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S E C T I O N 7.1 Patterns of Autosomal Inheritance E X P E C TAT I O N S Understand the difference between genetic conditions and genetic disorders. Describe genetic disorders involving autosomal and sex-linked inheritance. Perform laboratory simulations to explore heterozygous advantage. Figure 7.1 Albinism is a rare condition among many organisms. It results from a lack of melanin, a normal skin pigment. In 1649, an English boy visited his physician, complaining that he was producing black urine. The physician concluded that a fire in the boy’s belly was charring and blackening his bile, and that the resulting ashes were then passing into his urine. The physician treated the patient with bleedings, cold baths, a diet of cold liquids, and various drugs. Eventually, the boy grew tired of the therapy (which had no effect) and decided to let nature take its course. He grew into manhood, married, had many children, and lived a long, healthy life — always passing urine as black as ink. We now know that the boy was suffering from a hereditary condition called alkaptonuria. In most individuals, an enzyme converts the inky black urine to its usual colour. In individuals with the condition, the genes that code for the production of this enzyme are not functioning. Enzymes are proteins manufactured from specific instructions carried by specific genes. As you have learned in Chapter 6, genes indicate the exact sequence of amino acids required to make a given protein. The wrong instructions are given when an allele is mutated. This results in an inappropriate sequence of amino acids and creates a defective protein. BIO FACT Using special biochemical techniques, scientists discovered the disease alkaptonuria in an Egyptian mummy more than 3500 years old. 210 MHR • Genetic Continuity PAUSE RECORD Enzymes are important chemical catalysts in the body. How do catalysts affect chemical reactions? Are catalysts changed in any way during these reactions? Write your answers in your notebook. There are many genetic conditions within the human population. For example, albinism (as shown in Figure 7.1) is a rare genetic condition, but it is not life-threatening. Other genetic disorders, however, can cause severe medical problems. Why would harmful alleles that cause disease and early death continue to exist in our population? Recall what you have learned about dominant and recessive alleles and the concept of carriers. In heterozygotes, a normal dominant allele may mask the effects of a harmful recessive one. Thus, the parent is not affected but can pass on the harmful allele to offspring. Also, mutations constantly create new alleles, both harmful and harmless, within a population. Introduction of new alleles creates variation within the population. Variation allows individuals to better adapt to environmental change. Family pedigrees show us that some traits are inherited according to the principles that Mendel described. Traits can be carried by dominant or recessive alleles, and genes themselves are carried on chromosomes. As you have learned, some genes are carried only on a sex chromosome (usually the X chromosome) and are called sex-linked traits. Many others are carried on autosomes, which are any of the remaining 22 pairs of chromosomes that make up the human genome. Other genetic traits in the human population are not due to dominant or recessive alleles. Instead, they arise when there are changes in the number of chromosomes or in the actual structure of chromosomes. Autosomal Recessive Inheritance There are many autosomal recessive disorders. Such disorders are carried on the autosomes and are not specific to the sex of the person. One example of such a disorder is Tay-Sachs disease. Children with Tay-Sachs disease appear normal at birth; however, their brains and spinal cords begin to deteriorate at about eight months of age. By their first birthday, these children are blind, mentally handicapped, and display little muscular activity. Most die before their fifth birthday. Individuals with Tay-Sachs disease lack an enzyme in the lysosomes of their brain cells. Lysosomes are cell organelles in which large molecules are digested. The recessive allele does not code for the production of the enzyme responsible for breaking down specific lipids inside the lysosomes. As undigested lipids build up inside the affected person, the lysosomes become enlarged and eventually destroy the brain cells that house them (see Figure 7.2). Figure 7.2 Electron micrograph of brain tissue of a person affected with Tay-Sachs disease shows enlarged lysosomes filled with lipid deposits. An enzyme deficiency prevents these deposits from being degraded. There is no treatment for Tay-Sachs disease. However, a blood test has been developed to identify heterozygous carriers. Carriers have half the enzyme levels of normal individuals, which is enough to function normally. Before the development of this test, the incidence of TaySachs disease was particularly high among Ashkenazic Jews. The origins of Ashkenazic Jews lie in Central and Eastern Europe and today they comprise 90% of the North American Jewish population. It is believed that the long isolation of these people in small European communities led to the increased frequency of the recessive allele within their population. Although Tay-Sachs disease has always been rare in the general North American population (one in 300 000 births), it was far more common among Ashkenazic Jews and their descendants (one in 3600 births). Since the availability of the blood test for carriers, the incidence of Tay-Sachs disease within this Jewish population has dropped dramatically. Math LINK You can use simple Mendelian genetics to determine if a condition or disorder is due to an autosomal recessive allele. If both parents are heterozygous carriers of a recessive allele, what proportion of their children will be at risk of inheriting both copies of the allele? What proportion will be at risk if both parents are affected, meaning that they are both homozygous recessive? Construct Punnett squares and present your findings as genotype and phenotype ratios. See Chapter 4, Section 4.2 to review how Punnett squares are constructed. Another autosomal recessive disorder that affects young children is phenylketonuria (PKU). In individuals with this condition, an enzyme that converts phenylalanine to tyrosine is either absent or defective. Phenylalanine is an amino acid essential for regular growth and development, and for protein metabolism. Tyrosine, another amino acid, is used by the body to make melanin and certain hormones. The phenylalanine in children with PKU is broken down abnormally. In ways that we do not yet understand, the products of this process damage the developing nervous system. Babies with phenylketonuria appear normal at birth. If their condition is not diagnosed and treated, however, they will become severely mentally handicapped within a few months. Fortunately, newborns today are routinely tested for PKU. Infants who test positive for the disorder are placed on a special diet that prevents the Human Genetics • MHR 211 harmful products from accumulating. Once their nervous systems are fully developed, these individuals can go on to lead healthy lives. Albinism is a genetic condition in which the eyes, skin, and hair have no pigment. The colour of our hair, skin, and eyes is due to varying amounts of a brown pigment called melanin, which is produced in special pigment cells. People who are homozygous for this autosomal recessive allele either lack one of the enzymes required to produce melanin or, if the enzyme is present, lack the means to get the enzyme to enter the pigment cells. Codominant Inheritance Sickle cell anemia is one of the better-known examples a codominant genetic disorder. Affected individuals have a defect in the hemoglobin in red blood cells. This defect leads to blood clots and reduced blood flow to vital organs. As a result, they have little energy, suffer from various illnesses, and are in constant pain. Many die prematurely. Hemoglobin is a complex protein that is synthesized and transported in red blood cells. This unique molecule has the ability to pick up oxygen from the lungs, transport it to the tissues, and release it to the body’s cells. Like all proteins, hemoglobin is made up of a sequence of amino acids. The sequence in hemoglobin consists of four separate polypeptide chains (two identical alpha chains and two identical beta chains) of about 150 amino acids each, as shown in Figure 7.3. When individuals inherit the allele for sickle cell anemia, one amino acid (glutamic acid) at a specific location in the beta chain is replaced by another (valine), resulting in abnormal hemoglobin. Figure 7.4 shows the inheritance pattern for sickle cell anemia. The allele HbS indicates the abnormal hemoglobin in sickle cell anemia and the allele HbA indicates normal hemoglobin. The abnormal hemoglobin can pick up oxygen at the lungs and transport it to body tissues just as normal hemoglobin does. The oxygen diffuses from the blood across the capillary walls and into the tissue spaces. When the oxygen is released, however, the abnormal hemoglobin changes shape and begins to clump with other hemoglobin molecules in the red blood cell. The red blood cell becomes stiff and deformed, frequently forming a crescent or sickle shape (see Figure 7.5). These deformed cells block capillaries in the joints and vital organs. The condition becomes life-threatening when vessels to vital organs are blocked, because the blockage prevents other red blood cells from reaching these organs with a fresh supply of oxygen. The sickle cells are also very fragile and break down quickly. This results in a condition called anemia, where the overall red blood cell count is too low to support the body’s oxygen requirements. capillary iron heme group alpha chain beta chain molecule has helical shape beta chain alpha chain Red blood cells inside a capillary Red blood cell Figure 7.3 Red blood cells, shown moving through a capillary in the photograph at left, contain many molecules of hemoglobin like the one pictured at right. Each molecule 212 MHR • Genetic Continuity Hemoglobin molecule of hemoglobin is composed of two alpha and two beta chains of amino acids. sickle-cell trait sickle-cell trait HbAHbS HbAHbS HbAHbA HbAHbS normal sickle-cell trait HbAHbS HbSHbS sickle-cell trait sickle-cell disease Figure 7.4 Inheritance of sickle cell anemia. In this example, each parent is heterozygous for the sickle cell trait. Among the offspring, there is a 50% chance of inheriting the sickle cell trait, a 25% chance of having sickle cell anemia, and a 25% chance of not having the disease. Magnification: 90 000 x Magnification: 90 000 x Red blood cells containing normal hemoglobin are round and smooth, allowing them to pass through capillaries easily. Sickled red blood cells have elongated, blunt shapes that stick easily in capillaries and clog them. Figure 7.5 Electron micrographs of normal and sickled red blood cells. Human Genetics • MHR 213 Heterozygous Advantage The recessive allele that causes sickle cell anemia is thought to have originated in Africa. Until recently, homozygous recessive individuals never survived to become parents, indicating that the recessive allele was constantly being removed from the population. Yet in some African regions, almost half the population is heterozygous for sickle cell anemia. Geneticists wondered how this allele could remain at such high levels when it was constantly being removed from the population. The answer came from studying another serious disease in the regions where sickle cell anemia is most commonly found. In Africa, malaria is a leading cause of illness and death, particularly among the young. Studies revealed that children who were heterozygous for sickle cell anemia were less likely to contract malaria and therefore more likely to survive to parenthood. For reasons yet unknown, heterozygous females are also more fertile than homozygous females. Wo rd LINK The word “malaria” comes from the Italian words mala aria, meaning bad air, because it was once thought that the disease was caused by inhaling the air around stagnant waters or by drinking from them. BIO FACT The association of malaria with stagnant water is at least partly correct, since malaria is caused by an infection of red blood cells by protozoa of the genus Plasmodium. These protozoa are carried to their hosts by female mosquitoes of the Anopheles genus. Like other mosquitoes, they lay their eggs in slow-moving or stagnant water. The inheritance of one allele for sickle cell anemia is a classic example of heterozygous advantage, in which individuals with two different alleles for the same trait have a better rate of survival. Homozygous dominant individuals do not inherit the allele for sickle cell anemia. However, their normal-shaped red blood cells provide a perfect home for the protozoa that cause malaria. These homozygous dominant individuals are easily infected and, if born in malarial regions, often do not live to reproductive age. Homozygous recessive individuals with sickled cells may not contract malaria, but are likely to die young from the numerous symptoms of sickle cell anemia. In 214 MHR • Genetic Continuity comparison, heterozygous individuals produce enough normal red blood cells to meet their bodies’ oxygen demands and enough sickled cells to reduce their susceptibility to malaria. Clearly, in this case it is an advantage to be a heterozygous carrier of the sickle cell allele. In 1949, two biochemists, Linus Pauling and Harvey Itano, performed gel electrophoresis on both HbS and HbA hemoglobin molecules. Gel electrophoresis is a procedure in which molecules are placed on a viscous gel that is sandwiched between glass or plastic plates. The procedure is outlined in Figure 7.6. Pauling and Itano discovered that HbS and HbA migrated independently of one another and formed two distinct bands on the gel. They knew that the molecule that had the greatest negative charge would migrate faster and farther. This proved to be the normal HbA molecule. Can you explain why? Other scientists later explained that the HbS molecule travelled more slowly because it contained the neutral amino acid valine at a site where the more negative amino acid glutamic acid was found in the HbA molecule. Therefore, the more negative HbA molecule migrated faster across the gel toward the positively charged end, separating itself from the HbS molecule. This work paved the way for an important discovery in the field of genetics: the conclusion that genes code for the production of all proteins, not just enzymes. In the next investigation, you will model the inheritance of a recessive allele and heterozygous advantage in a population. PLAY To explore gel electrophoresis and DNA testing, refer to your Electronic Learning Partner. Autosomal Dominant Inheritance Researchers can use two pieces of evidence from Mendelian genetics to determine if an autosomal dominant allele is responsible for a trait. First, since a dominant allele is expressed in heterozygotes as well as in homozygous dominant individuals, the trait will appear in every generation. Second, if one parent is heterozygous and the other is homozygous recessive for the allele, then 50% of the offspring will have the trait. A Restriction enzymes Either one or several restriction enzymes are added to a sample of DNA. The enzymes cut the DNA into fragments. B The gel A gel, with a consistency similar to gelatin, is formed so small wells are left at one end. Small amounts of the DNA sample are placed into these wells. gel DNA fragments negative end power source E Before the DNA fragments are added to the wells, they are treated with a dye that glows under ultraviolet light, allowing the bands to be studied. positive end C The electrical field The gel is placed in a solution, and an electrical field is set up so one end of the gel is positive and the other end is negative. longer fragments shorter fragments completed gel D The fragments move The negatively charged DNA fragments travel toward the positive end. The smaller the fragment, the faster it moves through the gel. Fragments that are the farthest from the well are the smallest. Figure 7.6 Gel electrophoresis Human Genetics • MHR 215 Investigation SKILL FOCUS 7 • A Predicting Genes and Populations Performing and recording You have learned how certain autosomal recessive traits may affect humans. Such traits are inherited from parents who carry the recessive condition. Other organisms, too, carry recessive traits that may be passed on to offspring. In this investigation, your class will model the inheritance of alleles in a population of randomly mating American coots. The American coot is a large, duck-like bird with a very short, thick, red-tipped bill. It breeds throughout much of southern Canada and is a common summer resident of Lakes Erie and Ontario. Approximately 50% of the starting coots will be heterozygous (Aa), 25% will be dominant (AA) and 25% will be recessive (aa). As a participant, your job will be to record the genotypes of your offspring, compare them with those of others, and interpret the results. Modelling concepts Analyzing and interpreting Materials 2 equal stacks of large index cards (the stock supply), each marked “A” or “a” on one side only notebook pencil eraser Procedure 1. You will be given your initial genotype on two cards, one with each allele of your genotype. In your notebook, make a chart similar to the one shown here. Record the initial percentages of each genotype and your initial genotype on it. Data Chart Initial percentages American coot My initial genotype Pre-lab Questions F1 What will happen to the coot population if the recessive allele codes for a serious genetic disorder? What will happen to the coot population if the recessive allele also confers partial immunity against some other serious disorder? Problem How will you decide which coot genotype is best equipped to survive? Prediction Predict the percentage of the total population that each genotype will represent after five generations (steps 1–6 and 7) and 10 generations (step 8). 216 MHR • Genetic Continuity AA Aa aa AA Aa aa F2 F3 F4 F5 Final percentages 2. Place your two allele cards behind your back and shuffle them. Once mating season begins you may confidently approach another student with that classic line, “Coot, coot?” to which your “mate” will reply, “Coot, coot!” You and your “mate” will then simultaneously present one of your cards to each other. These two cards become the genotype of your first offspring, while the remaining two cards become the genotype of your second offspring. 3. If the genotype of either offspring is “aa,” it will die. Keep trying until you produce two surviving offspring (see Rules of the Game). 4. Now assume that your parent genotypes die and that you and your mate assume the genotypes of your offspring. You may need to get new cards from the stock supply to do this. Record your new genotype as the F1 generation on the chart. 5. Thank your partner, locate a new “mate,” and repeat steps 2 through 4, recording the genotypes of the new offspring as the F2 generation. Repeat this procedure until you have completed all five generations. 6. Pool the class data, tally the number of students with each genotype, and calculate and record the final percentage of AA, Aa, and aa genotypes. 7. Now begin again with your original genotype and repeat steps 1 through 6 while filling in a second chart. If any offspring is “AA,” however, you must flip a coin. If it lands “heads,” the offspring lives. If it lands “tails,” it dies. Parents must continue to “mate” until two viable offspring are created for each generation. 8. Tally the class data after five generations, then proceed through another five generations using a third chart and tally the data again. Post-lab Questions 1. According to the first chart tally, what happened to the population after five generations? 2. Which genotype did “nature” work to select against? 3. Would it be possible to completely eliminate this genotype from this population? 4. What changed in steps 7 and 8? 5. What happened to the population according to the second and third chart tallies in steps 7 and 8? Compare these results to those of the first chart tally. 6. Can the recessive allele be completely eliminated in steps 7 and 8? Conclude and Apply 7. Discuss the role of heterozygous advantage in maintaining genetic variation. 8. How can you relate the results you have observed to the pattern of sickle cell anemia inheritance in human populations? Exploring Further 9. Evidence suggests that Ashkenazic Jews in Europe who carried the allele for Tay-Sachs disease had a survival advantage over those who did not. Research this topic and write a report that identifies the illness the TaySachs allele may protect against. How is this story similar to what you have observed in this investigation? Rules of the Game The “aa” genotype in offspring is lethal. Offspring with this genotype will not survive to reproductive age. Therefore two “aa” parents cannot successfully mate. If you and your mate are both “aa,” one of you will need to obtain a new allele card (and thus genotype) from the stock supply. Human Genetics • MHR 217 normal mother affected father aa Aa a A a sperm Aa eggs a affected child Aa aa affected child normal child aa normal child Huntington disease, an autosomal dominant condition, is a lethal disorder in which the brain progressively deteriorates over a period of about 15 years. Its symptoms typically appear after age 35, which is often after the affected individuals have already had children. Early symptoms include irritability and mild memory loss, followed by involuntary arm and leg movements. As the brain deteriorates, these symptoms become more severe, leading to loss of muscular co-ordination, memory, and the ability to speak. Most people die in their forties or fifties without knowing if their children have inherited the mutant allele. Incomplete Dominance Figure 7.7 One example of autosomal dominant inheritance. Carriers of the dominant allele are affected. Although genetic disorders caused by autosomal dominant alleles are very rare in human populations, they continue to exist. Some of them are caused by rare, chance mutations. In other cases, symptoms arise only after affected individuals have passed the age at which most of them have had children. The Punnett square in Figure 7.7 shows how an autosomal dominant trait can be inherited. Progeria is a rare disorder that causes an individual to age rapidly. Progeria affects one in eight million newborns and does not run in families. This indicates that this very unusual affliction results from a random and spontaneous mutation of one gene. It also indicates that this mutated gene must be dominant over its normal partner, setting up a cascade of events that accelerates the ageing of the individual. SECTION K/U Explain the difference between genetic conditions and genetic disorders, and name one example of each. 2. C Explain how a disorder or abnormality can be passed along by autosomal recessive inheritance. 4. 218 REVIEW 1. 3. K/U The disease familial hypercholesterolemia (FH) is caused by incomplete dominance. That is, the heterozygote exhibits a phenotype somewhere midway between both dominant and recessive traits. Approximately one in 500 people are heterozygous, inheriting a defective allele for a gene that codes for the production of cell surface proteins called LDL receptors. Circulating LDL (low-density lipoproteins) cholesterols must bind to these receptors in order to be taken up and used by cells. With one defective allele, heterozygotes produce only half the required receptors and exhibit twice the normal blood cholesterol level. Homozygous recessives (about one in 1 000 000 people) do not produce any receptors and can have six times the normal blood cholesterol level. Over time, circulating LDLs build up in artery walls and eventually block them. This causes atherosclerosis, which leads to heart attacks and strokes. While heterozygous individuals may have heart attacks by the age of 35, homozygous recessive individuals who have the more serious form of the disease can be stricken by a heart attack at the age of two years. 5. I Predict why disorders caused by autosomal dominant alleles continue to exist in the human population. What evidence would you need to support your claim? 6. C Explain how DNA can be studied using gel electrophoresis. 7. MC What steps could you take to start building a list of genetic characteristics for people in your class? 8. I Explain some differences between the patterns of inheritance observed in autosomal recessive conditions versus autosomal dominant conditions. What is meant by heterozygous advantage? Can a recessive allele be eliminated from a population? Explain. K/U MHR • Genetic Continuity