Heterozygote Advantage Sickle cell anemia is often fatal. Until therapies developed to more effectively treat its symptoms, almost In the previous pages, natural selection has been discussed all affected individuals died as children. Even today, 31% as a process that removes variation from a population by fa- of patients in the United States die by the age of 15. The voring one allele over others at a genetic locus. However, if disease occurs because of a single amino acid change, re- heterozygotes are favored over homozygotes, then natural peated in the two beta chains of the hemoglobin molecule selection actually will tend to maintain variation in the In this change, a valine replaces the usual glutamic acid at population. The reason is simple. Instead of tending to re- a location on the surface of the protein near the oxygen- nove less successful alleles from a population, such het- binding site. Unlike glutamic acid, valine is nonpolar(hy- erozygote advantage will favor individuals with copies of drophobic). Its presence on the surface of the molecule th alleles, and thus will work to maintain both alleles in creates a"sticky"patch that attempts to escape from the the population. Some evolutionary biologists believe that polar water environment by binding to another similar heterozygote advantage is pervasive and can explain the patch. As long as oxygen is bound to the hemoglobin mol- high levels of polymorphism observed in natural popula ecule there is no problem, because the hemoglobin atoms tions. Others, however, believe that it is relatively rare shield the critical area of the surface. When oxygen levels fall, such as after exercise or when an individual is stressed Sickle cell anemia oxygen is not so readily bound to hemoglobin and the ex- The best documented example of heterozygote advantage globin molecules, eventually producin on other hemo- posed sticky patch binds to similar patch g long, fibrous is sickle cell anemia, a hereditary disease affecting hemo- clumps(figure 20. 11). The result is a deformed, " sickle globin in humans. Individuals with sickle cell anemia ex- shaped"red blood cell hibit symptoms of severe anemia and contain abnormal Individuals who are heterozygous or homozygous for red blood cells which are irregular in shape, with a great the valine-specifying allele(designated allele S) are said to number of long and sickle-shaped cells. The disease is possess the sickle cell trait. Heterozygotes produce some particularly common among African Americans. In chap- sickle-shaped red blood cells, but only 2% of the number ter 13, we noted that this disorder, which affects roughly seen in homozygous individuals. The reason is that in het 3 African Americans out of every 1000, is associated with erozygotes, one-half of the molecules do not contain va recessive allele. Using the Hardy-V finberg line at the critical location. Consequently, when a mole equation, you can calculate the frequency of the sickle cell cule produced by the non-sickle cell allele is added to the allele in the African-American population; this frequenc chain, there is no further "sticky"patch available to add is the square root of 0.003, or approximately 0.054. In additional molecules and chain elongation stops. Hence, contrast, the frequency of the allele among white Ameri- most chains in heterozygotes are too short to produce cans is only about 0.001 sickling of the cell. FIGURE 20.11 Why the sickle cell mutation causes hemoglobin to clump. The sickle cell mutation changes the sixth amino acid in the hemoglobin B chain(position B6) from glutamic acid (very polar) to valine (nonpolar). The unhappy result is that the nonpolar valine at position B6, protruding from a corner of the hemoglobin molecule fits into a nonpolar pocket on the opposite side of another hemoglobin molecule, causing the two molecules to clump together. As each molecule has both a B6 valine and an opposite nonpolar pocket, long hains form. When polar glutamic acid (the normal allele)occurs at position B6, it is not attracted to the nonpolar C Irving ge 432 Part vI EvolutionHeterozygote Advantage In the previous pages, natural selection has been discussed as a process that removes variation from a population by fa￾voring one allele over others at a genetic locus. However, if heterozygotes are favored over homozygotes, then natural selection actually will tend to maintain variation in the population. The reason is simple. Instead of tending to re￾move less successful alleles from a population, such het￾erozygote advantage will favor individuals with copies of both alleles, and thus will work to maintain both alleles in the population. Some evolutionary biologists believe that heterozygote advantage is pervasive and can explain the high levels of polymorphism observed in natural popula￾tions. Others, however, believe that it is relatively rare. Sickle Cell Anemia The best documented example of heterozygote advantage is sickle cell anemia, a hereditary disease affecting hemo￾globin in humans. Individuals with sickle cell anemia ex￾hibit symptoms of severe anemia and contain abnormal red blood cells which are irregular in shape, with a great number of long and sickle-shaped cells. The disease is particularly common among African Americans. In chap￾ter 13, we noted that this disorder, which affects roughly 3 African Americans out of every 1000, is associated with a particular recessive allele. Using the Hardy–Weinberg equation, you can calculate the frequency of the sickle cell allele in the African-American population; this frequency is the square root of 0.003, or approximately 0.054. In contrast, the frequency of the allele among white Ameri￾cans is only about 0.001. Sickle cell anemia is often fatal. Until therapies were developed to more effectively treat its symptoms, almost all affected individuals died as children. Even today, 31% of patients in the United States die by the age of 15. The disease occurs because of a single amino acid change, re￾peated in the two beta chains of the hemoglobin molecule. In this change, a valine replaces the usual glutamic acid at a location on the surface of the protein near the oxygen￾binding site. Unlike glutamic acid, valine is nonpolar (hy￾drophobic). Its presence on the surface of the molecule creates a “sticky” patch that attempts to escape from the polar water environment by binding to another similar patch. As long as oxygen is bound to the hemoglobin mol￾ecule there is no problem, because the hemoglobin atoms shield the critical area of the surface. When oxygen levels fall, such as after exercise or when an individual is stressed, oxygen is not so readily bound to hemoglobin and the ex￾posed sticky patch binds to similar patches on other hemo￾globin molecules, eventually producing long, fibrous clumps (figure 20.11). The result is a deformed, “sickle￾shaped” red blood cell. Individuals who are heterozygous or homozygous for the valine-specifying allele (designated allele S) are said to possess the sickle cell trait. Heterozygotes produce some sickle-shaped red blood cells, but only 2% of the number seen in homozygous individuals. The reason is that in het￾erozygotes, one-half of the molecules do not contain va￾line at the critical location. Consequently, when a mole￾cule produced by the non-sickle cell allele is added to the chain, there is no further “sticky” patch available to add additional molecules and chain elongation stops. Hence, most chains in heterozygotes are too short to produce sickling of the cell. 432 Part VI Evolution Val 6 FIGURE 20.11 Why the sickle cell mutation causes hemoglobin to clump. The sickle cell mutation changes the sixth amino acid in the hemoglobin β chain (position B6) from glutamic acid (very polar) to valine (nonpolar). The unhappy result is that the nonpolar valine at position B6, protruding from a corner of the hemoglobin molecule, fits into a nonpolar pocket on the opposite side of another hemoglobin molecule, causing the two molecules to clump together. As each molecule has both a B6 valine and an opposite nonpolar pocket, long chains form. When polar glutamic acid (the normal allele) occurs at position B6, it is not attracted to the nonpolar pocket, and no clumping occurs. 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