts of time?

Evoprints are a graphic representation that visually contrasts nucleotides that did not change against those that did change.

2.

How does natural selection explain why some sequences of DNA are conserved over vast amounts of time?

Sequence conservation over vast amounts of time is an example of a type of natural selection called purifying selection. This term was introduced in the evoprint tutorial. In purifying selection, selection eliminates or decreases the frequency of mutations that have a negative effect. In other words, the mutations reduced the reproductive success of the individuals that carried them. Natural selection then eliminated these mutations.

It is important that students recognize that mutations did occur in the regions that are conserved over time. These mutations may have very briefly persisted in the gene pool. Eventually, natural selection eliminated them from the gene pool. However, new mutations are occurring all the time.

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Content Standard C: Changes in DNA (mutations) occur spontaneously at low rates. Some of these changes make no difference to the organism, whereas others can change cells and organisms. Only mutations in germ cells can create the variation that changes an organism’s offspring.

9-w.

Explain to students that they are now ready to gather important information about a gene involved in some cases of cleft lip and palate. Their main goal is to identify sections of the Irf6 gene that have remained the same over large amounts of time. In some cases, these regions are especially important for proper functioning. Hand out one copy of Master 3.17, Irf6 Evoprint Comparison, to each student. Ask students to follow the directions on the handout.

Instruct students to proceed to http://science.education.nih.gov/supplements/evolution/student. They should click on “Lesson 3: Evolutionary Processes and Patterns Inform Medicine,” then “Activity 2: Evoprint Comparison.” When they finish, hold a class discussion about students’ answers to the questions.

Note: In this activity, students explore 1,701 nucleotides of the Irf6 gene. The full gene has over 18,000 nucleotides. Much of what the students see are the intron sequences flanking the third exon in the gene. The exon is near the center of the evoprint, from nucleotide 616 (starting with CTTAAAAAT, line 11) to 789 (look for GAGGGCCAT with T being nucleotide 789, line 14). The direction of transcription and translation is from the bottom to the top. The third exon is part of a DNA-binding domain, and some mutations within this exon cause Van der Woude syndrome. The bottom intron-containing conserved sequences are probably part of the gene’s regulatory machinery. If you are using the supplement with advanced classes, you may want to point out that many of the codons that span the exon show more substitutions in the third position of the codon. Substitutions to the third codon are often invisible to natural selection because they frequently do not change the amino acid in the protein due to the degeneracy of the genetic code. This is clearest on evoprints that compare multiple animals.

Answer key for questions on Master 3.17, Irf6 Evoprint Comparison

2.

Compare the human sequence with other individual species by checking the button next to the animal of your choice in the “Comparison of two sequences” section. Compare the human sequence with at least two other species. Make a rough estimate of the number of nucleotides that did not change. Record the comparisons you made and your estimates below.

See the data in Table 1 for a summary of the actual percent similarities of all the two-species comparisons. Be open to reasonable estimates from students.

3.

Describe how the number of changes you observe in the Irf6 gene relates to the amount of time since the species’ common ancestry with humans. Use the comparisons you completed in Step 2 and the data in Table 1 to help you with this task.

Students should recognize that the number of changes in the Irf6 gene increases as the time since common ancestry increases. There is an interesting exception in that rats, mice, and guinea pigs seem to show an accelerated rate of change. In other words, they have a greater number of changes than expected based on their time of divergence from humans.

Table 1. Time Since Common Ancestry with Humans and DNA Sequence Similarity

Species Time since common ancestry with humans (millions of years) Nucleotides that are the same (number) Similarity with human sequence (%)
Chimpanzee 8 1,685 99
Orangutan 15 1,653 97
Rhesus monkey 30 1,628 96
Dog 97 1,221 72
Horse 97 1,209 71
Cat 97 1,149 68
Cow 97 891 52
Rat 91 612 36
Mouse 91 573 34
Guinea pig 91 572 34
Armadillo 105 1,039 61
Opossum 176 518 30

4.

Explore the evoprint for the comparison of sequences from humans, chimpanzees, orangutans, rhesus monkeys, dogs, horses, cats, and cows. Use your observations and data from Tables 1 and 2 to complete the following tasks.

a.

Make a rough estimate of the percentage of nucleotides that did not change in this comparison.

Be open to a range of reasonable answers. Many students will suggest that about half the nucleotides did not change. In fact, 688 out of 1,701 nucleotides remained the same, or 40.4 percent.

b.

Use the data in Tables 1 and 2 and Figure 1 to calculate the amount of time represented in this comparison.

Using the method described in Step 6 of the activity, students should add the following number of years for all the branches on the tree: 8 + 15 + 30 + 53 + 83 + 85 + 97 + 97 = 468 million years.

Note: Questions 4b and 5a may be difficult for some students. If you feel that students will struggle unproductively, consider answering these questions as a class.

5.

Explore the evoprint for the comparison of sequences from humans, chimpanzees, orangutans, rhesus monkeys, dogs, horses, cats, cows, rats, mice, guinea pigs, armadillos, and opossums.

a.

Use the data in Tables 1, 2, and 3 and Figure 2 to calculate the amount of time represented in this evoprint.

The total amount of time depicted on an evoprint from the species on this tree is 8 + 15 + 30 + 26 + 64 + 91 + 53 + 83 + 85 + 97 + 105 + 176 + 176 = 1,009 million years, or 1.009 billion years.

b.

Identify two regions with eight or more nucleotides in a row that have not changed over the amount of time calculated in the previous step. Write out the nucleotides for these regions.

The following sequences have not changed in the 1,009 million years represented in the evoprint:

  • TTTACCTT
  • TGTAGCCAGA
  • TGGGCCAC
  • AGCCAGGGCTT
  • TGGAGGGCCATG
  • CAGTTTCA
  • GACTTATCA
  • GATGTCAT

10-w.

Explain to students that scientists recently studied the expression of the Irf6 gene in zebrafish. They discovered that the gene is turned on during fish development in the pharyngeal arches and in cells that become the mouth, pharynx, and other structures. Ask students if this finding is consistent with how the Irf6 gene functions in humans. Then ask how common ancestry helps explain this observation.

The discovery that zebrafish turn on the Irf6 gene early in development and in cells that form the mouth, head, and other structures (reported by Ben et al., 2005) is consistent with how the Irf6 gene functions in humans. This suggests that the Irf6 gene was present in the common ancestor of humans and fish and it performed a similar function.

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Students’ answers to this question will help you assess whether they understand the importance of common ancestry for studies in model organisms.


11-w.

Students answered questions in Lesson 1, Activity 2 about the use of model organisms like mice to understand health-related issues in humans (Step 13). Give students the opportunity to revise their answers to these questions.

Encourage students to make their revisions in a different-colored pen or pencil and to merely put a line through previous information they want to delete. This enables them to easily see how their thinking has changed.

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Tip from the field test: It may be tempting to skip Step 11-w to save time, but asking students to revise their previous answers is an important part of the learning process.


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Content Standard A: Scientists rely on technology to enhance the gathering and manipulation of data. New techniques and tools provide new evidence to guide inquiry and new methods to gather data, thereby contributing to the advance of science. The accuracy and precision of the data, and therefore the quality of the exploration, depends on the technology used.

12-w.

Ask students to get back into their groups of three and write a brief report that addresses the following:

  • Describe how an evoprint is a useful tool for collecting evidence to identify regions of the Irf6 gene that did not change over large amounts of time.
  • How does evolution explain why certain regions of the Irf6 gene have not changed over large amounts of time?

Consider assigning this step for homework.

Students should mention that evoprints are a useful way to examine evidence from DNA sequence comparisons across multiple species. By comparing multiple species, it is easier to identify regions of the gene that did not change over time.

In response to the second question, students should describe that mutations did occur in the regions that are conserved over time. However, selection eliminated or decreased the frequency of mutations that had a negative effect.

End of Web-based activity.



In classrooms using the print version of this activity: Logo5.eps


5-p.

Explain to students that they will learn about a tool called an “evoprint.” Scientists can use evoprints to identify regions of DNA that have not changed in different organisms over long periods of time. Introduce students to the evoprint using the following steps.

a.

Project the first page of Master 3.18, Evoprint Introduction. Explain that this image shows 1,701 nucleotides of the Irf6 gene in humans.


Note: In this activity, students explore 1,701 nucleotides of the Irf6 gene. The full gene has more than 18,000 nucleotides. Much of what the students see are intron sequences flanking the third exon in the gene. The exon is near the center of the evoprint, from nucleotide 616 (starting with CTTAAAAAT, line 11) to 789 (look for GAGGGCCAT with T being nucleotide 789, line 14). The direction of transcription and translation is from the bottom to the top. The third exon is part of a DNA-binding domain, and some mutations within this exon cause Van der Woude syndrome. The bottom intron-containing conserved sequences are probably part of the gene’s regulatory machinery. If you are using the supplement with advanced classes, you may want to point out that many of the codons that span the exon show more substitutions in the third position of the codon. Substitutions to the third codon are often invisible to natural selection because they frequently do not change the amino acid in the protein due to the degeneracy of the genetic code. This is clearest on evoprints that compare multiple animals.

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Content Standard C: Changes in DNA (mutations) occur spontaneously at low rates. Some of these changes make no differences to the organism, whereas others can change cells and organisms. Only mutations in germ cells can create the variation that changes an organism’s offspring.


b.

As you project the second page of Master 3.18, explain to students that this image is called an evoprint. It summarizes the comparison of the human and the cow sequences. Ask students what they notice about the image.

Students will readily notice that some of the nucleotides are still represented as capital letters and some are now shown as lowercase letters. You should explain that the capital letters represent nucleotides that are identical between the two species. Lowercase letters represent nucleotides that are different in the cow compared with the human. Mention that the human sequence is used as the reference sequence, so all the nucleotides in this image are the same as those in the image showing only the human sequence. The only difference is whether or not nucleotides are capitalized.

c.

Explain to students that humans and cows last shared a common ancestor 97 million years ago. The changes they observe in the evoprint could have occurred in the lineage that led to humans or the lineage that led to cows. Each lineage has been separate for 97 million years. Thus, the evoprint represents 194 million years. Ask, “How might natural selection explain why some sequences of DNA are conserved over vast amounts of time?”

Sequence conservation over vast amounts of time is an example of a type of natural selection called “purifying selection.” In purifying selection, selection eliminates or decreases the frequency of mutations that have a negative effect. In other words, the mutations reduced the reproductive success of the individuals that carried them. Natural selection then eliminated these mutations.

It is important that students recognize that mutations did occur in the regions that are conserved over time. These mutations may have very briefly persisted in the gene pool. Eventually, natural selection eliminated them from the gene pool. However, new mutations are occurring all the time.

d.

As you project the third page of Master 3.18, explain to students that this evoprint summarizes the comparison of the same region of DNA in four different species—humans, chimpanzees, orangutans, and rhesus monkeys. Again, ask students what they notice about the image.

Students will likely mention that there seem to be fewer changes in this evoprint compared with the human-cow evoprint. If students make this observation, ask them to try to explain the observation—why do they think there are more differences in the human-cow comparison?

e.

Remind students that the human-cow evoprint they examined represented 194 million years. Ask students what information they think they need to figure out the amount of time for the changes on the evoprint with four species.

Students may recognize that they need to know about the divergence times for humans and all the other species in the evoprint. If they do not recognize this, bring it to their attention.

f.

Explain to students that examining an evolutionary tree of the species in the evoprint can help them think about the amount of time represented in the evoprint. Project the fourth page of Master 3.18, depicting an evolutionary tree of all the species in the evoprint. Point to the different lineages on the tree and emphasize that, in each lineage, substitutions could occur. Because of this, they need to add together the times for all the branches on the evolutionary tree to calculate the amount of time in the evoprint.

To calculate the total amount of time represented in an evoprint for the four species in Master 3.18, students need to add the time from the common ancestor of humans and rhesus monkeys to modern humans (30 million years) + the time from the common ancestor of humans and rhesus monkeys to modern rhesus monkeys (30 million years) + the time from the common ancestor of humans and orangutans to modern orangutans (15 million years) + the time from the common ancestor of humans and chimpanzees to modern chimpanzees (8 million years) = 83 million years.

Note: Calculating times in an evoprint is potentially confusing. When comparing sequences between species, we need to consider that the sequences are evolving separately in each lineage in parallel time. Thus, to calculate the total amount of time, we need to add up all the times associated with each branch on the tree. It’s difficult for many students to comprehend parallel time for these comparisons.

If students struggle with this calculation, consider walking through it with them. As students view the evolutionary tree on the master, explain that to find the total time, they need to add up the time associated with every branch on the tree (excluding the root lineage). In other words, students need to account for every vertical line on the tree. Use a transparency pen to trace the lineage from humans to the common ancestor of humans and rhesus monkeys. Then write “30 million years.” Ask students what vertical lines are not accounted for. Students should note that the line leading from the common ancestor of rhesus monkeys and humans to modern rhesus monkeys is not included. Highlight this branch and ask how much time this branch represents. Write another “30 million years” on the master. Ask again what line or lines are not included. Students should note that the lineage leading from the common ancestor of humans and orangutans to modern orangutans is not included. Again, highlight this branch and write “15 million years.” Finally, highlight the branch from the common ancestor of humans and chimpanzees leading to modern chimpanzees and write “8 million years.” Explain to students that to find the total number of years in the evoprint, they need to add 30 million years + 30 million years + 15 million years + 8 million years = 83 million years.

The times to the last common ancestor presented in this activity are estimates, but they can be used here as though they were measured without error. In fact, these dates are measured with error, and they can change as we gain new information. Time estimates are from the TimeTree Web site, http://www.timetree.org.

6-p.

To help students get a sense of the vast amount of time represented on the evolutionary tree, ask the following questions. Let students make a few guesses, and then quickly provide the answers:

  • “How long ago was 1,000 seconds?”
    Answer: About 17 minutes ago
  • “How long ago was 1 million seconds?”
    Answer: About 11½ days ago
  • “How long ago was 1 billion seconds?”
    Answer: About 32 years ago

Ask students to reflect on how 1,000 years ago seems like such a long time. Then compare that with the 83 million years they calculated in the previous step. The difference is like comparing 17 minutes with 2.6 years.

This step helps students get some perspective on geologic time, which is difficult for many people to grasp. This step is meant to be brief.

7-p.

Explain to students that now the main goal is to identify sections of the Irf6 gene that have remained the same over large amounts of time. In some cases, these regions are especially important for proper functioning. Divide the class into groups of three. Each student needs one copy of Master 3.19, Investigating Irf6 Evoprints, and each group of three needs one copy of Master 3.20, Irf6 Evoprints. Ask students to follow the directions on Master 3.19. After students complete the work, hold a class discussion on the answers to the questions.

Answer key for questions in Master 3.19, Investigating Irf6 Evoprints

1.

Work as a group to examine the evoprints in which the human sequence was compared with one other species. For at least three of the comparisons, make a rough estimate of the number of nucleotides that did not change. Record the comparisons you made and your estimates below.

See the data in Table 1 for a summary of the actual percent similarities of all the two-species comparisons. Be open to reasonable estimates from students.

2.

Describe how the number of changes you observe in the Irf6 gene relates to the amount of time since the species’ common ancestry with humans. Use the comparisons you completed in Step 1 and the data in Table 1 to help you with this task.

Students should recognize that the number of changes in the Irf6 gene increases as the time since common ancestry increases. There is an interesting exception in that rats, mice, and guinea pigs seem to show an accelerated rate of change. In other words, they have a greater number of changes than expected based on their time of divergence from humans.

Table 1. Time Since Common Ancestry with Humans and DNA Sequence Similarity


Species Time since common ancestry with humans
(millions of years)
Nucleotides that are the same (number) Similarity with human sequence (%)
Chimpanzee 8 1,685 99
Orangutan 15 1,653 97
Rhesus monkey 30 1,628 96
Dog 97 1,221 72
Horse 97 1,209 71
Cat 97 1,149 68
Cow 97 891 52
Rat 91 612 36
Mouse 91 573 34
Guinea pig 91 572 34
Armadillo 105 1,039 61
Opossum 176 518 30

3.

Explore the evoprint for the comparison of sequences from humans, chimpanzees, orangutans, rhesus monkeys, dogs, horses, cats, and cows. Use your observations and data from Tables 1 and 2 to complete the following tasks.

a.

Make a rough estimate of the percentage of nucleotides that did not change in this comparison.

Be open to a range of reasonable answers. Many students will suggest that about half the nucleotides did not change. In fact, 688 out of 1,701 nucleotides remained the same, or 40.4 percent.

b.

Use the data in Tables 1 and 2 and Figure 1 to calculate the amount of time represented in this evoprint.

Using the same method as described in Step 5, students should add the following number of years for all the branches on the tree: 8 + 15 + 30 + 53 + 83 + 85 + 97 + 97 = 468 million years.

Note: Questions 3b and 4a may be difficult for some students. If you feel that students will struggle unproductively, consider answering these questions as a class.

4.

Explore the evoprint for the comparison of sequences from humans, chimpanzees, orangutans, rhesus monkeys, dogs, horses, cats, cows, rats, mice, guinea pigs, armadillos, and opossums.

a.

Use the data in Tables 1, 2, and 3 and Figure 2 to calculate the amount of time represented in this evoprint.

The total amount of time depicted on an evoprint from the species on this tree is 8 + 15 + 30 + 26 + 64 + 91 + 53 + 83 + 85 + 97 + 105 + 176 + 176 = 1,009 million years, or 1.009 billion years.

b.

Identify two regions with eight or more nucleotides in a row that have not changed over the amount of time calculated in the previous step. Write out the nucleotides for these regions.

The following sequences have not changed in the 1,009 million years represented in the evoprint:

  • TTTACCTT
  • TGTAGCCAGA
  • TGGGCCAC
  • AGCCAGGGCTT
  • TGGAGGGCCATG
  • CAGTTTCA
  • GACTTATCA
  • GATGTCAT

8-p.

Explain to students that scientists recently studied the expression of the Irf6 gene in zebrafish. They discovered that the gene is turned on during fish development in the pharyngeal arches and in cells that become the mouth, pharynx, and other structures. Ask students if this finding is consistent with how the Irf6 gene functions in humans. Then ask how common ancestry helps explain this observation.

The discovery that zebrafish turn on the Irf6 gene early in development and in structures that form the mouth, head, and other structures (reported by Ben et al., 2005) is consistent with how the Irf6 gene functions in humans. This suggests that the Irf6 gene was present in the common ancestor of humans and fish and it performed a similar function.

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Students’ answers to these questions again help you assess whether or not they understand the importance of common ancestry for studies in model organisms.


9-p.

Students answered questions in Lesson 1, Activity 2 about the use of model organisms like mice to understand health-related issues in humans (Step 13). Give students the opportunity to revise their answers to these questions.

Encourage students to make their revisions in a different-colored pen or pencil and to merely put a line through previous information they want to delete. This enables them to easily see how their thinking has changed.

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Tip from the field test: It may be tempting to skip Step 9 to save time, but asking students to revise their previous answers is an important part of the learning process.



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Content Standard A: Scientists rely on technology to enhance the gathering and manipulation of data. New techniques and tools provide new evidence to guide inquiry and new methods to gather data, thereby contributing to the advance of science. The accuracy and precision of the data, and therefore the quality of the exploration, depends on the technology used.

10-p.

Ask students to get back into their groups of three and write a brief report that addresses the following:

  • Describe how an evoprint is a useful tool for collecting evidence to identify regions of the Irf6 gene that did not change over large amounts of time.
  • How does evolution help explain why certain regions of the Irf6 gene have not changed over large amounts of time?

Consider assigning this step for homework.

Students should mention that evoprints are a useful way to examine evidence from DNA sequence comparisons across multiple species. By comparing multiple species, it’s easier to identify regions of the gene that did not change over time.

In response to the second question, students should describe that mutations did occur in the regions that are conserved over time. However, selection eliminated or decreased the frequency of mutations that had a negative effect.

Lesson 3 Organizer: Web Version

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Activity 1: Investigating a Mystery Disease
Estimated time: 100 minutes
Page and Step
Project Master 3.1 and read aloud with your students. Explain that students will be exploring this scenario and finding out what is causing the health problems. Page 93
Step 1
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Give each student one copy of Master 3.2. Have students work in groups of three to four to investigate two cases and determine each individual’s health problem. Page 93
Step 2
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Explain to students that the case analyses include two parts: analyzing blood cell images and analyzing the laboratory results of blood tests. Point out that an online reference manual will help them figure out the problem. Page 94
Step 3-w
Have students work through the activity on the Web site by clicking on “Lesson 3: Evolutionary Processes and Patterns Inform Medicine,” then “Activity 1: Investigating a Mystery Disease.” Page 94
Step 4-w
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Project Master 3.5. Use this chart to guide a class discussion of the results of students’ investigations. Page 95
Step 5
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Help students focus on thalassemia by asking the following questions:
  • “Have you heard of thalassemia?”
  • “Do you think thalassemia is a common disease?”
Page 96
Step 6
Project Master 3.6. Ask students to draw conclusions from this map. Page 96
Step 7
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After students recognize that thalassemia is more common in some places than others, ask them for a brief statement about variation for thalassemia in the human population. Page 97
Step 8
Project Master 3.7.
  • Review the information in Part 1 and then in Part 2.
  • Ask students if they see a relationship between the number of nonfunctional alleles of the alpha-globin gene and the severity of symptoms for alpha-thalassemia.
*If you want to include the optional activity, insert it after Step 9.
Page 98
Step 9
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Give each student 1 copy of Master 3.8. Have students work with their groups to answer the questions. Page 99
Step 10
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Ask students why a mutant alpha-globin allele would be maintained in the human population if it causes disease. Page 100
Step 11
Explain to the class that the original news story referenced another disease that has anemia as a symptom.
  • Project Master 3.9.
  • Ask students to make observations about the occurrence of malaria.
Page 100
Step 12
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Overlay the transparencies showing thalassemia and malaria (Masters 3.6 and 3.9). Ask students to draw conclusions about the distribution of these diseases. Page 100
Step 13
Introduce students to the hypothesis that people who have thalassemia may have an advantage in survival over people who do not have thalassemia if they contract malaria. Provide some brief information about malaria. Page 101
Steps 14 and 15
Explain that students will analyze data to determine whether malaria affects people who do and who do not have thalassemia differently.
  • Give students in half the groups one copy each of Master 3.10 and students in the other groups one copy each of Master 3.11.
Page 101
Step 16
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After students complete the analysis, hold a class discussion so groups can share their analyses and review their conclusions. Page 102
Step 17
Give each student one copy of Master 3.12. Ask students to answer the questions. Inform them that they will use their answers in the last activity of this supplement. Page 103
Step 18
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Ask students to revisit and revise their responses to the questions on Master 1.1 in Lesson 1, Activity 1, and Masters 2.5 and 2.10 in Lesson 2. Page 105
Step 19
Activity 2: Using Evolution to Guide Research
Estimated time: 50 minutes

Page and Step

Explain to students that the goal is to use an understanding of common ancestry to identify sections of a gene that have not changed over vast amounts of time. They will study a gene in which mutations cause some cases of cleft lip and palate. Ask,
  • “Have you heard of a condition called cleft lip and palate?”
  • “What do you think causes cleft lip and palate?”
Ask two or three students to share their ideas about the cause.
Page 110
Steps 1 and 2
Divide the class into groups of three. Hand out one copy of Master 3.14 to each student. Students should first read the questions at the end of the handout. After completing the reading, groups should work together on the answers. Have one or two groups share their answers in a class discussion. Pages 110 and 113
Steps 3 and 4
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Explain to students that they will use a technique to identify regions of DNA that have not changed in different organisms over long periods of time. Then have them log on to the Web site and click on “Lesson 3: Evolutionary Processes and Patterns Inform Medicine,” and then “Activity 2: Evoprint Tutorial.” Page 113
Step 5-w
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Project Master 3.15 and ask students to calculate the amount of time represented in evoprints that include all the species on the two different trees. Page 113
Step 6-w
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Ask students the following questions; let them make a quick guess, then quickly reveal the answers:
  • How long ago was 1,000 seconds? Answer: About 17 minutes ago
  • How long ago was 1 million seconds? Answer: About 11½ days ago
  • How long ago was 1 billion seconds? Answer: About 32 years ago
Page 115
Step 7-w

Display the questions on Master 3.16 one at a time. After students think about their answers, lead a class discussion on the questions.

Page 115
Step 8-w
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Explain to students that they will identify sections of the Irf6 gene that have remained the same over large amounts of time.
  • Give one copy of Master 3.17 to each student. Students should follow the directions on the handout.
  • Have students log on to the Web site and click on “Lesson 3: Evolutionary Processes and Patterns Inform Medicine,” then “Activity 2: Evoprint Comparison.”
Hold a class discussion about students’ answers to the questions.
Page 116
Step 9-w
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Explain the discovery that zebrafish express the Irf6 gene in cells that become the mouth, pharynx, and other structures. Ask,
  • Is this consistent with how the Irf6 gene functions in humans?
  • How does common ancestry help explain this observation?
Page 119
Step 10-w
Have students revise their answers to the questions in Step 13 from Lesson 1, Activity 2 about model organisms and health. Page 119
Step 11-w
Ask students to get back into their groups of three and write a report on the following:
  • Describe how an evoprint is a useful tool for collecting evidence to identify regions of the Irf6 gene that did not change over large amounts of time.
  • How does evolution explain why certain regions of the Irf6 gene have not changed over large amounts of time?
Page 120
Step 12-w

Logo6.eps = Involves copying a master.        Logo7.eps = Involves making a transparency.        Logo3.eps = Involves using the Internet.


Lesson 3 Organizer: Print Version

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Activity 1: Investigating a Mystery Disease
Estimated time: 100 minutes
Page and Step
Project Master 3.1, and read the news story with your students. Explain that students will be exploring this scenario and finding out what is causing the health problems. Page 93
Step 1
Logo7.eps
Give each student one copy of Master 3.2. Have students work in groups of three to four to investigate two cases and determine each individual’s health problem. Page 93
Step 2
Logo6.eps
Explain to students that the case analyses include two parts: analyzing blood cell images and analyzing the laboratory results of blood tests.
  • Point out where students can pick up the data for their assigned patients (from Master 3.3).
  • Give each group one copy of Master 3.4.
Page 95
Steps 3-p and 4-p
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Project Master 3.5. Use this chart to guide a class discussion of the results of students’ investigations. Page 95
Step 5
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Help students focus on thalassemia by asking the following questions:
  • “Have you heard of thalassemia?”
  • “Do you think thalassemia is a common disease?”
Page 96
Step 6
Project Master 3.6. Ask students to draw conclusions from this map. Page 96
Step 7
Logo7.eps
After students recognize that thalassemia is more common in some places than others, ask them for a brief statement about variation for thalassemia in the human population. Page 97
Step 8
Project Master 3.7.
  • Review the information in Part 1 and then in Part 2.
  • Ask students whether they see a relationship between the number of nonfunctional alleles of the alpha-globin gene and the severity of symptoms for alpha-thalassemia.
*If you want to include the optional activity, insert it after Step 9.
Page 98
Step 9
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Give each student one copy of Master 3.8. Have students work with their groups to answer the questions. Page 99
Step 10
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Ask students why a mutant alpha-globin allele would be maintained in the human population if it causes disease. Page 100
Step 11
Explain to the class that the original news story referenced another disease that has anemia as a symptom.
  • Project Master 3.9.
  • Ask students to make observations about the occurrence of malaria.
Page 100
Step 12
Logo7.eps
Overlay the transparencies showing thalassemia and malaria (Masters 3.6 and 3.9). Ask students to draw conclusions about the distribution of these diseases. Page 100
Step 13
Introduce students to the hypothesis that people who have thalassemia may have an advantage in survival over people who do not have thalassemia if they contract malaria. Provide some brief information about malaria to students. Page 101
Steps 14 and 15
Explain that students will analyze data to determine whether malaria affects people who do and who do not have thalassemia differently.
  • Give students in half the groups one copy each of Master 3.10 and students in the other groups, one copy each of Master 3.11.
Page 101
Step 16
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After students complete the analysis, hold a class discussion so groups can share their analyses and review their conclusions. Page 101
Step 17
Give each student one copy of Master 3.12. Ask students to answer the questions. Inform them that they will use their answers in the last activity of this supplement. Page 103
Step 18
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Ask students to revisit and revise their responses to the questions in on Master 1.1 in Lesson 1, Activity 1, and Masters 2.5 and 2.10 in Lesson 2. Page 105
Step 19
Activity 2: Using Evolution to Guide Research
Estimated time: 50 minutes
Page and Step
Describe to students that the goal is to use an understanding of common ancestry to identify sections of a gene that have not changed over vast amounts of time. They will study a gene in which mutations cause some cases of cleft lip and palate. Ask students,
  • “Have you heard of a condition called cleft lip and palate?”
  • “What do you think causes cleft lip and palate?”
Ask two or three students to share their ideas about the cause of cleft lip and palate.

Page 110
Steps 1 and 2

Divide the class into groups of three. Give one copy of Master 3.14 to each student. Students should first read the questions at the end of the handout. After completing the reading, should work together in groups on the answers. Have one or two groups share their answers in a class discussion. Pages 110–113
Steps 3 and 4
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Explain to students that they will learn about a tool called an “evoprint” that identifies regions of DNA that have not changed over long periods of time.
  • Project the first page of Master 3.18 (the Irf6 gene in human).
  • Show the human/cow evoprint comparison (page 2 of Master 3.18). Discuss student observations.
  • Ask, “How might natural selection explain why sequences of DNA are conserved over vast amounts of time?”
  • Show the human/chimpanzee/orangutan/rhesus monkey evoprint comparison (page 3 of Master 3.18). Discuss student observations.
  • Ask students how they think they should calculate the amount of time for the changes on this evoprint.
  • Describe how to calculate time on an evoprint by showing page 4 of Master 3.18. Point out that substitutions can occur in all lineages. As a result, they need to add together the times for all the branches on the evolutionary tree.
Page 120
Step 5-p
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Ask students the following questions; let them make a quick guess, then quickly reveal the answers.
  • “How long ago was 1,000 seconds?” Answer: About 17 minutes ago
  • “How long ago was 1 million seconds?” Answer: About 11½ days ago
  • “How long ago was 1 billion seconds?” Answer: About 32 years ago
Page 123
Step 6-p
Explain to students that they will identify sections of the Irf6 gene that have remained the same over large amounts of time.
  • Give each student one copy of Master 3.19.
  • Give each group of three one copy of Master 3.20.
  • After students complete their work, hold a class discussion on the answers to the questions.
Page 123
Step 7-p
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Explain the discovery that zebrafish express the Irf6 gene in cells that become the mouth, pharynx, and other structures. Ask students if this is consistent with how the Irf6 gene functions in humans and how common ancestry helps explain this observation. Page 126
Step 8-p
Have students revise their answers to the questions in Step 13 from Lesson 1, Activity 2 about model organisms and health. Page 126
Step 9-p
Ask students to get back into their groups of three and write a report on the following:
  • Describe how an evoprint is a useful tool for collecting evidence to identify regions of the Irf6 gene that did not change over large amounts of time.
  • How does evolution explain why certain regions of the Irf6 gene have not changed over large amounts of time?
Page 126
Step 10-p

Logo6.eps = Involves copying a master.         Logo7.eps = Involves making a transparency.


Lesson 3, Activity 1: Investigating a Mystery Disease, includes an optional activity to reinforce the inheritance of alpha-thalassemia. (Insert after Step 9 of Activity 1.)

Lesson 3 Optional Activity Organizer

Activity 1: Investigating a Mystery Disease—Extension Activity (Optional)
Estimated time: 20 minutes
Page and Step
Project Part 1 of Master 3.7. Remind students that each individual usually has four functional alleles of the alpha-globin gene. Introduce students to the way the alpha-globin alleles are written when working with genotypes. Page 105
Step 1
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Discuss examples of how an individual’s genotype for the alpha-globin gene is written:
  • The genotype for a normal individual is αα/αα.
  • The genotype for someone who has a mutation in one of the four alpha-globin genes is αα/α–.
Page 106
Step 2
Give each student one copy of Master 3.13. Explain that students will work on the master with their groups to learn how mutated, nonfunctional alleles of the alpha-globin gene are passed from parent to offspring. Page 106
Step 3
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Hold a class discussion to review the problems with the class. Allow different groups to present their results and explain their conclusions. Page 106
Step 4
Continue with the rest of Activity 1.

Logo6.eps = Involves copying a master.         Logo7.eps = Involves making a transparency.

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